bluuebunny/crossref_metadata_2025 huggingface dataset:
Androgens drive microvascular endothelial dysfunction in women with polycystic ovary syndrome: role of the endothelin B receptor
Authors: Usselman Charlotte W. , Yarovinsky Timur O. , Steele Frances E. , Leone Cheryl A. , Taylor Hugh S. , Bender Jeffrey R. , Stachenfeld Nina S.
Published: March 2019

Key points

Polycystic ovary syndrome (PCOS) is a complex syndrome with cardiovascular risk factors, including obesity and insulin resistance.

PCOS is also associated with high androgens, increases the risk of cardiovascular dysfunction in women. Due to the complexity of PCOS, had it has been challenging to isolate specific causes of the cardiovascular dysfunction.

Our measure of cardiovascular dysfunction (endothelial dysfunction) was most profound in lean women with PCOS.

The endothelin‐1‐induced vasodilation in these PCOS subject, was dependent on the ETBR but was not NO‐dependent.

We also demonstrated oestrogen administration improved endothelial function in lean and obese women with PCOS likely because oestrogen increased NO availability.

Our studies indicate a primary role for androgens in cardiovascular dysfunction in PCOS.

Endothelin‐1 (ET‐1) is an indicator of endothelial injury and dysfunction and is elevated in women with androgen excess polycystic ovary syndrome (AE‐PCOS). The endothelin B receptor (ETBR) subtype mediates vasodilatation, but is blunted in women with PCOS. We hypothesized that androgen drives endothelial dysfunction in AE‐PCOS women and oestradiol (EE) administration reverses these effects. We assessed microvascular endothelial function in women with (7 lean and 7 obese) and without AE‐PCOS (controls, 6 lean, 7 obese). Only obese AE‐PCOS women were insulin resistant (IR). We evaluated cutaneous vascular conductance (%CVCmax) with laser Doppler flowmetry during low dose intradermal microdialysis ET‐1 perfusions (1, 3, 4, 5 and 7 pmol) with either lactated Ringer solution alone, or with ETBR (BQ‐788), or nitric oxide (NO) inhibition (l‐NAME). Log[ET‐1]–%maxCVC dose–response curves demonstrated reduced vasodilatory responses to ET‐1 in lean AE‐PCOS (logED50, 0.59 ± 0.08) versus lean controls (logED50, 0.49 ± 0.09, P < 0.05), but not compared to obese AE‐PCOS (logED50, 0.65 ± 0.09). ETBR inhibition decreased ET‐1‐induced vasodilatation in AE‐PCOS women (logED50, 0.64 ± 0. 22, P < 0.05). This was mechanistically observed at the cellular level, with ET‐1‐induced, DAF‐FM‐measurable endothelial cell NO production, which was abrogated by dihydrotestosterone in an androgen receptor‐dependent manner. EE augmented the cutaneous vasodilating response to ET‐1(logED50 0.29 ± 0.21, 0.47 ± 0.09, P < 0.05 for lean and obese, respectively). Androgens drive endothelial dysfunction in lean and obese AE‐PCOS. We propose that the attenuated ET‐1‐induced vasodilatation in AE‐PCOS is a consequence of androgen receptor‐mediated, suppressed ETBR‐stimulated NO production, and is reversed with EE.
Understanding the Effects of a Discrete Element Soil Model's Parameters on Ground Vehicle Mobility
Authors: Wasfy Tamer M. , Mechergui Dave , Jayakumar Paramsothy
Published: March 2019

The Army's mission is to develop, integrate, and sustain the right technology solution for all manned and unmanned ground vehicles, and mobility is a key requirement for all ground vehicles. Mobility focuses on ground vehicles' capabilities that enable them to be deployable worldwide, operationally mobile in all environments, and protected from symmetrical and asymmetrical threats. In order for military ground vehicles to operate in any combat zone, mobility on off-road terrains should be extensively investigated. Mobility on off-road terrains is poorly understood because of the empirical and semi-empirical height-field based methods which are often used for predicting vehicle mobility, such as Bekker–Wong type models. Those methods do not capture the three-dimensional soil deformation/flow as well as the soil's nonlinear behavior. The discrete element method (DEM) in which soil is modeled using discrete particles was identified as a high-fidelity method that can capture the deformation of the soil and its nonlinear behavior. In this paper, a simulation study is undertaken to understand the influence of DEM soil model parameters on vehicle mobility. A typical wheeled vehicle model was built in ivress/dis software and simulated over different cohesive and noncohesive soils modeled using DEM, with a particular emphasis on weak soils (with both low friction angle and low cohesion). Some characteristics of these soils were varied, namely, the interparticle cohesion, the interparticle friction, the particle size, and the particle mass. The mobility measures, including vehicle speed, wheel sinkage, wheel slip, and tractive force were evaluated using the model and correlated to the DEM soil model parameters. This study shows that the vehicle speed increases with cohesion, friction, soil density, and particle size while wheel sinkage, wheel slip, and tractive force decrease with those parameters. The combined influence of those parameters is more complex. Extensive studies of those and other soil parameters need to be carried out in the future to understand their effect on vehicle mobility.
A Mechanical Model Based on Conformal Strain Energy and Its Application to Bending and Buckling of Nanobeam Structures
Authors: Rahimi Zaher , Sumelka Wojciech , Baleanu Dumitru
Published: March 2019

