Delphi Study to Reach International Consensus Among Vascular Surgeons on Major Arterial Vascular Surgical Complications

Background: The complications discussed with patients by surgeons prior to surgery vary, because no consensus on major complications exists. Such consensus may improve informed consent and shared decision-making. This study aimed to achieve consensus among vascular surgeons on which complications are considered ‘major’ and which ‘minor,’ following surgery for abdominal aortic aneurysm (AAA), carotid artery disease (CAD) and peripheral artery disease (PAD). Methods: Complications following vascular surgery were extracted from Cochrane reviews, national guidelines, and reporting standards. Vascular surgeons from Europe and North America rated complications as major or minor on five-point Likert scales via an electronic Delphi method. Consensus was reached if ≥ 80% of participants scored 1 or 2 (minor) or 4 or 5 (major). Results: Participants reached consensus on 9–12 major and 6–10 minor complications per disease. Myocardial infarction, stroke, renal failure and allergic reactions were considered to be major complications of all three diseases. All other major complications were treatment specific or dependent on disease severity, e.g., spinal cord ischemia, rupture following AAA repair, stroke for CAD or deep wound infection for PAD. Conclusion: Vascular surgeons reached international consensus on major and minor complications following AAA, CAD and PAD treatment. This consensus may be helpful in harmonizing the information patients receive and improving standardization of the informed consent procedure. Since major complications differed between diseases, consensus on disease-specific complications to be discussed with patients is necessary

Selective targeting of activating and inhibitory Smads by distinct WWP2 ubiquitin ligase isoforms differentially modulates TGFβ signalling and EMT

Ubiquitin-dependent mechanisms have emerged as essential regulatory elements controlling cellular levels of Smads and TGFß-dependent biological outputs such as epithelial–mesenchymal transition (EMT). In this study, we identify a HECT E3 ubiquitin ligase known as WWP2 (Full-length WWP2-FL), together with two WWP2 isoforms (N-terminal, WWP2-N; C-terminal WWP2-C), as novel Smad-binding partners. We show that WWP2-FL interacts exclusively with Smad2, Smad3 and Smad7 in the TGFß pathway. Interestingly, the WWP2-N isoform interacts with Smad2 and Smad3, whereas WWP2-C interacts only with Smad7. In addition, WWP2-FL and WWP2-C have a preference for Smad7 based on protein turnover and ubiquitination studies. Unexpectedly, we also find that WWP2-N, which lacks the HECT ubiquitin ligase domain, can also interact with WWP2-FL in a TGFß-regulated manner and activate endogenous WWP2 ubiquitin ligase activity causing degradation of unstimulated Smad2 and Smad3. Consistent with our protein interaction data, overexpression and knockdown approaches reveal that WWP2 isoforms differentially modulate TGFß-dependent transcription and EMT. Finally, we show that selective disruption of WWP2 interactions with inhibitory Smad7 can stabilise Smad7 protein levels and prevent TGFß-induced EMT. Collectively, our data suggest that WWP2-N can stimulate WWP2-FL leading to increased activity against unstimulated Smad2 and Smad3, and that Smad7 is a preferred substrate for WWP2-FL and WWP2-C following prolonged TGFß stimulation. Significantly, this is the first report of an interdependent biological role for distinct HECT E3 ubiquitin ligase isoforms, and highlights an entirely novel regulatory paradigm that selectively limits the level of inhibitory and activating Smads

A conceptual model for unifying variability in space and time: Rationale, validation, and illustrative applications

With the increasing demand for customized systems and rapidly evolving technology, software engineering faces many challenges. A particular challenge is the development and maintenance of systems that are highly variable both in space (concurrent variations of the system at one point in time) and time (sequential variations of the system, due to its evolution). Recent research aims to address this challenge by managing variability in space and time simultaneously. However, this research originates from two different areas, software product line engineering and software configuration management, resulting in non-uniform terminologies and a varying understanding of concepts. These problems hamper the communication and understanding of involved concepts, as well as the development of techniques that unify variability in space and time. To tackle these problems, we performed an iterative, expert-driven analysis of existing tools from both research areas to derive a conceptual model that integrates and unifies concepts of both dimensions of variability. In this article, we first explain the construction process and present the resulting conceptual model. We validate the model and discuss its coverage and granularity with respect to established concepts of variability in space and time. Furthermore, we perform a formal concept analysis to discuss the commonalities and differences among the tools we considered. Finally, we show illustrative applications to explain how the conceptual model can be used in practice to derive conforming tools. The conceptual model unifies concepts and relations used in software product line engineering and software configuration management, provides a unified terminology and common ground for researchers and developers for comparing their works, clarifies communication, and prevents redundant developments

Gas phase formation of extremely oxidized pinene reaction products in chamber and ambient air

High molecular weight (300–650 Da) naturally charged negative ions have previously been observed at a boreal forest site in Hyytiälä, Finland. The long-term measurements conducted in this work showed that these ions are observed practically every night between spring and autumn in Hyytiälä. The ambient mass spectral patterns could be reproduced in striking detail during additional measurements of α-pinene (C<sub>10</sub>H<sub>16</sub>) oxidation at low-OH conditions in the Jülich Plant Atmosphere Chamber (JPAC). The ions were identified as clusters of the nitrate ion (NO<sub>3</sub><sup>−</sup>) and α-pinene oxidation products reaching oxygen to carbon ratios of 0.7–1.3, while retaining most of the initial ten carbon atoms. Attributing the ions to clusters instead of single molecules was based on additional observations of the same extremely oxidized organics in clusters with HSO<sub>4</sub><sup>−</sup> (Hyytiälä) and C<sub>3</sub>F<sub>5</sub>O<sub>2</sub><sup>−</sup> (JPAC). The most abundant products in the ion spectra were identified as C<sub>10</sub>H<sub>14</sub>O<sub>7</sub>, C<sub>10</sub>H<sub>14</sub>O<sub>9</sub>, C<sub>10</sub>H<sub>16</sub>O<sub>9</sub>, and C<sub>10</sub>H<sub>14</sub>O<sub>11</sub>. The mechanism responsible for forming these molecules is still not clear, but the initial reaction is most likely ozone attack at the double bond, as the ions are mainly observed under dark conditions. β-pinene also formed highly oxidized products under the same conditions, but less efficiently, and mainly C<sub>9</sub> compounds which were not observed in Hyytiälä, where β-pinene on average is 4–5 times less abundant than α-pinene. Further, to explain the high O/C together with the relatively high H/C, we propose that geminal diols and/or hydroperoxide groups may be important. We estimate that the night-time concentration of the sum of the neutral extremely oxidized products is on the order of 0.1–1 ppt (~10<sup>6</sup>–10<sup>7</sup> molec cm<sup>−3</sup>). This is in a similar range as the amount of gaseous H<sub>2</sub>SO<sub>4</sub> in Hyytiälä during day-time. As these highly oxidized organics are roughly 3 times heavier, likely with extremely low vapor pressures, their role in the initial steps of new aerosol particle formation and growth may be important and needs to be explored in more detail in the future