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With unparalleled rotational stability, millisecond pulsars (MSPs) serve as ideal laboratories for numerous astrophysical studies, many of which require precise knowledge of the distance and/or velocity of the MSP. Here, we present the astrometric results for 18 MSPs of the "MSPSR$\pi$" project focusing exclusively on astrometry of MSPs, which includes the re-analysis of 3 previously published sources. On top of a standardized data reduction protocol, more complex strategies (i.e., normal and inverse-referenced 1D interpolation) were employed where possible to further improve astrometric precision. We derived astrometric parameters using sterne, a new Bayesian astrometry inference package that allows the incorporation of prior information based on pulsar timing where applicable. We measured significant ($>3\,\sigma$) parallax-based distances for 15 MSPs, including $0.81\pm0.02\,$kpc for PSR J1518+4904 -- the most significant model-independent distance ever measured for a double neutron star system. For each MSP with a well-constrained distance, we estimated its transverse space velocity and radial acceleration. Among the estimated radial accelerations, the updated ones of PSR J1012+5307 and PSR J1738+0333 impose new constraints on dipole gravitational radiation and the time derivative of Newton's gravitational constant. Additionally, significant angular broadening was detected for PSR J1643-1224, which offers an independent check of the postulated association between the HII region Sh 2-27 and the main scattering screen of PSR J1643-1224. Finally, the upper limit of the death line of $\gamma$-ray-emitting pulsars is refined with the new radial acceleration of the hitherto least energetic $\gamma$-ray pulsar PSR J1730-2304., Comment: 23 pages, 6 figures, 10 tables, published in MNRAS more...

Purpose: This commentary outlines the surgical pathway for patients with cleft lip and/or palate (CLP), identifies risks associated with opioid prescribing in this patient population, and summarizes strategies to safely minimize the need for perioperative opioid prescribing. Conclusions: Patients with orofacial clefts, CLP, undergo multiple reconstructive surgeries. The long-term effects of perioperative opioid prescriptions should concern all members of the cleft and craniofacial team. The amount of surgery each patient with a CLP may face varies by patient and can begin in infancy and continue to adulthood. In this commentary, the surgical pathway for CLP is reviewed, and the opioid crisis is addressed in regard to this vulnerable patient group. Solutions for cleft and craniofacial team members from evidence-based literature are summarized to minimize the use of opioids prescribed in this patient population. Approaches to reduce opioid use after CLP surgery are holistic and multidisciplinary. more...

In this paper, we integrate conflict studies with Active Inference, a developing framework which provides an integrative and systems-level perspective on cognition and behavior. This formalization, the Active Inference Conflict (AIC) model, situates conflict in terms of a multiscale process of communication, trust, and relationship management enacted by interacting entities. The AIC model helps capture and extend the insights of previous models applied to aspects of conflict and war, such as OODA loops (observe-orient-decide-act), the generations of warfare model, and the Rumsfeld Matrix. The AIC model aids in the analysis of pertinent aspects of modern conflict, such as cyber, psychological, biological, informational, financial, and ideological conflict, that are not amenable to coherent or consistent analysis using traditional models of human conflict. AIC is demonstrated to be of use in both monitoring and studying conflict, as well as in designing systems intended to facilitate controlled or managed conflict in scenarios characterized by business, operations, legal, technical, and social (BOLTS) components. Insights and implications from qualitative use are used as a foundation for offering recommendations for future research and social systems design. more...

This paper makes a case for integrating frameworks from two different knowledge domains, rhetorical studies and ecological studies, to catalog, monitor, and study digital image meme data, in order to support a more robust understanding of how memes produce and disseminate online narratives. In the digital public sphere, the primacy of image-based communication motivates an over-reliance on the image meme for public argumentation. Despite its ubiquity, the image meme format is currently understudied in large scale digital data analyses, relative to text -based formats such as natural language and hashtags. We argue that using a rhetorical approach (which emphasizes message form and audience) in large-scale analyses of multimedia and other digital artifacts can enhance analytic tools for categorizing, indexing, searching, and modeling online discourse. Further, by integrating a rhetorical and an ecosystem approach to studying digital discourse, we can formally trace multimedia rhetorical artifacts like image memes across platforms, media types, and languages. Combined rhetorical and ecosystem analyses can reveal how digital artifacts like image memes create, sustain, and disrupt public narratives and, thereby, socio-political dynamics. Three key elements of our approach are a) recognizing how parsimony and polysemy give image memes narrative power, b) focusing on how image memes engage audiences through identity construction, and c) applying “Rhetorical Ecosystem” mapping, based upon toolkit transfer and system design implications. Drawing from concepts in rhetoric, ecology, and complex systems analysis we introduce a Digital Rhetorical Ecosystem three-tiered model (DRE3) to explain how memes impact public narratives and beliefs. We then explore implications of this DRE3 model for the design and development of systems for computational analysis of digital discourse. more...

The gene cro promotes lytic growth of phages through binding of Cro protein dimers to regulatory DNA sites. Most Cro proteins are one-to-one orthologs, yet their sequence, structure and binding site sequences are quite divergent across lambdoid phages. We report the cocrystal structure of bacteriophage N15 Cro with a symmetric consensus site. We contrast this complex with an orthologous structure from phage λ, which has a dissimilar binding site sequence and a Cro protein that is highly divergent in sequence, dimerization interface and protein fold. The N15 Cro complex has less DNA bending and smaller DNA-induced changes in protein structure. N15 Cro makes fewer direct contacts and hydrogen bonds to bases, relying mostly on water-mediated and Van der Waals contacts to recognize the sequence. The recognition helices of N15 Cro and λ Cro make mostly nonhomologous and nonanalogous contacts. Interface alignment scores show that half-site binding geometries of N15 Cro and λ Cro are less similar to each other than to distantly related CI repressors. Despite this divergence, the Cro family shows several code-like protein–DNA sequence covariations. In some cases, orthologous genes can achieve a similar biological function using very different specific molecular interactions. more...