In the present work, a nonlocal model based on the conformal strain energy, utilizing the conformable derivative definition, has been obtained. The model has two additional free parameters compared to the classical (local) mechanical formulations. The first one specifies the amount of the integer and the noninteger gradient of strain in the strain energy relation, and the second one controls the order of the strain derivatives in the conformable energy relation. The obtained governing (nonlinear) equation has been solved by the Galerkin method and the effects of both free parameters have been shown. As a case study, the bending and buckling of nanobeam structures has been studied.
Numerical Algorithms for Simulation of One-Dimensional Mechanical Systems With Clearance-Type Nonlinearities
Authors: Wramner Lina
Published: March 2019

In many mechanical systems there are nonlinearities of clearance type. This type of nonlinearity often causes problems with convergence and accuracy in simulations, due to the discontinuities at impact. For systems with gap-activated springs connected to ground, it has been proposed in previous work to reformulate the problem as a linear complementary problem (LCP), which can be solved in a very efficient way. In this paper, a generalization of the LCP approach is proposed for systems with gap-activated springs connecting different bodies. The generalizations enable the LCP approach to be used for an arbitrary number of gap-activated springs connecting either different bodies or connecting bodies to ground. The springs can be activated in either compression or expansion or both and a gear ratio can be included between the bodies. The efficiency of the algorithm is demonstrated with an application example of a dual mass flywheel (DMF).
Insight Into the Drift Motion of a Bouncing Asymmetric Dimer
Authors: Zhang Runsen , Zhao Zhen , Zheng Xudong , Wang Qi
Published: March 2019

The drift motion of an asymmetric dimer bouncing on a harmonically vibrating plate is addressed in this paper. The direction of this motion is determined by the behavior of the dimer during a double impact. Namely, if the system parameters allow a sticking impact as a generic behavior, the dimer drifts in one direction, whereas if all impacts end in a reverse slip, the dimer drifts in the opposite direction. By this mechanism, the bifurcation coefficients dominating the drift direction are obtained and discussed. But strictly speaking, the drift direction does not change unless the reverse slipping displacement after a double impact is big enough. Thus, numerical simulations are carried out to find a more accurate threshold and check the rationality of theoretical results.
Verification and Validation of SuperMC3.2 Using VENUS-3 Benchmark Experiments
Authors: Baidoo I. K. , Zou J. , Li B. , Song J. , Wu B. , Yang Q. , Zhao Z.
Published: March 2019

Methodological processes for nuclear power plant (NPP) pressure vessels' (PV) neutron fluence rate determination take the form of experimental measurement or theoretical calculations. However, the process of experimental measurement takes longer periods, as it requires the incorporation of surveillance capsules into a PV system undergoing normal NPP operation. Therefore, strong reliance on computation and modeling of radiation-induced degradation is given much attention. In this work, the VENUS-3 benchmark has been analyzed using SuperMC code, with the intention of validating SuperMC for accurate reactor neutronics; dosimetry response calculations for in-core/ex-core structural components, particularly with respect to the VENUS-3 configuration type pressurized water reactors (PWRs). In this work, complete three-dimensional (3D) geometry including the source modeling for VENUS-3 facility has been developed with SuperMC. Neutron transport and calculations of equivalent fission flux for the experimental target quantities, 115In (n, n′), 58Ni (n, p), and 27Al (n, α), are also achieved. The calculation results show good agreement with the experimental measurement. The greater majority of the calculated values (C/E) were within the required accuracy of ±10% for reactor components' dosimetry calculations. Most of the calculated values were contained within 5% deviation from the experimental data. Additional calculations and detailed analysis for fast neutron flux distribution and iron displacement per atom rate (dpa/s), including the characteristic effect of partial length shielded assembly (PLSA) on VENUS-3 core barrel, are also discussed. It is therefore evidenced that the effectiveness of SuperMC code for in-core/ex-core reactor neutronics computations has been convincingly demonstrated through the VENUS-3 benchmark testing.
Robotic Fish Propelled by a Servo Motor and Ionic Polymer-Metal Composite Hybrid Tail
Authors: Chen Zheng , Hou Piqi , Ye Zhihang
Published: March 2019

