Anomalous Dynamics of Translocation

We study the dynamics of the passage of a polymer through a membrane pore (translocation), focusing on the scaling properties with the number of monomers $N$. The natural coordinate for translocation is the number of monomers on one side of the hole at a given time. Commonly used models which assume Brownian dynamics for this variable predict a mean (unforced) passage time $\tau$ that scales as $N^2$, even in the presence of an entropic barrier. However, the time it takes for a free polymer to diffuse a distance of the order of its radius by Rouse dynamics scales with an exponent larger than 2, and this should provide a lower bound to the translocation time. To resolve this discrepancy, we perform numerical simulations with Rouse dynamics for both phantom (in space dimensions $d=1$ and 2), and self-avoiding (in $d=2$) chains. The results indicate that for large $N$, translocation times scale in the same manner as diffusion times, but with a larger prefactor that depends on the size of the hole. Such scaling implies anomalous dynamics for the translocation process. In particular, the fluctuations in the monomer number at the hole are predicted to be non-diffusive at short times, while the average pulling velocity of the polymer in the presence of a chemical potential difference is predicted to depend on $N$.Comment: 9 pages, 9 figures. Submitted to Physical Review

The Surgical Infection Society revised guidelines on the management of intra-abdominal infection

Background: Previous evidence-based guidelines on the management of intra-abdominal infection (IAI) were published by the Surgical Infection Society (SIS) in 1992, 2002, and 2010. At the time the most recent guideline was released, the plan was to update the guideline every five years to ensure the timeliness and appropriateness of the recommendations. Methods: Based on the previous guidelines, the task force outlined a number of topics related to the treatment of patients with IAI and then developed key questions on these various topics. All questions were approached using general and specific literature searches, focusing on articles and other information published since 2008. These publications and additional materials published before 2008 were reviewed by the task force as a whole or by individual subgroups as to relevance to individual questions. Recommendations were developed by a process of iterative consensus, with all task force members voting to accept or reject each recommendation. Grading was based on the GRADE (Grades of Recommendation Assessment, Development, and Evaluation) system; the quality of the evidence was graded as high, moderate, or weak, and the strength of the recommendation was graded as strong or weak. Review of the document was performed by members of the SIS who were not on the task force. After responses were made to all critiques, the document was approved as an official guideline of the SIS by the Executive Council. Results: This guideline summarizes the current recommendations developed by the task force on the treatment of patients who have IAI. Evidence-based recommendations have been made regarding risk assessment in individual patients; source control; the timing, selection, and duration of antimicrobial therapy; and suggested approaches to patients who fail initial therapy. Additional recommendations related to the treatment of pediatric patients with IAI have been included. Summary: The current recommendations of the SIS regarding the treatment of patients with IAI are provided in this guideline

Nature and reporting characteristics of UK health technology assessment systematic reviews

BACKGROUND: A recent study by Page et al. (PLoS Med. 2016;13(5):e1002028) claimed that increasing numbers of reviews are being published and many are poorly-conducted and reported. The aim of the present study was to assess how well reporting standards of systematic reviews produced in a Health Technology Assessment (HTA) context compare with reporting in Cochrane and other 'non-Cochrane' systematic reviews from the same years (2004 and 2014), as reported by Page et al. (PLoS Med. 2016;13(5):e1002028). METHODS: All relevant UK HTA programme systematic reviews published in 2004 and 2014 were identified. After piloting of the form, two reviewers each extracted relevant data on conduct and reporting from these reviews. These data were compared with data for Cochrane and "non-Cochrane" systematic reviews, as published by Page et al. (PLoS Med. 2016;13(5):e1002028). All data were tabulated and summarized. RESULTS: There were 30 UK HTA programme systematic reviews and 300 other systematic reviews, including Cochrane reviews (n = 45). The percentage of HTA reviews with required elements of conduct and reporting was frequently very similar to Cochrane and much higher than all other systematic reviews, e.g. availability of protocols (90, 98 and 16% respectively); the specification of study design criteria (100, 100, 79%); the reporting of outcomes (100, 100, 78%), quality assessment (100, 100, 70%); the searching of trial registries for unpublished data (70, 62, 19%); reporting of reasons for excluding studies (91, 91 and 70%) and reporting of authors' conflicts of interests (100, 100, 87%). HTA reviews only compared less favourably with Cochrane and other reviews in assessments of publication bias. CONCLUSIONS: UK HTA systematic reviews are often produced within a specific policy-making context. This context has implications for timelines, tools and resources. However, UK HTA systematic reviews still tend to present standards of conduct and reporting equivalent to "gold standard" Cochrane reviews and superior to systematic reviews more generally

