bluuebunny/crossref_metadata_2025_split huggingface dataset:
Synergy between sacubitril and valsartan leads to hemodynamic, antifibrotic, and exercise tolerance benefits in rats with preexisting heart failure
Authors: Maslov Mikhail Y. , Foianini Stephan , Mayer Dita , Orlov Michael V. , Lovich Mark A. 
Published: November 2018

Simultaneous neprilysin inhibition (NEPi) and angiotensin receptor blockade (ARB) with sacubitril/valsartan improves cardiac function and exercise tolerance in patients with heart failure. However, it is not known whether these therapeutic benefits are primarily due to NEPi with sacubitril or ARB with valsartan or their combination. Therefore, the aim of the present study was to investigate the potential contribution of sacubitril and valsartan to the benefits of the combination therapy on left ventricular (LV) function and exercise tolerance. Heart failure was induced by volume overload via partial disruption of the aortic valve in rats. Therapy began 4 wk after valve disruption and lasted through 8 wk. Drugs were administered daily via oral gavage [sacubitril/valsartan (68 mg/kg), valsartan (31 mg/kg), and sacubitril (31 mg/kg)]. Hemodynamic assessments were conducted using Millar technology, and an exercise tolerance test was conducted using a rodent treadmill. Therapy with sacubitril/valsartan improved load-dependent indexes of LV contractility (dP/d tmax) and relaxation (dP/d tmin), exercise tolerance, and mitigated myocardial fibrosis, whereas monotherapies with valsartan, or sacubitril did not. Both sacubitril/valsartan and valsartan similarly improved a load-independent index of contractility [slope of the end-systolic pressure-volume relationship ( Ees)]. Sacubitril did not improve Ees. First, synergy of NEPi with sacubitril and ARB with valsartan leads to the improvement of load-dependent LV contractility and relaxation, exercise tolerance, and reduction of myocardial collagen content. Second, the improvement in load-independent LV contractility with sacubitril/valsartan appears to be solely due to ARB with valsartan constituent. NEW & NOTEWORTHY Our data suggest the following explanation for the effects of sacubitril/valsartan: 1) synergy of sacubitril and valsartan leads to the improvement of load-dependent left ventricular contractility and relaxation, exercise tolerance, and reduction of myocardial fibrosis and 2) improvement in load-independent left ventricular contractility is solely due to the valsartan constituent. The findings offer a better understanding of the outcomes observed in clinical studies and might facilitate the continuing development of the next generations of angiotensin receptor neprilysin inhibitors.
Neuromuscular junction abnormalities in a zebrafish loss-of-function model of TDP-43
Authors: Bose Poulomee , Armstrong Gary A. B. , Drapeau Pierre 
Published: November 2018

Almost 90% of amyotrophic lateral sclerosis (ALS) cases are characterized by the presence of aggregates of insoluble, misfolded cytoplasmic TAR DNA binding protein of 43 kDa (TDP-43). Distal axonopathy with impaired neuromuscular junctions (NMJs) before motor neuron degeneration or clinical onset of symptoms has been hypothesized as an early pathology in ALS. However, synaptic defects at the NMJ caused by TDP-43 mutations have not been characterized. In this study, we examined a previously reported zebrafish line expressing the tardbpY220X/Y220Xvariant, which results in an unstable and degraded protein. These tardbp−/−larvae, however, mature normally due to the upregulated expression of an alternative splice variant of the tardbp paralog tardbp-like, or tardbpl. We generated a mutant line with a CRISPR/Cas9-mediated 5-base pair deletion encompassing the ATG start codon of tardbpl and in-crossed these with tardbp−/−mutants to obtain tardbp−/−and tardbpl−/−double mutants, herein referred to as hom/hom. We subsequently characterized morphological, coiling, locomotor, synaptic, and NMJ structural abnormalities in the hom/hom mutants and in their genotypic controls. We observed that hom/hom mutants displayed gross morphological defects, early lethality, reduced locomotor function, aberrant quantal transmission, and perturbed synapse architecture at the NMJ. We further employed pharmacological manipulations in an effort to rescue phenotypic defects and observed that tardbp+/−; tardbpl−/−(herein referred to as het/hom) mutants, but not hom/hom mutants, were sensitive to chronic treatments of BAY K 8644, an L-type calcium channel agonist. This result highlights the importance of partial vs. complete loss of allelic functions of TDP-43.NEW & NOTEWORTHY This study highlights the importance of partial vs. complete loss of allelic functions of TDP-43 in a zebrafish loss of function model, thus making it an attractive tool for drug screening approaches.
Temporal and spatial asymmetries during stationary cycling cause different feedforward and feedback modifications in the muscular control of the lower limbs
Authors: Zych Magdalena , Rankin Ian , Holland Donal , Severini Giacomo 
Published: November 2018

