Arterial oxygen content is precisely maintained by graded erythrocytotic responses in settings of high/normal serum iron levels, and predicts exercise capacity: an observational study of hypoxaemic patients with pulmonary arteriovenous malformations.

Oxygen, haemoglobin and cardiac output are integrated components of oxygen transport: each gram of haemoglobin transports 1.34 mls of oxygen in the blood. Low arterial partial pressure of oxygen (PaO2), and haemoglobin saturation (SaO2), are the indices used in clinical assessments, and usually result from low inspired oxygen concentrations, or alveolar/airways disease. Our objective was to examine low blood oxygen/haemoglobin relationships in chronically compensated states without concurrent hypoxic pulmonary vasoreactivity.165 consecutive unselected patients with pulmonary arteriovenous malformations were studied, in 98 cases, pre/post embolisation treatment. 159 (96%) had hereditary haemorrhagic telangiectasia. Arterial oxygen content was calculated by SaO2 x haemoglobin x 1.34/100.There was wide variation in SaO2 on air (78.5-99, median 95)% but due to secondary erythrocytosis and resultant polycythaemia, SaO2 explained only 0.1% of the variance in arterial oxygen content per unit blood volume. Secondary erythrocytosis was achievable with low iron stores, but only if serum iron was high-normal: Low serum iron levels were associated with reduced haemoglobin per erythrocyte, and overall arterial oxygen content was lower in iron deficient patients (median 16.0 [IQR 14.9, 17.4]mls/dL compared to 18.8 [IQR 17.4, 20.1]mls/dL, p<0.0001). Exercise tolerance appeared unrelated to SaO2 but was significantly worse in patients with lower oxygen content (p<0.0001). A pre-defined athletic group had higher Hb:SaO2 and serum iron:ferritin ratios than non-athletes with normal exercise capacity. PAVM embolisation increased SaO2, but arterial oxygen content was precisely restored by a subsequent fall in haemoglobin: 86 (87.8%) patients reported no change in exercise tolerance at post-embolisation follow-up.Haemoglobin and oxygen measurements in isolation do not indicate the more physiologically relevant oxygen content per unit blood volume. This can be maintained for SaO2 ≥78.5%, and resets to the same arterial oxygen content after correction of hypoxaemia. Serum iron concentrations, not ferritin, seem to predict more successful polycythaemic responses

Ischaemic strokes in patients with pulmonary arteriovenous malformations and hereditary hemorrhagic telangiectasia: associations with iron deficiency and platelets.

<div><p>Background</p><p>Pulmonary first pass filtration of particles marginally exceeding ∼7 µm (the size of a red blood cell) is used routinely in diagnostics, and allows cellular aggregates forming or entering the circulation in the preceding cardiac cycle to lodge safely in pulmonary capillaries/arterioles. Pulmonary arteriovenous malformations compromise capillary bed filtration, and are commonly associated with ischaemic stroke. Cohorts with CT-scan evident malformations associated with the highest contrast echocardiographic shunt grades are known to be at higher stroke risk. Our goal was to identify within this broad grouping, which patients were at higher risk of stroke.</p><p>Methodology</p><p>497 consecutive patients with CT-proven pulmonary arteriovenous malformations due to hereditary haemorrhagic telangiectasia were studied. Relationships with radiologically-confirmed clinical ischaemic stroke were examined using logistic regression, receiver operating characteristic analyses, and platelet studies.</p><p>Principal Findings</p><p>Sixty-one individuals (12.3%) had acute, non-iatrogenic ischaemic clinical strokes at a median age of 52 (IQR 41–63) years. In crude and age-adjusted logistic regression, stroke risk was associated not with venous thromboemboli or conventional neurovascular risk factors, but with low serum iron (adjusted odds ratio 0.96 [95% confidence intervals 0.92, 1.00]), and more weakly with low oxygen saturations reflecting a larger right-to-left shunt (adjusted OR 0.96 [0.92, 1.01]). For the same pulmonary arteriovenous malformations, the stroke risk would approximately double with serum iron 6 µmol/L compared to mid-normal range (7–27 µmol/L). Platelet studies confirmed overlooked data that iron deficiency is associated with exuberant platelet aggregation to serotonin (5HT), correcting following iron treatment. By MANOVA, adjusting for participant and 5HT, iron or ferritin explained 14% of the variance in log-transformed aggregation-rate (p = 0.039/p = 0.021).</p><p>Significance</p><p>These data suggest that patients with compromised pulmonary capillary filtration due to pulmonary arteriovenous malformations are at increased risk of ischaemic stroke if they are iron deficient, and that mechanisms are likely to include enhanced aggregation of circulating platelets.</p></div

