Haemodynamic changes in visceral hybrid repairs of type III and type V thoracoabdominal aortic aneurysms

The visceral hybrid procedure combining retrograde visceral bypass grafting and completion endovascular stent grafting is a feasible alternative to conventional open surgical or wholly endovascular repairs of thoracoabdominal aneurysms (TAAA). However, the wide variability in visceral hybrid configurations means that a priori prediction of surgical outcome based on haemodynamic flow profiles such as velocity pattern and wall shear stress post repair remain challenging. We sought to appraise the clinical relevance of computational fluid dynamics (CFD) analyses in the setting of visceral hybrid TAAA repairs. Two patients, one with a type III and the other with a type V TAAA, underwent successful elective and emergency visceral hybrid repairs, respectively. Flow patterns and haemodynamic parameters were analysed using reconstructed pre- and post-operative CT scans. Both type III and type V TAAAs showed highly disturbed flow patterns with varying helicity values preoperatively within their respective aneurysms. Low time-averaged wall shear stress (TAWSS) and high endothelial cell action potential (ECAP) and relative residence time (RRT) associated with thrombogenic susceptibility was observed in the posterior aspect of both TAAAs preoperatively. Despite differing bypass configurations in the elective and emergency repairs, both treatment options appear to improve haemodynamic performance compared to preoperative study. However, we observed reduced TAWSS in the right iliac artery (portending a theoretical risk of future graft and possibly limb thrombosis), after the elective type III visceral hybrid repair, but not the emergency type V repair. We surmise that this difference may be attributed to the higher neo-bifurcation of the aortic stent graft in the type III as compared to the type V repair. Our results demonstrate that CFD can be used in complicated visceral hybrid repair to yield potentially actionable predictive insights with implications on surveillance and enhanced post-operative management, even in patients with complicated geometrical bypass configurations

Macroscopic nucleation phenomena in continuum media with long-range interactions

Nucleation, commonly associated with discontinuous transformations between metastable and stable phases, is crucial in fields as diverse as atmospheric science and nanoscale electronics. Traditionally, it is considered a microscopic process (at most nano-meter), implying the formation of a microscopic nucleus of the stable phase. Here we show for the first time, that considering long-range interactions mediated by elastic distortions, nucleation can be a macroscopic process, with the size of the critical nucleus proportional to the total system size. This provides a new concept of "macroscopic barrier-crossing nucleation". We demonstrate the effect in molecular dynamics simulations of a model spin-crossover system with two molecular states of different sizes, causing elastic distortions.Comment: 12 pages, 4 figures. Supplementary information accompanies this paper at http://www.nature.com/scientificreport

Risk factors for delayed presentation and referral of symptomatic cancer: Evidence for common cancers

Background:It has been suggested that the known poorer survival from cancer in the United Kingdom, compared with other European countries, can be attributed to more advanced cancer stage at presentation. There is, therefore, a need to understand the diagnostic process, and to ascertain the risk factors for increased time to presentation.Methods:We report the results from two worldwide systematic reviews of the literature on patient-mediated and practitioner-mediated delays, identifying the factors that may influence these.Results:Across cancer sites, non-recognition of symptom seriousness is the main patient-mediated factor resulting in increased time to presentation. There is strong evidence of an association between older age and patient delay for breast cancer, between lower socio-economic status and delay for upper gastrointestinal and urological cancers and between lower education level and delay for breast and colorectal cancers. Fear of cancer is a contributor to delayed presentation, while sanctioning of help seeking by others can be a powerful mediator of reduced time to presentation. For practitioner delay, ‘misdiagnosis’ occurring either through treating patients symptomatically or relating symptoms to a health problem other than cancer, was an important theme across cancer sites. For some cancers, this could also be linked to inadequate patient examination, use of inappropriate tests or failing to follow-up negative or inconclusive test results.Conclusion:Having sought help for potential cancer symptoms, it is therefore important that practitioners recognise these symptoms, and examine, investigate and refer appropriately. © 2009 Cancer Research UK All rights reserved

A new class of pluripotent stem cell cytotoxic small molecules

10.1371/journal.pone.0085039PLoS ONE93-POLN

Validation of a HLA-A2 tetramer flow cytometric method, IFNgamma real time RT-PCR, and IFNgamma ELISPOT for detection of immunologic response to gp100 and MelanA/MART-1 in melanoma patients