Arterioureterale Fisteln sind seltene, lebensbedrohliche und schwer zu diagnostizierende Krankheitsbilder. Risikofaktoren sind Operationen im kleinen Becken (chirurgisch, urologisch, gynakologisch, gefaschirurgisch), Bestrahlungen im kleinen Becken, Doppel-J(DJ)-Harnleiterschienendauerversorgung sowie vorhergehende Gefaspathologien. Es wurden retrospektiv alle Falle (n = 5) mit arterioureteraler Fistel der letzten 10 Jahre im Krankenhausdokumentationssystem aufgesucht und ausgewertet. Fur die Falle wurden die klinischen Symptome, die Diagnostik und Therapie sowie das Outcome dargestellt und miteinander verglichen. Bei 4 Fallen handelte es sich um Frauen. Das haufigste initiale Symptom war eine Makrohamaturie (4/5). Alle Patienten waren DJ-dauerversorgt nach radikalchirurgischer OP und Radiatio des kleinen Beckens. Initiale Diagnostik mit Nachweis der Fistel war in einem Fall die retrograde Darstellung, in 2 die provokatorische Angiographie und in 2 Fallen die Laparotomie bei Kreislaufinstabilitat. Zur Therapie wurden 3 Patientinnen operiert und 2 interventionell mit einem Stent versorgt. Letztendlich verstarb eine Patientin. Zwei Patientinnen hatten eine Nierenfisteldauerversorgung und 2 Patienten konnten weiter DJ-dauerversorgt versorgt bleiben. Aufgrund aggressiver Therapieregime muss mit einer steigenden Anzahl von Patienten mit arterioureteralen Fisteln gerechnet werden. Eine Identifikation dieser Patienten uber das Risikoprofil ist essentiell. more...

Spider venom GDPD-like phospholipases D (SicTox) have been identified to be one of the major toxins in recluse spider venom. They are divided into two major clades: the α clade and the β clade. Most α clade toxins present high activity against lipids with choline head groups such as sphingomyelin, while activities in β clade toxins vary and include preference for substrates containing ethanolamine headgroups (Sicarius terrosus, St_βIB1). A structural comparison of available structures of phospholipases D (PLDs) reveals a conserved aromatic cage in the α clade. To test the potential influence of the aromatic cage on membrane-lipid specificity we performed molecular dynamics (MD) simulations of the binding of several PLDs onto lipid bilayers containing choline headgroups; two SicTox from the α clade, Loxosceles intermedia αIA1 (Li_αIA) and Loxosceles laeta αIII1 (Ll_αIII1), and one from the β clade, St_βIB1. The simulation results reveal that the aromatic cage captures a choline-headgroup and suggest that the cage plays a major role in lipid specificity. We also simulated an engineered St_βIB1, where we introduced the aromatic cage, and this led to binding with choline-containing lipids. Moreover, a multiple sequence alignment revealed the conservation of the aromatic cage among the α clade PLDs. Here, we confirmed that the i-face of α and β clade PLDs is involved in their binding to choline and ethanolamine-containing bilayers, respectively. Furthermore, our results suggest a major role in choline lipid recognition of the aromatic cage of the α clade PLDs. The MD simulation results are supported by in vitro liposome binding assay experiments. more...

Spider venom GDPD-like phospholipases D (SicTox) have been identified to be one of the major toxins in recluse spider venom. They are divided into two major clades: the α clade and the β clade. Most α clade toxins present high activity against lipids with choline head groups such as sphingomyelin, while activities in β clade toxins vary and include preference for substrates containing ethanolamine headgroups (Sicarius terrosus, St_βIB1). A structural comparison of available PLDs structures reveals a conserved aromatic cage in the α clade. To test the potential influence of the aromatic cage on membrane-lipid specificity we performed molecular-dynamics (MD) simulations of the binding of several PLDs onto lipid bilayers containing choline headgroups; two SicTox from the α clade, Loxosceles intermedia αIA1 (Li_αIA) and Loxosceles laeta αIII1 (Ll_αIII1), and one from the β clade, St_βIB1. The simulation results reveal that the aromatic cage captures a choline-headgroup and suggest that the cage plays a major role in lipid specificity. We also simulated an engineered St_βIB1, where we introduced the aromatic cage, and this led to binding with choline-containing lipids. Moreover, a multiple sequence alignment revealed the conservation of the aromatic cage among the α clade PLDs. Here, we confirmed the membrane binding site of α and β clade PLDs on choline and ethanolamine-containing bilayers, respectively. Furthermore, our results suggest a major role in choline lipid recognition of the aromatic cage of the α clade PLDs. The MD simulation results are supported by in vitro liposome binding assay experiments. more...

The theory and practice of knowledge management shares concerns and approaches with a number of other areas of research, some of which preceded its formalization as a field. In the age of the internet, the challenges that the field of knowledge management addresses, such as the difficulty of synthesizing, interpreting, and managing large streams of information, are no longer confined to professional disciplines and are present in everyday life. The commonality and timelessness of these concerns presents a potential problem for the field of knowledge management that, ironically, the field itself often seeks to address: the creation of silos, sometimes referred to as “islands”, in the knowledge base. The purpose of this paper is to present an exploratory bibliometric analysis of the various areas of research which share concerns, approach, and scope in common with knowledge management. Search-strings associated with selected areas of research were used to query Google Scholar in various combinations in search of co-occurrence, results were quantified and visualized. The results show variable couplings and differential prevalence of keywords, and serve as a starting point for targeted analyses and next steps. more...