Cardiosphere-derived cells suppress allogeneic lymphocytes by production of PGE2 acting via the EP4 receptor

derived cells (CDCs) are a cardiac progenitor cell population, which have been shown to possess cardiac regenerative properties and can improve heart function in a variety of cardiac diseases. Studies in large animal models have predominantly focussed on using autologous cells for safety, however allogeneic cell banks would allow for a practical, cost-effective and efficient use in a clinical setting. The aim of this work was to determine the immunomodulatory status of these cells using CDCs and lymphocytes from 5 dogs. CDCs expressed MHC I but not MHC II molecules and in mixed lymphocyte reactions demonstrated a lack of lymphocyte proliferation in response to MHC-mismatched CDCs. Furthermore, MHC-mismatched CDCs suppressed lymphocyte proliferation and activation in response to Concanavalin A. Transwell experiments demonstrated that this was predominantly due to direct cell-cell contact in addition to soluble mediators whereby CDCs produced high levels of PGE2 under inflammatory conditions. This led to down-regulation of CD25 expression on lymphocytes via the EP4 receptor. Blocking prostaglandin synthesis restored both, proliferation and activation (measured via CD25 expression) of stimulated lymphocytes. We demonstrated for the first time in a large animal model that CDCs inhibit proliferation in allo-reactive lymphocytes and have potent immunosuppressive activity mediated via PGE2

Elastic and anelastic relaxation behaviour of perovskite multiferroics II: PbZr0.53_{0.53}Ti0.47_{0.47}O3_3 (PZT)–PbFe0.5_{0.5}Ta0.5_{0.5}O3_3 (PFT)

Elastic and anelastic properties of ceramic samples of multiferroic perovskites with nominal compositions across the binary join PbZr$_{0.53}$Ti$_{0.47}$O$_3$–PbFe$_{0.5}$Ta$_{0.5}$O$_3$ (PZT–PFT) have been assembled to create a binary phase diagram and to address the role of strain relaxation associated with their phase transitions. Structural relationships are similar to those observed previously for PbZr$_{0.53}$Ti$_{0.47}$O$_3$–PbFe$_{0.5}$Nb$_{0.5}$O$_3$ (PZT–PFN), but the magnitude of the tetragonal shear strain associated with the ferroelectric order parameter appears to be much smaller. This leads to relaxor character for the development of ferroelectric properties in the end member PbFe$_{0.5}$Ta$_{0.5}$O$_3$. As for PZT–PFN, there appear to be two discrete instabilities rather than simply a reorientation of the electric dipole in the transition sequence cubic–tetragonal–monoclinic, and the second transition has characteristics typical of an improper ferroelastic. At intermediate compositions, the ferroelastic microstructure has strain heterogeneities on a mesoscopic length scale and, probably, also on a microscopic scale. This results in a wide anelastic freezing interval for strain-related defects rather than the freezing of discrete twin walls that would occur in a conventional ferroelastic material. In PFT, however, the acoustic loss behaviour more nearly resembles that due to freezing of conventional ferroelastic twin walls. Precursor softening of the shear modulus in both PFT and PFN does not fit with a Vogel–Fulcher description, but in PFT there is a temperature interval where the softening conforms to a power law suggestive of the role of fluctuations of the order parameter with dispersion along one branch of the Brillouin zone. Magnetic ordering appears to be coupled only weakly with a volume strain and not with shear strain but, as with multiferroic PZT–PFN perovskites, takes place within crystals which have significant strain heterogeneities on different length scales.RUS facilities in Cambridge were established with funding from the Natural Environment Research Council (Grants NE/B505738/1, NE/F017081/1). The present work was supported by Grant No. EP/ I036079/1 from the Engineering and Physical Sciences Research Council. We thank Dr. Sam Crossley for his assistance with dielectric analysis and the use of his software to run those measurements. JAS gratefully acknowledges the hospitality of the Max Planck Institute for Chemical Physics of Solids. The Nanopaleomagnetism lab has received funding from the European Research Council under the European Union’s Seventh Framework Programme (FP/2007– 2013)/ERC Grant Agreement 320750. SED and HS acknowledge support from the Winton Programme for the physics of sustainability. HS also acknowledges support from the Funai Foundation for Information Technology and the British Council Japan Association. Part of the work was carried out at the University of Puerto Rico, supported by the DOEEBSCoR project DEG02-ER46526