Motor adaptations are useful for studying the way in which the lower limbs are controlled by the brain. However, motor adaptation paradigms for the lower limbs are typically based on locomotion tasks, where the necessity of maintaining postural stability is the main driver of adaptation and could possibly mask other underlying processes. In this study we investigated whether small temporal or spatial asymmetries can trigger motor adaptations during stationary cycling, where stability is not directly compromised. Fourteen healthy individuals participated in two experiments: in one of the experiments, the angle between the crank arms of the pedals was altered by 10° to induce a temporal asymmetry; in the other experiment, the length of the right pedal was shortened by 2.4 cm to induce a spatial asymmetry. We recorded the acceleration of the crank arms and the electromographic signals of 16 muscles (8 per leg). The analysis of the accelerometer data was used to investigate the presence of motor adaptations. Muscle synergy analysis was performed on each side to quantify changes in neuromuscular control. We found that motor adaptations are present in response to temporal asymmetries and are obtained by progressively shifting the activation patterns of two synergies on the right leg. Spatial asymmetries, on the other hand, appear to trigger a feedback-driven response that does not present an aftereffect. This response is characterized by a steplike decrease in activity in the right gastrocnemius when the asymmetry is present and likely reflects the altered task demands. NEW & NOTEWORTHY The processes driving lower limb motor adaptations are not fully clear, and previous research appears to indicate that adaptations are mainly driven by stability. We show that lower limb adaptations can be obtained also in the absence of an explicit balance threat. We also show that adaptations are present when kinematic error cannot be compensated for, suggesting the presence of intrinsic error measures regulating the timing of activation of the two legs.
100 Years of Progress in Understanding the General Circulation of the Atmosphere
Authors: Held Isaac M. 
Published: November 2018

Abstract
Some of the advances of the past century in our understanding of the general circulation of the atmosphere are described, starting with a brief summary of some of the key developments from the first half of the twentieth century, but with a primary focus on the period beginning with the midcentury breakthrough in baroclinic instability and quasigeostrophic dynamics. In addition to baroclinic instability, topics touched upon include the following: stationary wave theory, the role played by the two-layer model, scaling arguments for the eddy heat flux, the subtlety of large-scale eddy momentum fluxes, the Eliassen–Palm flux and the transformed Eulerian mean formulation, the structure of storm tracks, and the controls on the Hadley cell.
A Canadian Academic Hospital’s Initial MAID Experience: A Health-Care Systems Review
Authors: Ball Ian M. , Hodge Brent , Jansen Sandy , Nickle Susan , Sibbald Robert W. 
Published: November 2018

Background: Following the Supreme Court of Canada’s Carter Decision, medical assistance in dying (MAID) became possible with individual court orders in February 2016. Subsequently, on June 17, 2016, legislation was passed that eliminated the need for court orders, essentially making physicians the arbiters of these requests. Canadian health-care facilities now face the challenge of addressing this unprecedented patient health-care need. Aim: To describe the manner in which London Health Sciences Center has approached local and regional requests for MAID, including the administration, ethics, privacy, and clinical process. Design: A health-care systems descriptive study. Setting/Participants: Between June 6, 2016, and May 30, 2018, London Health Sciences Center’s MAID Internal Resource Committee triaged and referred 260 cases. Ninety-six received the requisite assessments were deemed eligible for and received MAID. Results: The procedure was completed in hospital 59 (61%) times, and 37 (39%) times in the community (either private residence or long-Term Care facility). Nineteen patients did not meet MAID criteria and 63 patients died while awaiting the procedure. The median wait time between first request and referral was 1 day. The median time between referral and the procedure was 12.0 days. The ratio of referrals to completed cases is 96 of 260 (or 37% conversion rate). Conclusion: Our MAID processes, including our committee structure, referral triage process, and physical site have all undergone extensive review and improvement cycles throughout these first 2 years with the aim of ensuring that this procedure is managed in a respectful, confidential, safe, efficient, and patient-centered manner.
Clinical Use and Efficacy of Levetiracetam for Absence Epilepsies
Authors: Nolan Danielle , Lester Shannon G. , Rau Stephanie M. , Shellhaas Reneé A. 
Published: November 2018