Purpose Photodynamic diagnosis and white-light TURB with adjuvant intravesical chemotherapy (ICT) is widely used in treatment of bladder cancer. This non-inferiority trial is designed to demonstrate non-inferiority regarding recurrence-free survival (RFS) of Hexvix® TURB followed by immediate instillation compared to white-light TURB with immediate instillation followed by maintenance ICT. Methods Between 07/2010 and 12/2016, 129 patients with EORTC intermediate risk non-muscle invasive bladder cancer treated with TURB were included in this multicentre phase III study. Patients were randomized and received either white-light TURB with immediate ICT followed by maintenance ICT (n = 62, 20 mg Mitomycin weekly for 6 weeks as induction phase, afterwards 20 mg/month for 6 months) or Hexvix® TURB with immediate ICT only (n = 67, 40 mg Mitomycin). Primary study endpoint was RFS after 12 months. Hexvix® TURB was counted as non-inferior to white light alone if the upper limit of the one-sided 95% confidence interval of hazard ratio was lower than 1.676. Due to the non-inferiority design, the per-protocol population was used as the primary analysis population (n = 113) Results Median follow-up was 1.81 years. Hexvix® group showed more events (recurrence or death) than white-light group (19 vs. 10) resulting in a HR of 1.29 (upper limit of one-sided 95%-CI = 2.45; pnon-inferiority = 0.249). The ITT population yielded similar results (HR = 1.67); 3.18], pnon-inferiority = 0.493). There was no significant difference in overall survival between both groups (p = 0.257). Conclusion Non-inferiority of Hexvix® TURB relative to white-light TURB with maintenance Mitomycin instillation in intermediate risk urothelial carcinoma of the bladder was not proven. Hence a higher effect of maintenance ICT is to assume compared to a Hexvix®-improved TURB only, confirming its important role in patient treatment. more...

Asynchronous and remote collaborative written projects (research, field guides, code, etc.) in emergent, interdisciplinary teams can be an incredibly productive and enjoyable pursuit. The convergence of diverse perspectives, personalities, and expertise in the rapid production of written deliverables can provide immense value and insight, not just to the situation, problem, or opportunity space the team was formed to address, but also to the disciplines each author brought to the table. Yet, asynchronous and remote collaborative writing can also be rather perilous. Managing deadlines, handling disputes, communicating, staying on mission, managing resources, collective editing (and over-editing), and avoiding contradiction are only some of the challenges. While the presence of a catechism-styled operations orderand the use of a team “Facilitator” can greatly improve the likelihood of success, making sure all of the authors have an alignment on protocol and etiquette while writing as a catechism-based team prevents unnecessary misunderstandings and keeps things on schedule. This "3-Paragraph Order" for Collaborative Writing, or C-3PO,is meant to rapidly onboard authors to collaborative writing procedures and etiquette.&nbsp more...

The Facilitator’s Catechism (FC) is an operations order formatted as a project-management document. The FC is intended to be used & refined by remote teams in order to greatly increase organizational alignment, project comparability, reliability, and productivity in the pursuit of timely deliverables while reducing work-about-work. It is built from the battle-tested, project management techniques used by the National Militaries and by the Defense Advanced Research Projects Agency. This playbook is meant to be a document that assists with that adoption, ensuring clarity and providing a Single Source of Truth (SSoT) for the intents of its application and its usage. It offers context on the background of catechisms (Part I), a step-by-step guide on how to deploy it for the first time (Part II), and examples, templates, further reading, and resources for making it a part of your regular individual or team work-flow (Supplemental Resources). more...

Proliferative kidney disease (PKD) is an emerging disease that recently resulted in a large mortality event of salmonids in the Yellowstone River (Montana, USA). Total PKD fish mortalities in the Yellowstone River were estimated in the tens of thousands, which resulted in a multi‐week river closure and an estimated economic loss of US$500,000. This event shocked scientists, managers, and the public, as this was the first occurrence of the disease in the Yellowstone River, the only reported occurrence of the disease in Montana in the past 25 yr, and arguably the largest wild PKD fish kill in the world. To understand why the Yellowstone River fish kill occurred, we used molecular and historical data to evaluate evidence for several hypotheses: Was the causative parasite Tetracapsuloides bryosalmonae a novel invader, was the fish kill associated with a unique parasite strain, and/or was the outbreak caused by unprecedented environmental conditions? We found that T. bryosalmonae is widely distributed in Montana and have documented occurrence of this parasite in archived fish collected in the Yellowstone River prior to the fish kill. T. bryosalmonae had minimal phylogeographic population structure, as the DNA of parasites sampled from the Yellowstone River and distant water bodies were very similar. These results suggest that T. bryosalmonae could be endemic in Montana. Due to data limitations, we could not reject the hypothesis that the fish kill was caused by a novel and more virulent genetic strain of the parasite. Finally, we found that single‐year environmental conditions are insufficient to explain the cause of the 2016 Yellowstone River PKD outbreak. Other regional rivers where we documented T. bryosalmonae had similar or even more extreme conditions than the Yellowstone River and similar or more extreme conditions have occurred in the Yellowstone River in the recent past, yet mass PKD mortalities have not been documented in either instance. We conclude by placing these results and unresolved hypotheses into the broader context of international research on T. bryosalmonae and PKD, which strongly suggests that a better understanding of bryozoans, the primary host of T. bryosalmonae, is required for better ecosystem understanding. more...