The developmental dynamics of terrorist organizations

We identify robust statistical patterns in the frequency and severity of violent attacks by terrorist organizations as they grow and age. Using group-level static and dynamic analyses of terrorist events worldwide from 1968-2008 and a simulation model of organizational dynamics, we show that the production of violent events tends to accelerate with increasing size and experience. This coupling of frequency, experience and size arises from a fundamental positive feedback loop in which attacks lead to growth which leads to increased production of new attacks. In contrast, event severity is independent of both size and experience. Thus larger, more experienced organizations are more deadly because they attack more frequently, not because their attacks are more deadly, and large events are equally likely to come from large and small organizations. These results hold across political ideologies and time, suggesting that the frequency and severity of terrorism may be constrained by fundamental processes.Comment: 28 pages, 8 figures, 4 tables, supplementary materia

Aviation turbulence: dynamics, forecasting, and response to climate change

Atmospheric turbulence is a major hazard in the aviation industry and can cause injuries to passengers and crew. Understanding the physical and dynamical generation mechanisms of turbulence aids with the development of new forecasting algorithms and, therefore, reduces the impact that it has on the aviation industry. The scope of this paper is to review the dynamics of aviation turbulence, its response to climate change, and current forecasting methods at the cruising altitude of aircraft. Aviation-affecting turbulence comes from three main sources: vertical wind shear instabilities, convection, and mountain waves. Understanding these features helps researchers to develop better turbulence diagnostics. Recent research suggests that turbulence will increase in frequency and strength with climate change, and therefore, turbulence forecasting may become more important in the future. The current methods of forecasting are unable to predict every turbulence event, and research is ongoing to find the best solution to this problem by combining turbulence predictors and using ensemble forecasts to increase skill. The skill of operational turbulence forecasts has increased steadily over recent decades, mirroring improvements in our understanding. However, more work is needed—ideally in collaboration with the aviation industry—to improve observations and increase forecast skill, to help maintain and enhance aviation safety standards in the future

How Digital Are the Digital Humanities? An Analysis of Two Scholarly Blogging Platforms

In this paper we compare two academic networking platforms, HASTAC and Hypotheses, to show the distinct ways in which they serve specific communities in the Digital Humanities (DH) in different national and disciplinary contexts. After providing background information on both platforms, we apply co-word analysis and topic modeling to show thematic similarities and differences between the two sites, focusing particularly on how they frame DH as a new paradigm in humanities research. We encounter a much higher ratio of posts using humanities-related terms compared to their digital counterparts, suggesting a one-way dependency of digital humanities-related terms on the corresponding unprefixed labels. The results also show that the terms digital archive, digital literacy, and digital pedagogy are relatively independent from the respective unprefixed terms, and that digital publishing, digital libraries, and digital media show considerable cross-pollination between the specialization and the general noun. The topic modeling reproduces these findings and reveals further differences between the two platforms. Our findings also indicate local differences in how the emerging field of DH is conceptualized and show dynamic topical shifts inside these respective contexts

Macrofossil evidence for a rapid and severe Cretaceous–Paleogene mass extinction in Antarctica

Debate continues about the nature of the Cretaceous–Paleogene (K–Pg) mass extinction event. An abrupt crisis triggered by a bolide impact contrasts with ideas of a more gradual extinction involving flood volcanism or climatic changes. Evidence from high latitudes has also been used to suggest that the severity of the extinction decreased from low latitudes towards the poles. Here we present a record of the K–Pg extinction based on extensive assemblages of marine macrofossils (primarily new data from benthic molluscs) from a highly expanded Cretaceous–Paleogene succession: the López de Bertodano Formation of Seymour Island, Antarctica. We show that the extinction was rapid and severe in Antarctica, with no significant biotic decline during the latest Cretaceous, contrary to previous studies. These data are consistent with a catastrophic driver for the extinction, such as bolide impact, rather than a significant contribution from Deccan Traps volcanism during the late Maastrichtian

