Collision Detection and Administration Methods for Many Particles with Different Sizes

This paper deals with the calculation of the motion and the adminis-tration of the contacts for systems with many colliding bodies of round shape and possibly large size-differences. Both two dimensional (2D) and three dimensional (3D) cases are investigated, while the efficiency of the employed algorithms is compared. For the integration of the equations of motion, standard methods are used, but to reduce the effort for collision detection, more sophisticated administration algorithms for the neighbor-hood search are prosented. Especially for large systems with many parti-cles and a wide, polydisperse size distribution, this is a challenge. Three methods, the Verlet-Neighbor List (VL), the Linked Cell (LC) method, and the Linked Linear List (LLL), are discussed and compared for 2D and 3D. Only LLL performs well for strongly different particle sizes

Myelofibrosis: molecular and cell biological aspects

A subset of myeloproliferative disorders (MPN) and myelodyplastic syndromes (MDS) evolves to fibrosis of the bone marrow associated with haematopoietic insufficiency. We have been interested in chemokines involved in fibrogenesis within the bone marrow. Besides TGFβ we could identify a number of additional mediators including osteoprotegerin and bone morphogenic proteins. In MPN JAK2 or MPL mutation are not linked to the propensity for bone marrow fibrosis. The hypothesis that an increased intramedullary decay of megakaryocytes undergoing appotosis takes place within the marrow, thus liberating fibrogenic cytokines, could not be confirmed. On the contrary, megakaryocytes in primary fibrosis revealed low expression of proapoptotic genes such as BNIP3. Interestingly, BNIP 3 expression was down regulated in megakaryocytic cell lines kept in hypoxic conditions. Furthermore, expression arrays revealed hypoxia inducible genes to be up-regulated in primary myelofibrosis. Fibrotic MPN are characterized by aberrant proplatelet formation which represent cytoplasmic pseudopodia and normally extend into the sinus. In fibrotic MPN orientation of proplatelet growth appears to be disturbed, which could lead to an aberrant deposition of platelets in the marrow with consecutive liberation of fibrogenic cytokines

Evidence supporting the best clinical management of patients with multimorbidity and polypharmacy: a systematic guideline review and expert consensus

This is the author accepted manuscript. The final version is available from Wiley via the DOI in this record.The complexity and heterogeneity of patients with multimorbidity and polypharmacy renders traditional disease-oriented guidelines often inadequate and complicates clinical decision making. To address this challenge, guidelines have been developed on multimorbidity or polypharmacy. To systematically analyse their recommendations, we conducted a systematic guideline review using the Ariadne principles for managing multimorbidity as analytical framework. The information synthesis included a multistep consensus process involving 18 multidisciplinary experts from seven countries. We included eight guidelines (four each on multimorbidity and polypharmacy) and extracted about 250 recommendations. The guideline addressed (i) the identification of the target population (risk factors); (ii) the assessment of interacting conditions and treatments: medical history, clinical and psychosocial assessment including physiological status and frailty, reviews of medication and encounters with healthcare providers highlighting informational continuity; (iii) the need to incorporate patient preferences and goal setting: eliciting preferences and expectations, the process of shared decision making in relation to treatment options and the level of involvement of patients and carers; (iv) individualized management: guiding principles on optimization of treatment benefits over possible harms, treatment communication and the information content of medication/care plans; (v) monitoring and follow-up: strategies in care planning, self-management and medication-related aspects, communication with patients including safety instructions and adherence, coordination of care regarding referral and discharge management, medication appropriateness and safety concerns. The spectrum of clinical and self-management issues varied from guiding principles to specific recommendations and tools providing actionable support. The limited availability of reliable risk prediction models, feasible interventions of proven effectiveness and decision aids, and limited consensus on appropriate outcomes of care highlight major research deficits. An integrated approach to both multimorbidity and polypharmacy should be considered in future guidelines.Journal of Internal MedicineKarolinska Institutet Strategic Research Area in Epidemiology (SfoEpi

The Ethics of Corporate Governance

How should corporate directors determine what is the right decision? For at least the past 30 years the debate has raged as to whether shareholder value should take precedence over corporate social responsibility when crucial decisions arise. Directors face pressure, not least from ethical investors, to do the good thing when they seek to make the right choice. Corporate governance theory has tended to look to agency theory and the need of boards to curb excessive executive power to guide directors' decisions. While useful for those purposes, agency theory provides only limited guidance. Supplementing it with the alternatives - stakeholder theory and stewardship theory - tends to put directors in conflict with their legal obligations to work in the interests of shareholders. This paper seeks to reframe the discussion about corporate governance in terms of the ethical debate between consequential, teleological approaches to ethics and idealist, deontological ones, suggesting that directors are - for good reason - more inclined toward utilitarian judgments like those underpinning shareholder value. But the problems with shareholder value have become so great that a different framework is needed: strategic value, with an emphasis on long-term value creation judged from a decidedly utilitarian standpoint