Innovation teams formed in incubators, research accelerators, hackathon weekends, and within organizations need to quickly align on narrative, workflow, and objectives in order to achieve success. Many of these teams disintegrate or fail to perform due to lack of alignment. Operations orders, such as those in use by the military, have demonstrable impact on organizational efficacy and success. This paper summarizes the history, development, and impact of military operations orders, discusses the history and development of their business counterparts, and presents the “The Innovator’s Catechism”, a catechism-styled operations order for use by early-stage innovation teams. This operations order is built from the “Facilitator’s Catechism”, an operations order for rapidly formed research teams, with acknowledgment for the special information requirements present for emergent and early-stage teams that are market-facing. more...

The amino-acid sequences of soluble, globular proteins must have hydrophobic residues to form a stable core, but excess sequence hydrophobicity can lead to loss of native state conformational specificity and aggregation. Previous studies of polar-to-hydrophobic mutations in the β-sheet of the Arc repressor dimer showed that a single substitution at position 11 (N11L) leads to population of an alternate dimeric fold in which the β-sheet is replaced by helix. Two additional hydrophobic mutations at positions 9 and 13 (Q9V and R13V) lead to population of a differently folded octamer along with both dimeric folds. Here we conduct a comprehensive study of the sequence determinants of this progressive loss of fold specificity. We find that the alternate dimer-fold specifically results from the N11L substitution and is not promoted by other hydrophobic substitutions in the β-sheet. We also find that three highly hydrophobic substitutions at positions 9, 11, and 13 are necessary and sufficient for oligomer formation, but the oligomer size depends on the identity of the hydrophobic residue in question. The hydrophobic substitutions increase thermal stability, illustrating how increased hydrophobicity can increase folding stability even as it degrades conformational specificity. The oligomeric variants are predicted to be aggregation-prone but may be hindered from doing so by proline residues that flank the β-sheet region. Loss of conformational specificity due to increased hydrophobicity can manifest itself at any level of structure, depending upon the specific mutations and the context in which they occur. more...

New protein folds may evolve from existing folds through metamorphic evolution involving a dramatic switch in structure. To mimic pathways by which amino acid sequence changes could induce a change in fold, we designed two folded hybrids of Xfaso 1 and Pfl 6, a pair of homologous Cro protein sequences with ~40% identity but different folds (all-α vs. α + β, respectively). Each hybrid, XPH1 or XPH2, is 85% identical in sequence to its parent, Xfaso 1 or Pfl 6, respectively; 55% identical to its noncognate parent; and ~70% identical to the other hybrid. XPH1 and XPH2 also feature a designed hybrid chameleon sequence corresponding to the C-terminal region, which switched from α-helical to β-sheet structure during Cro evolution. We report solution nuclear magnetic resonance (NMR) structures of XPH1 and XPH2 at 0.3 A and 0.5 A backbone root mean square deviation (RMSD), respectively. XPH1 retains a global fold generally similar to Xfaso 1, and XPH2 retains a fold similar to Pfl 6, as measured by TM-align scores (~0.7), DALI Z-scores (7-9), and backbone RMSD (2-3 A RMSD for the most ordered regions). However, these scores also indicate significant deviations in structure. Most notably, XPH1 and XPH2 have different, and intermediate, secondary structure content relative to Xfaso 1 and Pfl 6. The multistep progression in sequence, from Xfaso 1 to XPH1 to XPH2 to Pfl 6, thus involves both abrupt and gradual changes in folding pattern. The plasticity of some protein folds may allow for "polymetamorphic" evolution through intermediate structures. more...

Social impact bonds, a recent innovation in social finance, are designed to harness capital and knowledge from private nonprofit, for-profit, and public entities to address pressing social problems. Although there is great policy interest in understanding how social impact bonds can be used to tackle social problems, the emergent nature of social impact bonds makes it hard to find relevant data and evidence. To overcome this challenge, we use single-significant-case sampling as our research design strategy. We conduct an in-depth case study of the Social Innovation Financing Youth Recidivism project (SIF) in Massachusetts. Our case study is comprised of a qualitative analysis of the multi-party contract and multi-year quantitative benefit-cost analysis to understand transaction costs. We draw upon contract theory to develop an analytical framework for the case analysis and highlight the risks and safeguards for the various parties to the contract, and conduct a formal benefit-cost analysis to map out transaction costs. We conclude with a discussion of study implications and future research. more...

Since the early 2000's there has been growing interest in using the Social Return on Investment (SROI) as a measure for assessing the performance of social enterprises. By analogy with its business counterpart, the Return on Investment (ROI), the SROI is a metric that compares the monetized social costs of a program with the monetized social benefits of achieving an outcome (or set of outcomes). For example, calculating the SROI of a nonprofit half-way house for drug addicts might involve estimating the reduced social costs attributable to successful rehabilitation of addicts, and comparing this to the social costs of operating the half-way house. Alternatively, the total return of a for-profit social enterprise providing affordable housing might consist both of the traditional private return on investment along with the economic value of meeting the housing needs of lower income households. Early descriptions of the methodology for calculating the SROI suggest that the approach initially evolved from standard methodologies found in the business finance literature for evaluating investments, with the important twist that nonprofit sector returns/payoffs are defined in broader social terms (Thornley, Anderson, & Dixon, 2016). Yet, someone who is familiar with the economic literature on cost benefit analysis (CBA) as it is applied to the evaluation of public programs cannot help but be struck by the similarity between the outcomes that CBA is intended to measure, and those that are the object of efforts to calculate the SROI. One implication is that the literature on the theory and practice of cost benefit analysis offers useful lessons about how to measure the social return on investment, as well as about potential caveats and limitations that need to be confronted when attempting to undertake an analysis of the SROI. The paper discusses the potential uses and limitations of CBA and SROI as tools that governments, private donor/investors, and foundations can use to help set funding priorities, and evaluate performance. It summarizes: (1) the conceptual foundations of CBA and its application to SROI analysis, (2) issues raised in the implementation of CBA and SROI in practice, and (3) discusses when CBA and/or SROI approaches are a useful lens for setting priorities and/or evaluating performance, as well as important limitations of such methods. more...