Long-term efficacy of botulinum toxin A for treatment of blepharospasm,hemifacial spasm, and spastic entropion: a multicentre study using two drug-dose escalation indexes

PURPOSE: To investigate the long-term effectiveness and safety of botulinum neurotoxin A (BoNT-A) treatment in patients with blepharospasm (BEB), hemifacial spasm (HFS), and entropion (EN) and to use for the first time two modified indexes, 'botulin toxin escalation index-U' (BEI-U) and 'botulin toxin escalation index percentage' (BEI-%), in the dose-escalation evaluation. METHODS: All patients in this multicentre study were followed for at least 10 years and main outcomes were clinical efficacy, duration of relief, BEI-U and BEI-%, and frequency of adverse events. RESULTS: BEB, HFS, and EN patients received a mean BoNT-A dose with a significant inter-group difference (P<0.0005, respectively). The mean (+/-SD) effect duration was statistically different (P=0.009) among three patient groups. Regarding the BoNT-A escalation indexes, the mean (+/-SD) values of BEI-U and BEI-% were statistically different (P=0.035 and 0.047, respectively) among the three groups. In BEB patients, the BEI-% was significantly increased in younger compared with older patients (P=0.008). The most frequent adverse events were upper lid ptosis, diplopia, ecchymosis, and localized bruising. CONCLUSIONS: This long-term multicentre study supports a high efficacy and good safety profile of BoNT-A for treatment of BEB, HFS, and EN. The BEI indexes indicate a significantly greater BoNT-A-dose escalation for BEB patients compared with HFS or EN patients and a significantly greater BEI-% in younger vsolder BEB patients. These results confirm a greater efficacy in the elderly and provide a framework for long-term studies with a more flexible and reliable evaluation of drug-dose escalation

Targeting medication non-adherence behavior in selected autoimmune diseases: a systematic approach to digital health program development

Background 29 autoimmune diseases, including Rheumatoid Arthritis, gout, Crohn’s Disease, and Systematic Lupus Erythematosus affect 7.6-9.4% of the population. While effective therapy is available, many patients do not follow treatment or use medications as directed. Digital health and Web 2.0 interventions have demonstrated much promise in increasing medication and treatment adherence, but to date many Internet tools have proven disappointing. In fact, most digital interventions continue to suffer from high attrition in patient populations, are burdensome for healthcare professionals, and have relatively short life spans. Objective Digital health tools have traditionally centered on the transformation of existing interventions (such as diaries, trackers, stage-based or cognitive behavioral therapy programs, coupons, or symptom checklists) to electronic format. Advanced digital interventions have also incorporated attributes of Web 2.0 such as social networking, text messaging, and the use of video. Despite these efforts, there has not been little measurable impact in non-adherence for illnesses that require medical interventions, and research must look to other strategies or development methodologies. As a first step in investigating the feasibility of developing such a tool, the objective of the current study is to systematically rate factors of non-adherence that have been reported in past research studies. Methods Grounded Theory, recognized as a rigorous method that facilitates the emergence of new themes through systematic analysis, data collection and coding, was used to analyze quantitative, qualitative and mixed method studies addressing the following autoimmune diseases: Rheumatoid Arthritis, gout, Crohn’s Disease, Systematic Lupus Erythematosus, and inflammatory bowel disease. Studies were only included if they contained primary data addressing the relationship with non-adherence. Results Out of the 27 studies, four non-modifiable and 11 modifiable risk factors were discovered. Over one third of articles identified the following risk factors as common contributors to medication non-adherence (percent of studies reporting): patients not understanding treatment (44%), side effects (41%), age (37%), dose regimen (33%), and perceived medication ineffectiveness (33%). An unanticipated finding that emerged was the need for risk stratification tools (81%) with patient-centric approaches (67%). Conclusions This study systematically identifies and categorizes medication non-adherence risk factors in select autoimmune diseases. Findings indicate that patients understanding of their disease and the role of medication are paramount. An unexpected finding was that the majority of research articles called for the creation of tailored, patient-centric interventions that dispel personal misconceptions about disease, pharmacotherapy, and how the body responds to treatment. To our knowledge, these interventions do not yet exist in digital format. Rather than adopting a systems level approach, digital health programs should focus on cohorts with heterogeneous needs, and develop tailored interventions based on individual non-adherence patterns