A worked example of "best fit" framework synthesis: A systematic review of views concerning the taking of some potential chemopreventive agents

<p>Abstract</p> <p>Background</p> <p>A variety of different approaches to the synthesis of qualitative data are advocated in the literature. The aim of this paper is to describe the application of a pragmatic method of qualitative evidence synthesis and the lessons learned from adopting this "best fit" framework synthesis approach.</p> <p>Methods</p> <p>An evaluation of framework synthesis as an approach to the qualitative systematic review of evidence exploring the views of adults to the taking of potential agents within the context of the primary prevention of colorectal cancer.</p> <p>Results</p> <p>Twenty papers from North America, Australia, the UK and Europe met the criteria for inclusion. Fourteen themes were identified <it>a priori </it>from a related, existing conceptual model identified in the literature, which were then used to code the extracted data. Further analysis resulted in the generation of a more sophisticated model with additional themes. The synthesis required a combination of secondary framework and thematic analysis approaches and was conducted within a health technology assessment timeframe.</p> <p>Conclusion</p> <p>The novel and pragmatic "best fit" approach to framework synthesis developed and described here was found to be fit for purpose. Future research should seek to test further this approach to qualitative data synthesis.</p

Differences in access to coronary care unit among patients with acute myocardial infarction in Rome: old, ill, and poor people hold the burden of inefficiency

BACKGROUND: Direct admission to Coronary Care Unit (CCU) on hospital arrival can be considered as a good proxy for adequate management in patients with acute myocardial infarction (AMI), as it has been associated with better prognosis. We analyzed a cohort of patients with AMI hospitalized in Rome (Italy) in 1997–2000 to assess the proportion directly admitted to CCU and to investigate the effect of patient characteristics such as gender, age, illness severity on admission, and socio-economic status (SES) on CCU admission practices. METHODS: Using discharge data, we analyzed a cohort of 9127 AMI patients. Illness severity on admission was determined using the Deyo's adaptation of the Charlson's comorbidity index, and each patient was assigned to one to four SES groups (level I referring to the highest SES) defined by a socioeconomic index, derived by the characteristics of the census tract of residence. The effect of gender, age, illness severity and SES, on risk of non-admission to CCU was investigated using a logistic regression model (OR, CI 95%). RESULTS: Only 53.9% of patients were directly admitted to CCU, and access to optimal care was more frequently offered to younger patients (OR = 0.35; 95%CI = 0.25–0.48 when comparing 85+ to >=50 years), those with less severe illness (OR = 0.48; 95%CI = 0.37–0.61 when comparing Charlson index 3+ to 0) and the socially advantaged (OR = 0.81; 95%CI = 0.66–0.99 when comparing low to high SES). CONCLUSION: In Rome, Italy, standard optimal coronary care is underprovided. It seems to be granted preferentially to the better off, even after controversial clinical criteria, such as age and severity of illness, are taken into account

Deadly diving? Physiological and behavioural management of decompression stress in diving mammals

© The Author(s), 2011. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Proceedings of the Royal Society B Biological Sciences 279 (2012): 1041-1050, doi:10.1098/rspb.2011.2088.Decompression sickness (DCS; ‘the bends’) is a disease associated with gas uptake at pressure. The basic pathology and cause are relatively well known to human divers. Breath-hold diving marine mammals were thought to be relatively immune to DCS owing to multiple anatomical, physiological and behavioural adaptations that reduce nitrogen gas (N2) loading during dives. However, recent observations have shown that gas bubbles may form and tissue injury may occur in marine mammals under certain circumstances. Gas kinetic models based on measured time-depth profiles further suggest the potential occurrence of high blood and tissue N2 tensions. We review evidence for gas-bubble incidence in marine mammal tissues and discuss the theory behind gas loading and bubble formation. We suggest that diving mammals vary their physiological responses according to multiple stressors, and that the perspective on marine mammal diving physiology should change from simply minimizing N2 loading to management of the N2 load. This suggests several avenues for further study, ranging from the effects of gas bubbles at molecular, cellular and organ function levels, to comparative studies relating the presence/absence of gas bubbles to diving behaviour. Technological advances in imaging and remote instrumentation are likely to advance this field in coming years.This paper and the workshop it stemmed from were funded by the Woods Hole Oceanographic Institution Marine Mammal Centre