Introduction Lambdoid craniosynostosis is an extremely rare anomaly in which there is premature fusion of one or both lambdoid sutures. The mainstay of treatment is surgical intervention, for which various procedures have been described, but there is a paucity of data on long-term outcomes. This study examines the long-term outcomes in the surgical management of this challenging condition, showing that accurate diagnosis and careful planning can lead to safe and consistent results. Materials and methods A retrospective chart review was performed looking at all cases of isolated lambdoid craniosynostosis treated with surgical intervention by the senior author from 1999 to 2016. Data collected included gender, age at diagnosis, age at surgery, length of follow up, method of diagnosis, side of affected suture, pre-operative and post-operative physical exam findings, surgical technique, complications, re-operation rate, and associated torticollis. Results Twenty-five patients (N = 25) were included in the study. All patients underwent posterior calvarial remodeling with/without barrel stave osteotomies and full thickness calvarial bone grafts. Mean length of follow up after operative intervention was 43.8 months (+/- 23.2 months). All patients were judged to have significantly improved head contour which was near-normal at conversational distance during post-operative follow up by the senior author. Residual plagiocephaly was present in 24% of patients. There were no major complications in this series. Reoperation rate was 8%. Seventy-six percent of patients also presented with torticollis, of which 37% had refractory torticollis that required sternocleidomastoid (SCM) release by the senior author. Discussion The authors present one of the largest series of operative cases of isolated lambdoid craniosynostosis to date. Our data show that with accurate diagnosis and careful planning, safe and consistent long-term results can be achieved with surgical intervention. A significant number of patients in our series also presented with concomitant torticollis. The authors recommend that all patients being evaluated for posterior plagiocephaly should also be evaluated for torticollis, because without recognition and intervention, patients may continue to have residual facial asymmetry and head shape abnormalities despite optimal surgical correction of the lambdoid synostosis. more...

According to the current definition of the German guideline for prevention of venous thromboembolism, urological surgery includes a high number of high-risk patients. All patients undergoing urological surgery between 2012 and 2016 were analyzed with regard to complications (bleeding or thrombosis).This study is a retrospective and monocentric cohort study. Included were all patients who underwent surgery between 2012 and 2016 at the Urological Department at the University Hospital of Luebeck. Information was collected relating to anticoagulation, patient-specific and surgery-specific risk factors, and complications.In all, 3609 surgeries were analyzed: 77.8% of patients received no medical prophylaxis, 10.2% received an aggregation inhibitor, and 8.5% synthetic, unfractionated or low molecular weight heparin. Heparin was administered to 80.4% of patients after surgery. During an average hospital stay of 4.5 days, 93.3% of the patients received no change in anticoagulation. Merely 0.8% of all patients suffered from clinical thomboembolic events within 28 days. In contrast the number of bleedings was higher with 20.3% (minor: 4.8%, major: 15.5%).We found a slight risk for postoperative thromboembolism (0.8%). The risk for postoperative bleeding in contrast was 20.3%, including 15.5% major bleedings. The results are discussed in relation to the current guidelines. more...

Arterioureteral fistulas are rare, life-threatening, and difficult to diagnose. Risk factors are medical interventions in the lesser pelvis (general, urological, gynecological, and vascular surgery), radiation therapy of the lesser pelvis, permanent double J catheters, and previous vessel malformations.We retrospectively evaluated all cases of arterioureteral fistulas registered over the last 10 years in the clinic's documentation system. For all cases, clinical symptoms, diagnostics, therapies as well as clinical outcome were evaluated.Four of the 5 patients were women. The most common initial symptom was a gross hematuria (4/5). All patients had a permanent double J catheter after extensive surgery of the lesser pelvis. In one case the initial diagnosis was done by retrograde ureterography, in 2 patients by provocative angiography and in the other 2 cases with a laparotomy due to cardiovascular problems. Three patients were treated by open surgery and 2 patients were treated by stenting of the iliac artery. One patient died, 2 patients had a permanent kidney fistula, and 2 patients continued treatment with a permanent double J catheter.Based on the more aggressive therapy regimens, we expect that the number of patients presenting with arterioureteral fistulas will continue to rise. The identification of these patients based on their risk profile is essential. more...

Regulatory impact analyses (RIAs) weigh the benefits of regulations against the burdens they impose and are invaluable tools for informing decision makers. We offer 10 tips for nonspecialist policymakers and interested stakeholders who will be reading RIAs as consumers.1.Core problem: Determine whether the RIA identifies the core problem (compelling public need) the regulation is intended to address.2.Alternatives: Look for an objective, policy-neutral evaluation of the relative merits of reasonable alternatives.3.Baseline: Check whether the RIA presents a reasonable “counterfactual” against which benefits and costs are measured.4.Increments: Evaluate whether totals and averages obscure relevant distinctions and trade-offs.5.Uncertainty: Recognize that all estimates involve uncertainty, and ask what effect key assumptions, data, and models have on those estimates.6.Transparency: Look for transparency and objectivity of analytical inputs.7.Benefits: Examine how projected benefits relate to stated objectives.8.Costs: Understand what costs are included.9.Distribution: Consider how benefits and costs are distributed.10.Symmetrical treatment: Ensure that benefits and costs are presented symmetrically. more...