Background: Levetiracetam is prescribed for a broad spectrum of seizure types but does not have a specific indication for absence epilepsy. We hypothesized that levetiracetam is commonly prescribed for children with absence epilepsies and evaluated the efficacy of this medication for absence epilepsy treatment in clinical practice. We also hypothesized that electroencephalographic (EEG) findings could help predict levetiracetam efficacy. Methods: We reviewed the charts of all patients treated for new-onset absence epilepsies at our pediatric neurology clinic between January 2011 and January 2016. Among 158 children diagnosed with absence epilepsies, 72 were treated with levetiracetam. Results: Levetiracetam was discontinued in 74% (n = 53/72) because of incomplete seizure control (59%, n = 35/72) and/or intolerable side effects (41%, n = 24/72) after a median 8.5 months (interquartile range 2, 17 months). Among patients for whom levetiracetam was effective, 44% (n = 8/18) had polyspikes on their initial EEG, versus 27% (n = 14/52) of patients for whom levetiracetam was discontinued ( P = .17). The maximal prescribed dose was lower for children in whom levetiracetam was effective (29 ± 13 mg/kg/d) than those for whom levetiracetam failed (42 ± 20 mg/kg/d; P = .005). Conclusion: In routine clinical practice, levetiracetam is often chosen for patients with absence seizures. However, only about one-quarter of children with absence epilepsy in this study became seizure free with levetiracetam. When effective, levetiracetam can control absence epilepsy at a relatively low dose. Lack of seizure control requiring continued dose escalation should prompt early consideration of a therapeutic medication transition.
The Spaces of Nostalgia(s) and the Politics of Belonging in Contemporary Chernivtsi, Western Ukraine
Authors: Koziura Karolina 
Published: November 2018

This article is part of the special cluster titled Bukovina and Bukovinians after the Second World War: (Re)shaping and (re)thinking a region after genocide and ‘ethnic unmixing’, guest edited by Gaëlle Fisher and Maren Röger. This article explores ways in which Habsburg nostalgia has become an important factor in contemporary place-making strategies in the city of Chernivtsi, Western Ukraine. Through the analysis of diasporic homecomings, city center revitalization, and nationalist rhetoric surrounding the politics of monuments, I explore hybrid and diverse ways in which Habsburg nostalgia operates in a given setting. Rather than a static and homogenous form of place attachment, in Chernivtsi different cultural practices associated with Habsburg nostalgia coexist with each other and depending on the political context as well as the social position of the “nostalgic agents” manifest themselves differently. Drawing from my long-term ethnographic fieldwork, I argue that in order to fully understand individuals’ attachment to space, it is necessary to grasp both the subtle emotional ways in which the city is experienced by individuals as well as problematize the role of the built environment in the visualization of collective memory and emotions of particular groups. The focus on changing manifestations of the Habsburg nostalgia can bring then a better understanding of the range and scope of the city’s symbolic resources that might be mobilized for various purposes.
Bukovina: A Borderland Region in (Trans-)national Historiographies after 1945 and 1989–1991
Authors: Fisher Gaëlle , Röger Maren 
Published: November 2018