Color adjectives, standards, and thresholds: an experimental investigation

Are color adjectives (“red”, “green”, etc.) relative adjectives or absolute adjectives? Existing theories of the meaning of color adjectives attempt to answer that question using informal (“armchair”) judgments. The informal judgments of theorists conflict: it has been proposed that color adjectives are absolute with standards anchored at the minimum degree on the scale, that they are absolute but have near- midpoint standards, and that they are relative. In this paper we report two experiments, one based on entailment patterns and one based on presupposition accommodation, that investigate the meaning of scalar adjectives. We find evidence confirming the existence of subgroups of the population who operate with different standards for color adjectives. The evidence of interpersonal variation in where standards are located on the relevant scale and how those standards can be adjusted indicates that the existing theories of the meaning of color adjectives are at best only partially correct. We also find evidence that paradigmatic relative adjectives (“tall”, “wide”) behave in ways that are not predicted by the standard theory of scalar adjectives. We discuss several different possible explanations for this unexpected behavior. We conclude by discussing the relevance of our findings for philosophical debates about the nature and extent of semantically encoded context sensitivity in which color adjectives have played a key role

Efficient Capture of Infected Neutrophils by Dendritic Cells in the Skin Inhibits the Early Anti-Leishmania Response

Neutrophils and dendritic cells (DCs) converge at localized sites of acute inflammation in the skin following pathogen deposition by the bites of arthropod vectors or by needle injection. Prior studies in mice have shown that neutrophils are the predominant recruited and infected cells during the earliest stage of Leishmania major infection in the skin, and that neutrophil depletion promotes host resistance to sand fly transmitted infection. How the massive influx of neutrophils aimed at wound repair and sterilization might modulate the function of DCs in the skin has not been previously addressed. The infected neutrophils recovered from the skin expressed elevated apoptotic markers compared to uninfected neutrophils, and were preferentially captured by dermal DCs when injected back into the mouse ear dermis. Following challenge with L. major directly, the majority of the infected DCs recovered from the skin at 24 hr stained positive for neutrophil markers, indicating that they acquired their parasites via uptake of infected neutrophils. When infected, dermal DCs were recovered from neutrophil depleted mice, their expression of activation markers was markedly enhanced, as was their capacity to present Leishmania antigens ex vivo. Neutrophil depletion also enhanced the priming of L. major specific CD4+ T cells in vivo. The findings suggest that following their rapid uptake by neutrophils in the skin, L. major exploits the immunosuppressive effects associated with the apoptotic cell clearance function of DCs to inhibit the development of acquired resistance until the acute neutrophilic response is resolved

A Prokaryotic S1P Lyase Degrades Extracellular S1P In Vitro and In Vivo: Implication for Treating Hyperproliferative Disorders

Sphingosine-1-phosphate (S1P) regulates a broad spectrum of fundamental cellular processes like proliferation, death, migration and cytokine production. Therefore, elevated levels of S1P may be causal to various pathologic conditions including cancer, fibrosis, inflammation, autoimmune diseases and aberrant angiogenesis. Here we report that S1P lyase from the prokaryote Symbiobacterium thermophilum (StSPL) degrades extracellular S1P in vitro and in blood. Moreover, we investigated its effect on cellular responses typical of fibrosis, cancer and aberrant angiogenesis using renal mesangial cells, endothelial cells, breast (MCF-7) and colon (HCT 116) carcinoma cells as disease models. In all cell types, wild-type StSPL, but not an inactive mutant, disrupted MAPK phosphorylation stimulated by exogenous S1P. Functionally, disruption of S1P receptor signaling by S1P depletion inhibited proliferation and expression of connective tissue growth factor in mesangial cells, proliferation, migration and VEGF expression in carcinoma cells, and proliferation and migration of endothelial cells. Upon intravenous injection of StSPL in mice, plasma S1P levels rapidly declined by 70% within 1 h and then recovered to normal 6 h after injection. Using the chicken chorioallantoic membrane model we further demonstrate that also under in vivo conditions StSPL, but not the inactive mutant, inhibited tumor cell-induced angiogenesis as an S1P-dependent process. Our data demonstrate that recombinant StSPL is active under extracellular conditions and holds promise as a new enzyme therapeutic for diseases associated with increased levels of S1P and S1P receptor signaling