Es werden die Sicherheit und die Effektivitat der intensitatsmodulierten HDR-Brachytherapie (IMBT) mit einer deutlichen fokalen Dosiseskalation in der Therapie des Prostatakarzinoms prospektiv untersucht. Zwei unterschiedliche Patientengruppen wurden behandelt. Einmal die Primartherapiegruppe (n = 139) und die Rezidivtherapiegruppe (n = 11). Folgende Parameter wurden ausgewertet: Datum der Erstdiagnose, Gleason-Score, initialer PSA-Wert, PSA-Nadir, Prostatavolumen im transrektalen Ultraschall in ml, Prostatastanzbiopsie, Datum der Brachytherapie, antihormonelle Therapie, Chemotherapie, Uroflow-Untersuchung und Restharnbestimmung pra- und postoperativ, Anzahl der Nadeln im jeweiligen Prostatalappen, Auswertung der Nachsorgedaten. In unserer Studie zeigt sich in der Primargruppe ein PSA-Wert zum Nachsorgezeitpunkt im Bereich von 0–4 ng/ml bei 87,6 % sowie in der Rezidivgruppe bei 81,8 %. 55,8 % in der Primartherapiegruppe erreichten einen PSA-Nadir 5 ng/ml. In der Rezidivgruppe hatten 100 % einen PSA-Nadir more...

This chapter addresses the question of whether states can improve the accuracy of revenue forecasts by using more advanced time series and Bayesian vector autoregression (BVAR) forecasting methods. Using state revenue data from Virginia, we first estimate baseline forecasts using autoregression (AR) and vector autoregression (VAR). We present the theoretical case for estimating a BVAR model, and then we present and compare forecasts based on the AR, VAR, and BVAR. Although there are gains in forecast accuracy in using the BVAR, the BVAR is not a panacea for forecasting the extremely volatile corporate income tax revenue series. more...

The current consensus among biologists is that evolution does not have a direction. Here, Foy et al. compare recently-born gene families to genes that are chronologically “more evolved,” finding a striking directionality in the evolution... To detect a direction to evolution, without the pitfalls of reconstructing ancestral states, we need to compare “more evolved” to “less evolved” entities. But because all extant species have the same common ancestor, none are chronologically more evolved than any other. However, different gene families were born at different times, allowing us to compare young protein-coding genes to those that are older and hence have been evolving for longer. To be retained during evolution, a protein must not only have a function, but must also avoid toxic dysfunction such as protein aggregation. There is conflict between the two requirements: hydrophobic amino acids form the cores of protein folds, but also promote aggregation. Young genes avoid strongly hydrophobic amino acids, which is presumably the simplest solution to the aggregation problem. Here we show that young genes’ few hydrophobic residues are clustered near one another along the primary sequence, presumably to assist folding. The higher aggregation risk created by the higher hydrophobicity of older genes is counteracted by more subtle effects in the ordering of the amino acids, including a reduction in the clustering of hydrophobic residues until they eventually become more interspersed than if distributed randomly. This interspersion has previously been reported to be a general property of proteins, but here we find that it is restricted to old genes. Quantitatively, the index of dispersion delineates a gradual trend, i.e., a decrease in the clustering of hydrophobic amino acids over billions of years. more...

Venom has been associated with the ecological success of many groups of organisms, most notably reptiles, gastropods, and arachnids. In some cases, diversification has been directly linked to tailoring of venoms for dietary specialization. Spiders in particular are known for their diverse venoms and wide range of predatory behaviors, although there is much to learn about scales of variation in venom composition and function. The current study focuses on venom characteristics in different sexes within a species of spider. We chose the genusTetragnatha(Tetragnathidae) because of its unusual courtship behavior involving interlocking of the venom delivering chelicerae (i.e., the jaws), and several species in the genus are already known to have sexually dimorphic venoms. Here, we use transcriptome and proteome analyses to identify venom components that are dimorphic inTetragnatha versicolor. We present cDNA sequences including unique, male-specific high molecular weight proteins that have remote, if any, detectable similarity to known venom components in spiders or other venomous lineages and have no detectable homologs in existing databases. While the function of these proteins is not known, their presence in association with the cheliceral locking mechanism during mating together with the presence of prolonged male-male mating attempts in a related, cheliceral-locking species (Doryonychus raptor) lacking the dimorphism suggests potential for a role in sexual communication. more...

SummaryIntroduction: The endovenous thermal ablation of the great saphenous vein due to varicosis changes the blood circulation in the groin. This could affect the venous drainage of the penis, especially the drainage of the corpus spongiosum over the external pudendal vein. There are a few cases in our clinic until now which had an enhanced swelling of the glans penis beside an erection.Objective: Is the enhancement of penile swelling caused by the targeted thermal ablation of the GSV without affecting the saphenofemoral tributaries in the groin?Material and Methods: To verify this enhanced swelling of the glans penis and change in the erectile function we want to ask 56 patients with a modified IIEF questionnaire.The IIEF is a validated questionnaire with a additional question for the swelling of the glans. We check the reliability of the additional question with 16 healthy males.Possible results: Hypothesis 1 (H+): There is an improvement of the erectile function. Hypothesis 2 (H-): There is a decrease of the erectile function. Hypothesis 3 (H0): There is no change of the erectile function. Schedule: 1.Preliminary assessment: Sept. 2014: ethical approval, Reliability of the additional question. 2. Main assessment: Oct. 2014 to May 2016. 3. Analysis of the data: May 2016 to Aug. 2016 4. Report of data: August 2016. more...