This article is part of the special cluster titled Bukovina and Bukovinians after the Second World War: (Re)shaping and (re)thinking a region after genocide and ‘ethnic unmixing’, guest edited by Gaëlle Fisher and Maren Röger. This introductory essay provides an overview of the historiography of the borderland region of Bukovina after 1945 and 1989–1991. Presenting the approaches adopted in different national contexts after the end of the Second World War, it points to the methodological nationalism which characterized research on the region during the Cold War. We show that while the historiography of Bukovina on the ground, in Romania and the Soviet Union, refracted wider national ideologies, abroad, particularly in West Germany and Israel, it remained for a long time the prerogative of small groups of “Bukovinians,” who saw it as their “lost home.” We explore both the similarities and differences between these narratives and stakeholders as well as the changes that took place after 1989–1991, especially in Romania and Ukraine. We show that while divided, the actors behind the narratives and thereby the narratives themselves have been connected in complex ways over the decades and particularly since the collapse of communism. Indeed, while for a long time the study of Bukovina resisted transnationalism, it nevertheless constituted and constitutes an ultimately transnational research object. Today, Bukovina remains a space of contest but it is also a space of opportunity, not least for researchers interested in the contested histories of borderland regions. This essay therefore contextualizes the themes and issues addressed in the following cluster of articles and identifies avenues for future research in this field.
A scientist engineer’s contribution to therapeutic discovery and development
Authors: Wilson Jennifer L 
Published: November 2018

An engineering perspective views cells as complex circuits that process inputs – drugs, environmental cues – to create complex outcomes – disease, growth, death – and this perspective has immense potential for drug development. Logical rules can describe the features of cells and reductionist approaches have exploited these rules for drug development. In contrast, the reductionist approach serially characterizes cellular components and develops a deep understanding of each component’s specific role. This approach underutilizes the full system of biomolecules relevant to disease pathology and drug effects. An engineering perspective provides the tools to understand and leverage the full extent of biological systems; applying both reverse and forward engineering, a strength of the engineering approach has demonstrated progress in advancing understanding of disease and drug mechanisms. Drug development lacks sufficient engineering specifications, or empirical models, of drug pharmacodynamic effects and future efforts to derive empirical models of drug effects will streamline this development. At this stage of progress, the scientist engineer is uniquely poised to solve problems in therapeutics related to modulating multiple diseases with a single or multiple therapeutic agents and identifying pharmacodynamics biomarkers with knowledge of drug pathways. This article underscores the value of these principles in an age where drug development costs are soaring and finding efficacious therapies is challenging. Impact statement Many untreated diseases are not monogenic and are instead caused by multiple genetic defects. Because of this complexity, computational, logical, and systems understanding will be essential to discovering novel therapies. The scientist engineer is uniquely disposed to use this type of understanding to advance therapeutic discovery. This work highlights benefits of the scientist engineer perspective and underscores the potential impact of these approaches for future therapeutic development. By framing the scientist engineer’s tool set and increasing awareness about this approach, this article stands to impact future therapeutic development efforts in an age of rising development costs and high drug attrition.
Efficacy of a Virtual Arthroscopic Simulator for Orthopaedic Surgery Residents by Year in Training
Authors: Yari Shahram S. , Jandhyala Chanakya K. , Sharareh Behnam , Athiviraham Aravind , Shybut Theodore B. 
Published: November 2018

Background: Virtual reality arthroscopic simulators are an attractive option for resident training and are increasingly used across training programs. However, no study has analyzed the utility of simulators for trainees based on their level of training/postgraduate year (PGY). Purpose/Hypothesis: The primary aim of this study was to determine the utility of the ArthroS arthroscopic simulator for orthopaedic trainees based on their level of training. We hypothesized that residents at all levels would show similar improvements in performance after completion of the training modules. Study Design: Descriptive laboratory study. Methods: Eighteen orthopaedic surgery residents performed diagnostic knee and shoulder tasks on the ArthroS simulator. Participants completed a series of training modules and then repeated the diagnostic tasks. Correlation coefficients ( r2) were calculated for improvements in the mean composite score (based on the Imperial Global Arthroscopy Rating Scale [IGARS]) as a function of PGY. Results: The mean improvement in the composite score for participants as a whole was 11.2 ± 10.0 points ( P = .0003) for the knee simulator and 14.9 ± 10.9 points ( P = .0352) for the shoulder simulator. When broken down by PGY, all groups showed improvement, with greater improvements seen for junior-level residents in the knee simulator and greater improvements seen for senior-level residents in the shoulder simulator. Analysis of variance for the score improvement variable among the different PGY groups yielded an f value of 1.640 ( P = .2258) for the knee simulator data and an f value of 0.2292 ( P = .917) for the shoulder simulator data. The correlation coefficient ( r2) was –0.866 for the knee score improvement and 0.887 for the shoulder score improvement. Conclusion: Residents training on a virtual arthroscopic simulator made significant improvements in both knee and shoulder arthroscopic surgery skills. Clinical Relevance: The current study adds to mounting evidence supporting virtual arthroscopic simulator–based training for orthopaedic residents. Most significantly, this study also provides a baseline for evidence-based targeted use of arthroscopic simulators based on resident training level.
Nudge to better care - blood cultures and catheter-related bloodstream infections in Germany at two points in time (2006, 2015)
Authors: Salm Florian , Schwab Frank , Behnke Michael , Brunkhorst Frank M. , Scherag André , Geffers Christine , Gastmeier Petra 
Published: November 2018

