Wave energy absorption by a floating air bag

license: © 2016 Cambridge University Pres

A multi-modal data resource for investigating topographic heterogeneity in patient-derived xenograft tumors.

Patient-derived xenografts (PDXs) are an essential pre-clinical resource for investigating tumor biology. However, cellular heterogeneity within and across PDX tumors can strongly impact the interpretation of PDX studies. Here, we generated a multi-modal, large-scale dataset to investigate PDX heterogeneity in metastatic colorectal cancer (CRC) across tumor models, spatial scales and genomic, transcriptomic, proteomic and imaging assay modalities. To showcase this dataset, we present analysis to assess sources of PDX variation, including anatomical orientation within the implanted tumor, mouse contribution, and differences between replicate PDX tumors. A unique aspect of our dataset is deep characterization of intra-tumor heterogeneity via immunofluorescence imaging, which enables investigation of variation across multiple spatial scales, from subcellular to whole tumor levels. Our study provides a benchmark data resource to investigate PDX models of metastatic CRC and serves as a template for future, quantitative investigations of spatial heterogeneity within and across PDX tumor models

Optimal positive end-expiratory pressure in mechanically ventilated patients: a clinical study

The optimal level of positive end-expiratory pressure (PEEP) is still widely debated in treating acute respiratory distress syndrome (ARDS) patients. Current methods of selecting PEEP only provide a range of values and do not provide unique patient-specific solutions. Model-based methods offer a novel way of using non-invasive pressure-volume (PV) measurements to estimate patient recruitability. This paper examines the clinical viability of such models in pilot clinical trials to assist therapy, optimise patient-specific PEEP, assess the disease state and response over time

Dynamic functional residual capacity can be estimated using a stress-strain approach

Invited. Available online 9 June 2010.Background Acute Respiratory Distress Syndrome (ARDS) results in collapse of alveolar units and loss of lung volume at the end of expiration. Mechanical ventilation is used to treat patients with ARDS or Acute Lung Injury (ALI), with the end objective being to increase the dynamic functional residual capacity (dFRC), and thus increasing overall functional residual capacity (FRC). Simple methods to estimate dFRC at a given positive end expiratory pressure (PEEP) level in patients with ARDS/ALI currently does not exist. Current viable methods are time-consuming and relatively invasive. Methods Previous studies have found a constant linear relationship between the global stress and strain in the lung independent of lung condition. This study utilizes the constant stress–strain ratio and an individual patient's volume responsiveness to PEEP to estimate dFRC at any level of PEEP. The estimation model identifies two global parameters to estimate a patient specific dFRC, ß and mß. The parameter ß captures physiological parameters of FRC, lung and respiratory elastance and varies depending on the PEEP level used, and mß is the gradient of ß vs. PEEP. Results dFRC was estimated at different PEEP values and compared to the measured dFRC using retrospective data from 12 different patients with different levels of lung injury. The median percentage error is 18% (IQR: 6.49) for PEEP = 5 cm H2O, 10% (IQR: 9.18) for PEEP = 7 cm H2O, 28% (IQR: 12.33) for PEEP = 10 cm H2O, 3% (IQR: 2.10) for PEEP = 12 cm H2O and 10% (IQR: 9.11) for PEEP = 15 cm H2O. The results were further validated using a cross-correlation (N = 100,000). Linear regression between the estimated and measured dFRC with a median R2 of 0.948 (IQR: 0.915, 0.968; 90% CI: 0.814, 0.984) over the N = 100,000 cross-validation tests. Conclusions The results suggest that a model based approach to estimating dFRC may be viable in a clinical scenario without any interruption to ventilation and can thus provide an alternative to measuring dFRC by disconnecting the patient from the ventilator or by using advanced ventilators. The overall results provide a means of estimating dFRC at any PEEP levels. Although reasonable clinical accuracy is limited to the linear region of the static PV curve, the model can evaluate the impact of changes in PEEP or other mechanical ventilation settings

The influence of prior training on GPs’ attitudes to sickness absence certification post-fit note.

AimTo investigate the attitudes to health and work of general practitioners (GPs) with training in occupational medicine (OM) compared with non-OM trained GPs, since the introduction of the fit note.BackgroundChanges to the UK sickness certification system since 2010 and the introduction of the fit note required GPs to change their focus to what patients can do, rather than what they cannot do in relation to work. In an effort to reduce the UK sickness absence burden, GPs completion of the fit note should help to keep people in work, or assist patients to return to work as quickly as possible after a period of absence.MethodsQuestionnaire data were collected via the 7th National General Practitioner Worklife Survey.FindingsResults indicate that responses from GPs who had undertaken training in OM, and GPs having received some form of work and health training in the 12-month period before the study were associated with significantly more positive attitudes to patients’ returning to work and to the fit note. This study reveals evidence of a difference between trained and non-trained GPs in their attitude to the fit note, and to work and health generally. Further work investigating the effect of specific training in OM on the management and recognition of ill-health by GPs is recommended.</jats:sec