<p>Abstract</p> <p>Background</p> <p>HLA-A2 tetramer flow cytometry, IFNγ real time RT-PCR and IFNγ ELISPOT assays are commonly used as surrogate immunological endpoints for cancer immunotherapy. While these are often used as research assays to assess patient's immunologic response, assay validation is necessary to ensure reliable and reproducible results and enable more accurate data interpretation. Here we describe a rigorous validation approach for each of these assays prior to their use for clinical sample analysis.</p> <p>Methods</p> <p>Standard operating procedures for each assay were established. HLA-A2 (A*0201) tetramer assay specific for gp100_209(210M)and MART-1_26–35(27L), IFNγ real time RT-PCR and ELISPOT methods were validated using tumor infiltrating lymphocyte cell lines (TIL) isolated from HLA-A2 melanoma patients. TIL cells, specific for gp100 (TIL 1520) or MART-1 (TIL 1143 and TIL1235), were used alone or spiked into cryopreserved HLA-A2 PBMC from healthy subjects. TIL/PBMC were stimulated with peptides (gp100₂₀₉, gp100_pool, MART-1_27–35, or influenza-M1 and negative control peptide HIV) to further assess assay performance characteristics for real time RT-PCR and ELISPOT methods. Validation parameters included specificity, accuracy, precision, linearity of dilution, limit of detection (LOD) and limit of quantification (LOQ). In addition, distribution was established in normal HLA-A2 PBMC samples. Reference ranges for assay controls were established.</p> <p>Results</p> <p>The validation process demonstrated that the HLA-A2 tetramer, IFNγ real time RT-PCR, and IFNγ ELISPOT were highly specific for each antigen, with minimal cross-reactivity between gp100 and MelanA/MART-1. The assays were sensitive; detection could be achieved at as few as 1/4545–1/6667 cells by tetramer analysis, 1/50,000 cells by real time RT-PCR, and 1/10,000–1/20,000 by ELISPOT. The assays met criteria for precision with %CV < 20% (except ELISPOT using high PBMC numbers with %CV < 25%) although flow cytometric assays and cell based functional assays are known to have high assay variability. Most importantly, assays were demonstrated to be effective for their intended use. A positive IFNγ response (by RT-PCR and ELISPOT) to gp100 was demonstrated in PBMC from 3 melanoma patients. Another patient showed a positive MART-1 response measured by all 3 validated methods.</p> <p>Conclusion</p> <p>Our results demonstrated the tetramer flow cytometry assay, IFNγ real-time RT-PCR, and INFγ ELISPOT met validation criteria. Validation approaches provide a guide for others in the field to validate these and other similar assays for assessment of patient T cell response. These methods can be applied not only to cancer vaccines but to other therapeutic proteins as part of immunogenicity and safety analyses.</p

A written self-help intervention for depressed adults comparing behavioural activation combined with physical activity promotion with a self-help intervention based upon behavioural activation alone: study protocol for a parallel group pilot randomised controlled trial (BAcPAc)

notes: PMCID: PMC4061537types: Journal Article© 2014 Farrand et al.; licensee BioMed Central Ltd.Challenges remain to find ways to support patients with depression who have low levels of physical activity (PA) to overcome perceived barriers and enhance the perceived value of PA for preventing future relapse. There is an evidence-base for behavioural activation (BA) for depression, which focuses on supporting patients to restore activities that have been avoided, but practitioners have no specific training in promoting PA. We aimed to design and evaluate an integrated BA and PA (BAcPAc) practitioner-led, written, self-help intervention to enhance both physical and mental health.NPRI-

A supernova origin for dust in a high-redshift quasar

Interstellar dust plays a crucial role in the evolution of the Universe by assisting the formation of molecules, by triggering the formation of the first low-mass stars, and by absorbing stellar ultraviolet-optical light and subsequently re-emitting it at infrared/millimetre wavelengths. Dust is thought to be produced predominantly in the envelopes of evolved (age >1 Gyr), low-mass stars. This picture has, however, recently been brought into question by the discovery of large masses of dust in the host galaxies of quasars at redshift z>6, when the age of the Universe was less than 1 Gyr. Theoretical studies, corroborated by observations of nearby supernova remnants, have suggested that supernovae provide a fast and efficient dust formation environment in the early Universe. Here we report infrared observations of a quasar at redshift 6.2, which are used to obtain directly its dust extinction curve. We then show that such a curve is in excellent agreement with supernova dust models. This result demonstrates a supernova origin for dust in this high-redshift quasar, from which we infer that most of the dust at high redshifts has probably the same origin.Comment: To Appear in Nature, September 30, 200