Abstract
Background
Blood cultures (BCs) are the gold standard for diagnosing sepsis and are prerequisite for a targeted antibiotic treatment and essential for patient outcomes. Aim of the study was to analyze the frequency of BCs, the rate of central line-associated bloodstream infections (CLABSIs) and to study the association between both parameters on intensive care units in Germany over time.

Methods
Cross-sectional studies at two points in time (2006, 2015) on ICUs participating in the German hospital infection surveillance system. CLABSIs were defined according to the Center for Disease Control and Prevention (CDC). Univariable and multivariable analyses were performed using generalized linear models.

Results
A total of 639 ICUs participated in 2006 or 2015 and 90 ICUs (“core group”) in both years. Overall, 2,427,921 patient days from 644,575 patients were analyzed. In the ICU core group the frequency of BCs per 1000 patient days doubled from 57.8 (interquartile range [IQR] 29.8–101.2; 2006) to 128.2 (IQR 71.6–183.2; 2015). In the same time, the pooled median CLABSI rate decreased from 0.8 (IQR 0–1.9; 2006) per 1000 central-line catheter days to 0.2 (IQR 0–0.9; 2015).

Conclusions
From 2006 to 2015 the frequency of BCs increased on ICUs in Germany and is now within the recommended 100 to 200 BCs sets per 1000 patient days.
Postmortem Findings in a Young Man With Congenital Generalized Lipodystrophy, Type 4 Due to CAVIN1 Mutations
Authors: Patni Nivedita , Vuitch Frank , Garg Abhimanyu 
Published: November 2018

Abstract

Context
Congenital generalized lipodystrophy, type 4 (CGL4) is a rare autosomal recessive disorder caused by mutations in caveolae-associated protein 1. Patients with CGL4 also have myopathy and cardiomyopathy with a predisposition for sudden death due to ventricular arrhythmias. However, the underlying pathology for these morbidities remains unknown. Therefore, we report on an autopsy of a Hispanic boy with CGL4.

Case Description
Our patient had early-onset generalized lipodystrophy, feeding difficulties, myopathy, atlanto-axial dislocation, and learning disabilities. He was diagnosed with catecholaminergic polymorphic ventricular tachycardia (CPVT) at age 8 years, had poor compliance with medications, and died suddenly at age 15.3 years. Autopsy showed marked loss of subcutaneous and omental fat with no inflammatory cells in adipose tissue and normal adipocytes in the parathyroid glands. There were adipocytes interdigitating cardiac muscle fibers, with fibro-fatty infiltration in the right ventricle, near coronary sinus, and atrioventricular node. There was no evidence of coronary heart disease. The quadriceps femoris muscle did not show adipocyte infiltration, inflammation, or fibrosis. The muscularis mucosa layer was thickened in the esophagus and at the gastro-duodenal junction, and the esophagus had prominent, large nerves in the subserosa. The liver weighed 3000 g, with minimal chronic inflammation and steatosis in 40% of parenchyma, primarily in zones 2 and 3. There was no spermatogenesis in the spermatic tubules.

Conclusions
Our data suggest that fibro-fatty infiltration of the right ventricle may contribute to CPVT in patients with CGL4. Thick muscularis mucosa and large nerves in the esophagus likely contributed to dysphagia and dysmotility. A lack of spermatids suggests infertility in affected male patients.