Supplementary information on early-stage floating offshore wind platform designs

This document serves as supplementary information to the authors' review paper on early-stage floating offshore wind turbine (FOWT) platform designs. The review paper is the second part in a study on FOWT platform designs, following a review of FOWT platforms which currently have or have previously had a prototype, demonstration, or farm scale project at-sea. The present review covers 86 past and current early-stage platform designs, ranging from early conceptual designs to platforms which have undergone lab tests simulating extreme conditions. In this supplementary information document, more details are provided about all 86 platforms reviewed. For each device, the following is included (if available): (i) a description of the platform and its unique features, (ii) a rough timeline of development, (iii) design goals and constraints, (iv) evolution of the design, (v) lab testing information, and (vi) published dimensions. Two sections are included: one section contains the platforms that are no longer in development (i.e., there has been no new development since 2018), and the other section contains the platforms still in development today. Within each sub-section, platforms designed to hold a single turbine are presented first, then platforms designed to hold multiple turbines, and finally hybrid platforms

Actions of Octocoral and Tobacco Cembranoids on Nicotinic Receptors

Nicotinic acetylcholine receptors (AChRs) are pentameric proteins that form agonist-gated cation channels through the plasma membrane. AChR agonists and antagonists are potential candidates for the treatment of neurodegenerative diseases. Cembranoids are naturally occurring diterpenoids that contain a 14-carbon ring. These diterpenoids interact with AChRs in complex ways: as irreversible inhibitors at the agonist sites, as noncompetitive inhibitors, or as positive modulators, but no cembranoid was ever shown to have agonistic activity on AChRs. The cembranoid eupalmerin acetate displays positive modulation of agonist-induced currents in the muscle-type AChR and in the related gamma-aminobutyric acid (GABA) type A receptor. Moreover, cembranoids display important biological effects, many of them mediated by nicotinic receptors. Cembranoids from tobacco are neuroprotective through a nicotinic anti-apoptotic mechanism preventing excitotoxic neuronal death which in part could result from anti-inflammatory properties of cembranoids. Moreover, tobacco cembranoids also have anti-inflammatory properties which could enhance their neuroprotective properties. Cembranoids from tobacco affect nicotine-related behavior: they increase the transient initial ataxia caused by first nicotine injection into naive rats and inhibit the expression of locomotor sensitization to repeated injections of nicotine. In addition, cembranoids are known to act as antitumor compounds. In conclusion, cembranoids provide a promising source of lead drugs for many clinical areas, including neuroprotection, smoking-cessation, and anti-cancer therapies

Image-based measurement of alveoli volume expansion in an animal model of a diseased lung

Currently, there does not exist reliable MV treatment or protocols in critical care to treat acute respiratory diseases, and thus no proven way to optimise care to minimise the mortality, length of stay or cost. The overall approach of this research is to improve protocols by using appropriate computer models that take into account the essential lung mechanics. The aim of this research is to create an automated algorithm for tracking the boundary of individual or groups of alveoli, and to convert this into a pressure volume curve for three different types of alveoli. A technique called in vivo microscopy has been developed by Schiller et al which visualizes the inflation and deflation of individual alveoli in a surfactant deactivation model of lung injury in pigs. Three different types of alveoli were tracked using data from Schiller et al, type I, II and III. These types correspond to healthy alveoli, non-collapsing but partially diseased alveoli, and fully collapsing diseased alveoli respectively. The boundaries of all the alveoli that were tracked, compared well visually to the movies. Pressure versus Area curves were derived for both inflation and deflation, they captured the expected physiological behaviour, and were qualitatively similar to the quasi-static pressure area curves derived in Schiller et al, Quantitative differences are due to the dynamic effects of ventilation which were not investigated in Schiller et al

Repurposing tofacitinib as an anti-myeloma therapeutic to reverse growth-promoting effects of the bone marrow microenvironment.

The myeloma bone marrow microenvironment promotes proliferation of malignant plasma cells and resistance to therapy. Activation of JAK/STAT signaling is thought to be a central component of these microenvironment-induced phenotypes. In a prior drug repurposing screen, we identified tofacitinib, a pan-JAK inhibitor Food and Drug Administration (FDA) approved for rheumatoid arthritis, as an agent that may reverse the tumor-stimulating effects of bone marrow mesenchymal stromal cells. Herein, we validated in vitro, in stromal-responsive human myeloma cell lines, and in vivo, in orthotopic disseminated xenograft models of myeloma, that tofacitinib showed efficacy in myeloma models. Furthermore, tofacitinib strongly synergized with venetoclax in coculture with bone marrow stromal cells but not in monoculture. Surprisingly, we found that ruxolitinib, an FDA approved agent targeting JAK1 and JAK2, did not lead to the same anti-myeloma effects. Combination with a novel irreversible JAK3-selective inhibitor also did not enhance ruxolitinib effects. Transcriptome analysis and unbiased phosphoproteomics revealed that bone marrow stromal cells stimulate a JAK/STAT-mediated proliferative program in myeloma cells, and tofacitinib reversed the large majority of these pro-growth signals. Taken together, our results suggest that tofacitinib reverses the growth-promoting effects of the tumor microenvironment. As tofacitinib is already FDA approved, these results can be rapidly translated into potential clinical benefits for myeloma patients