Goal-Driven Structured Argumentation for Patient Management in a Multimorbidity Setting

We use computational argumentation to both analyse and generate solutions for reasoning in multimorbidity about consistent recommendations, according to different patient-centric goals. Reasoning in this setting carries a complexity related to the multiple variables involved. These variables reflect the co-existing health conditions that should be considered when defining a proper therapy. However, current Clinical Decision Support Systems (CDSSs) are not equipped to deal with such a situation. They do not go beyond the straightforward application of the rules that build their knowledge base and simple interpretation of Computer-Interpretable Guidelines (CIGs). We provide a computational argumentation system equipped with goal-seeking mechanisms to combine independently generated recommendations, with the ability to resolve conflicts and generate explanations for its results. We also discuss its advantages over and relation to Multiple-criteria Decision-making (MCDM) in this particular setting.- (undefined

Leptin is a four-helix bundle: secondary structure by NMR

AbstractLeptin is a signaling protein that in its mutant forms has been associated with obesity and Type II diabetes. The lack of sequence similarity has precluded analogies based on structural resemblance to known systems. Backbone NMR signals for mouse leptin (13C/15N -labeled) have been assigned and its secondary structure reveals it to be a four-helix bundle cytokine. Helix lengths and disulfide pattern are in agreement with leptin as a member of the short-helix cytokine family. A three-dimensional model was built verifying the mechanical consistency of the identified elements with a short-helix cytokine core

Health-related preferences of older patients with multimorbidity: An evidence map

Objectives To systematically identify knowledge clusters and research gaps in the health-related preferences of older patients with multimorbidity by mapping current evidence.Design Evidence map (systematic review variant).Data sources MEDLINE, EMBASE, PsycINFO, PSYNDEX, CINAHL and Science Citation Index/Social Science Citation Index/-Expanded from inception to April 2018.Study selection Studies reporting primary research on health-related preferences of older patients (mean age ≥60 years) with multimorbidity (≥2 chronic/acute conditions).Data extraction Two independent reviewers assessed studies for eligibility, extracted data and clustered the studies using MAXQDA-18 content analysis software.Results The 152 included studies (62% from North America, 28% from Europe) comprised 57 093 patients overall (range 9–9105). All used an observational design except for one interventional study: 63 (41%) were qualitative (59 cross-sectional, 4 longitudinal), 85 (57%) quantitative (63 cross-sectional, 22 longitudinal) and 3 (2%) used mixed methods. The setting was specialised care in 85 (56%) and primary care in 54 (36%) studies. We identified seven clusters of studies on preferences: end-of-life care (n=51, 34%), self-management (n=34, 22%), treatment (n=32, 21%), involvement in shared decision making (n=25, 17%), health outcome prioritisation/goal setting (n=19, 13%), healthcare service (n=12, 8%) and screening/diagnostic testing (n=1, 1%). Terminology (eg, preferences, views and perspectives) and concepts (eg, trade-offs, decision regret, goal setting) used to describe health-related preferences varied substantially between studies.Conclusion Our study provides the first evidence map on the preferences of older patients with multimorbidity. Included studies were mostly conducted in developed countries and covered a broad range of issues. Evidence on patient preferences concerning decision-making on screening and diagnostic testing was scarce. Differences in employed terminology, decision-making components and concepts, as well as the sparsity of intervention studies, are challenges for future research into evidence-based decision support seeking to elicit the preferences of older patients with multimorbidity and help them construct preferences.Trial registration number Open Science Framework (OSF): DOI 10.17605/OSF.IO/MCRWQ

Colorectal cancer liver metastatic growth depends on PAD4-driven citrullination of the extracellular matrix

Citrullination of proteins, a post-translational conversion of arginine residues to citrulline, is recognized in rheumatoid arthritis, but largely undocumented in cancer. Here we show that citrullination of the extracellular matrix by cancer cell derived peptidylarginine deiminase 4 (PAD4) is essential for the growth of liver metastases from colorectal cancer (CRC). Using proteomics, we demonstrate that liver metastases exhibit higher levels of citrullination and PAD4 than unaffected liver, primary CRC or adjacent colonic mucosa. Functional significance for citrullination in metastatic growth is evident in murine models where inhibition of citrullination substantially reduces liver metastatic burden. Additionally, citrullination of a key matrix component collagen type I promotes greater adhesion and decreased migration of CRC cells along with increased expression of characteristic epithelial markers, suggesting a role for citrullination in promoting mesenchymal-to-epithelial transition and liver metastasis. Overall, our study reveals the potential for PAD4-dependant citrullination to drive the progression of CRC liver metastasis