Venoms of the sicariid spiders contain phospholipase D enzyme toxins that can cause severe dermonecrosis and even death in humans. These enzymes convert sphingolipid and lysolipid substrates to cyclic phosphates by activating a hydroxyl nucleophile present in both classes of lipid. The most medically relevant substrates are thought to be sphingomyelin and/or lysophosphatidylcholine. To better understand the substrate preference of these toxins, we used (31)P NMR to compare the activity of three related but phylogenetically diverse sicariid toxins against a diverse panel of sphingolipid and lysolipid substrates. Two of the three showed significantly faster turnover of sphingolipids over lysolipids, and all three showed a strong preference for positively charged (choline and/or ethanolamine) over neutral (glycerol and serine) headgroups. Strikingly, however, the enzymes vary widely in their preference for choline, the headgroup of both sphingomyelin and lysophosphatidylcholine, versus ethanolamine. An enzyme from Sicarius terrosus showed a strong preference for ethanolamine over choline, whereas two paralogous enzymes from Loxosceles arizonica either preferred choline or showed no significant preference. Intrigued by the novel substrate preference of the Sicarius enzyme, we solved its crystal structure at 2.1 Å resolution. The evolution of variable substrate specificity may help explain the reduced dermonecrotic potential of some natural toxin variants, because mammalian sphingolipids use primarily choline as a positively charged headgroup; it may also be relevant for sicariid predatory behavior, because ethanolamine-containing sphingolipids are common in insect prey. more...

Background Umbilical hernia is a common congenital anomaly, and can result in the appearance of a protuberant umbilicus. In select cases, inversion of the umbilical skin can be impaired by the presence of thickened dermis or fascial remnants of the umbilical stalk. Description of operative technique After umbilical herniorrhaphy, the skin is everted over the left index finger and radial partial thickness incisions in the fascia and dermis of the undersurface of the umbilicus. The umbilical skin is then inverted and secured to the fascia. Conclusion This operative technique can allow complete inversion of the umbilical skin creating an aesthetically appealing umbilical hernia repair. more...

Preview Inaccurate results on HIV tests are rare, but they do occur. Therefore, it is important that primary care physicians understand the laboratory techniques involved. Which assays are used for detection of the virus? How are results of such tests interpreted? What factors cause false-positive and falsenegative results? Drs Cordes and Ryan answer these questions and clarify the uncertainty surrounding HIV testing. more...

Venom has been associated with the ecological success of many groups of organisms, most notably reptiles, gastropods, and arachnids. In some cases, diversification has been directly linked to tailoring of venoms for dietary specialization. Spiders in particular are known for their diverse venoms and wide range of predatory behaviors, although there is much to learn about scales of variation in venom composition and function. The current study focuses on venom characteristics in different sexes within a species of spider. We chose the genus Tetragnatha (Tetragnathidae) because of its unusual courtship behavior involving interlocking of the venom delivering chelicerae (i.e., the jaws), and several species in the genus are already known to have sexually dimorphic venoms. Here, we use transcriptome and proteome analyses to identify venom components that are dimorphic in Tetragnatha versicolor. We present cDNA sequences of unique high molecular weight proteins that are only present in males and that have remote, if any, detectable similarity to known venom components in spiders or other venomous lineages and several have no detectable homologs in existing databases. While the function of these proteins is not known, their presence in association with the cheliceral locking mechanism during mating together with the presence of prolonged male-male mating attempts in a related, cheliceral-locking species (Doryonychus raptor) lacking the dimorphism suggests potential for a role in sexual communication. more...

To detect a direction to evolution, without the pitfalls of reconstructing ancestral states, we need to compare “more evolved” to “less evolved” entities. But because all extant species have the same common ancestor, none are chronologically more evolved than any other. However, different gene families were born at different times, allowing us to compare young protein-coding genes to those that are older and hence have been evolving for longer. To be retained during evolution, a protein must not only have a function, but must also avoid toxic dysfunction such as protein aggregation. There is conflict between the two requirements; hydrophobic amino acids form the cores of protein folds, but also promote aggregation. Young genes avoid strongly hydrophobic amino acids, which is presumably the simplest solution to the aggregation problem. Here we show that young genes’ few hydrophobic residues are clustered near one another along the primary sequence, presumably to assist folding. The higher aggregation risk created by the higher hydrophobicity of older genes is counteracted by more subtle effects in the ordering of the amino acids, including a reduction in the clustering of hydrophobic residues until they eventually become more interspersed than if distributed randomly. This interspersion has previously been reported to be a general property of proteins, but here we find that it is restricted to old genes. Quantitatively, the index of dispersion delineates a gradual trend, i.e. a decrease in the clustering of hydrophobic amino acids over billions of years. more...

Insertions and deletions in protein sequences, or indels, can disrupt structure and may result in changes in protein folds during evolution or in association with alternative splicing. Pfl 6 and Xfaso 1 are two proteins in the Cro family that share a common ancestor but have different folds. Sequence alignments of the two proteins show two gaps, one at the N terminus, where the sequence of Xfaso 1 is two residues shorter, and one near the center of the sequence, where the sequence of Pfl 6 is five residues shorter. To test the potential importance of indels in Cro protein evolution, we generated hybrid variants of Pfl 6 and Xfaso 1 with indels in one or both regions, chosen according to several plausible sequence alignments. All but one deletion variant completely unfolded both proteins, showing that a longer N-terminal sequence was critical for Pfl 6 folding and a longer central region sequence was critical for Xfaso 1 folding. By contrast, Xfaso 1 tolerated a longer N-terminal sequence with very little destabilization, and Pfl 6 tolerated central region insertions, albeit with substantial effects on thermal stability and some perturbation of the surrounding structure. None of the mutations appeared to convert one stable fold into the other. Based on this two-protein comparison, short insertion and deletion mutations probably played a role in evolutionary fold change in the Cro family, but were also not the only factors. more...

Arc repressor is a homodimeric protein with a ribbon-helix-helix fold. A single polar-to- hydrophobic substitution (N11L) at a solvent-exposed position leads to population of an alternate dimeric fold in which 310 helices replace a b-sheet. Here we find that the variant Q9V/N11L/R13V (S-VLV), with two additional polar-to-hydrophobic surface mutations in the same b-sheet, forms a highly stable, reversibly folded octamer with approximately half thea-helical content of wild-type Arc. At low protein concentration and low ionic strength, S-VLV also populates both dimeric topologies previously observed for N11L, as judged by NMR chemical shift comparisons. Thus, accumulation of simple hydrophobic mutations in Arc progressively reduces fold specificity, leading first to a sequence with two folds and then to a manifold bridge sequence with at least three different topologies. Residues 9-14 of S-VLV form a highly hydrophobic stretch that is predicted to be amyloidogenic, but we do not observe aggregates of higher order than octamer. Increases in sequence hydrophobicity can promote amyloid aggregation but also exert broader and more complex effects on fold specificity. Altered native folds, changes in fold coupled to oligomerization, toxic pre-amyloid oligomers, and amyloid fibrils may represent a near continuum of accessible alternatives in protein structure space. more...

We prospectively examined the effect and the safety of intensity-modulated HDR brachytherapy (IMBT) with focal dose escalation.A total of 139 patients undergoing primary therapy for prostate cancer and 11 patients with recurrence were included. Data analysis focused on the following factors: date of primary diagnosis, Gleason score, initial prostate-specific antigen (PSA) value, PSA nadir, volume of the prostate in the transrectal ultrasound, biopsy of the prostate gland, androgen deprivation, chemotherapy, uroflowmetry, pre- and postoperative post-void residual urine (PVR), number of the needles in the prostate lobes and analysis of follow-up data.In the primary therapy group, 87.6 % of the patients had a PSA of 0-4 ng/ml at the time of follow-up, while in the recurrence group 81.8 % of patients were within this range. Overall, 55.8 % of patients in the primary group had a PSA nadir under 0.1 ng/ml, 37.2 % under 1 ng/ml, 5.8 % under 5 ng/ml and 1.2 % (1 patient) over 5 ng/ml. In the recurrence group, 100 % had a PSA nadir under 0.1 ng/dl. Fifty patients of the primary group reported grade 1 toxicity (Common Toxicity Criteria): 29 localized to the bladder and 21 to the rectum. Seventeen patients had grade 2 toxicity of the bladder and 1 patient had grade 3 toxicity of the bladder. Finally there was one grade 4 toxicity due to perforation of the sigmoid colon. In the recurrence group, 3 patients with grade 1 toxicity were observed (2 bladder and 1 bowl). Also 3 patients had grade 2 toxicity of the bladder, 1 patient had a grade 3 bladder toxicity and 1 patient had grade 4 toxicity due to bowl fistula. There were no grade 5 toxicities.The modifications of the "Kiel method" with focal dose escalation was proven as effective in locally advanced prostate carcinoma and in local recurrences of the disease with low level toxicity. more...

The need for deficit reduction has prompted several proposals for modifying the income tax deduction for charitable contributions. This paper combines aggregate tax return data with data on finances of individual nonprofit organizations and data on patterns of household giving to simulate the potential effects on nonprofit organizations of scaling back the charitable deduction. The paper also reviews the various rationales for providing a tax subsidy to charitable contributions. more...

Regions of amino-acid sequence that are compatible with multiple folds may facilitate evolutionary transitions in protein structure. In a previous study, we described a heuristically designed chameleon sequence (SASF1, structurally ambivalent sequence fragment 1) that could adopt either of two naturally occurring conformations (α-helical or β-sheet) when incorporated as part of the C-terminal dimerization subdomain of two structurally divergent transcription factors, P22 Cro and λ Cro. Here we describe longer chameleon designs (SASF2 and SASF3) that in the case of SASF3 correspond to the full C-terminal half of the ordered region of a P22 Cro/λ Cro sequence alignment (residues 34-57). P22-SASF2 and λ(WDD)-SASF2 show moderate thermal stability in denaturation curves monitored by circular dichroism (T(m) values of 46 and 55°C, respectively), while P22-SASF3 and λ(WDD)-SASF3 have somewhat reduced stability (T(m) values of 33 and 49°C, respectively). (13)C and (1)H NMR secondary chemical shift analysis confirms two C-terminal α-helices for P22-SASF2 (residues 36-45 and 54-57) and two C-terminal β-strands for λ(WDD)-SASF2 (residues 40-45 and 50-52), corresponding to secondary structure locations in the two parent sequences. Backbone relaxation data show that both chameleon sequences have a relatively well-ordered structure. Comparisons of (15)N-(1)H correlation spectra for SASF2 and SASF3-containing proteins strongly suggest that SASF3 retains the chameleonism of SASF2. Both Cro C-terminal conformations can be encoded in a single sequence, showing the plausibility of linking different Cro folds by smooth evolutionary transitions. The N-terminal subdomain, though largely conserved in structure, also exerts an important contextual influence on the structure of the C-terminal region. more...