In this paper, a new robotic fish propelled by a hybrid tail, which is actuated by two active joints, is developed. The first joint is driven by a servo motor, which generates flapping motions for main propulsion. The second joint is actuated by a soft actuator, an ionic polymer-metal composite (IPMC) artificial muscle, which directs the propelled fluid for steering. A state-space dynamic model is developed to capture the two-dimensional (2D) motion dynamics of the robotic fish. The model fully captures the actuation dynamics of the IPMC soft actuator, two-link tail motion dynamics, and body motion dynamics. Experimental results have shown that the robotic fish is capable of swimming forward (up to 0.45 body length/s) and turning left and right (up to 40 deg/s) with a small turning radius (less than half a body length). Finally, the dynamic model has been validated with experimental data, in terms of steady-state forward speed and turning speed at steady-state versus flapping frequency.
Control and Powertrain Management for Multi-Autonomous Hybrid Vehicles
Authors: Ghasemi Masood , Song Xingyong
Published: March 2019

The need for less fuel consumption and the trend of higher level of autonomy together urge the power optimization in multihybrid autonomous vehicles. Both the multivehicle coordination control and the hybrid powertrain energy management should be optimized to maximize fuel savings. In this paper, we intend to have a computationally efficient framework to optimize them individually and then evaluate the overall control performance. The optimization is conducted in series. First is at the multivehicle system's level where the distributed locally optimal solution is given for vehicles with nonlinear dynamics. Second, the powertrain management optimization is conducted at the hybrid powertrain level. We provide an analytical formulation of the powertrain optimization for each hybrid vehicle by using Pontryagin's minimum principle (PMP). By approximating the optimal instantaneous fuel consumption rate as a polynomial of the engine speed, we can formulate the optimization problem into a set of algebraic equations, which enables the computationally efficient real-time implementation. To justify the applicability of the methodology in real-time, we give directions on numerical iterative solutions for these algebraic equations. The analysis on the stability of the method is shown through statistical analysis. Finally, further simulations are given to confirm the efficacy and the robustness of the proposed optimal approach. An off-road example is given in the simulation, although the framework developed can be applied to on-road scenario as well.
Adaptive Unified Monitoring System Design for Tire-Road Information
Authors: Cheng Shuo , Mei Ming-ming , Ran Xu , Li Liang , Zhao Lin
Published: March 2019

Knowledge of the tire-road information is not only very crucial in many active safety applications but also significant for self-driving cars. The tire-road information mainly consists of tire-road friction coefficient and road-tire friction forces. However, precise measurement of tire-road friction coefficient and tire forces requires expensive equipment. Therefore, the monitoring of tire-road information utilizing either accurate models or improved estimation algorithms is essential. Considering easy availability and good economy, this paper proposes a novel adaptive unified monitoring system (AUMS) to simultaneously observe the tire-road friction coefficient and tire forces, i.e., vertical, longitudinal, and lateral tire forces. First, the vertical tire forces can be calculated considering vehicle body roll and load transfer. The longitudinal and lateral tire forces are estimated by an adaptive unified sliding mode observer (AUSMO). Then, the road-tire friction coefficient is observed through the designed mode-switch observer (MSO). The designed MSO contains two modes: when the vehicle is under driving or brake, a slip slope method (SSM) is used, and a recursive least-squares (RLS) identification method is utilized in the SSM; when the vehicle is under steering, a comprehensive friction estimation method is adopted. The performance of the proposed AUMS is verified by both the matlab/simulinkCarSim co-simulation and the real car experiment. The results demonstrate the effectiveness of the proposed AUMS to provide accurate monitoring of tire-road information.
Damage Classification and Feature Extraction in Steel Moment-Resisting Frame Using Time-Varying Autoregressive Model
Authors: Pamwani Lavish , Agarwal Vikram , Shelke Amit
Published: March 2019

In this paper, the time-varying autoregressive (TVAR) model is integrated with the K-means—clustering technique to detect the damage in the steel moment-resisting frame. The damage is detected in the frame using nonstationary acceleration response of the structure excited using ambient white noise. The proposed technique identifies and quantifies the damage in the beam-to-column connection and column-to-column splice plate connection caused due to loosening of the connecting bolts. The algorithm models the nonstationary acceleration time history and evaluates the TVAR coefficients (TVARCs) for pristine and damage states. These coefficients are represented as a cluster in the TVARC subspace and segregated and classified using K-means—segmentation technique. The K-means—approach is adapted to simultaneously perform partition clustering and remove outliers. Eigenstructure evaluation of the segregated TVARC cluster is performed to detect the temporal damage. The topological and statistical parameters of the TVARC clusters are used to quantify the magnitude of the damage. The damage is quantified using the Mahalanobis distance (MD) and the Itakura distance (ID) serving as the statistical distance between the healthy and damage TVARC clusters. MD calculates a multidimensional statistical distance between two clusters using the covariance between the state vectors, whereas ID measures the dissimilarity of the autoregressive (AR) parameter between reference state and unknown states. These statistical distances are used as damage-sensitive feature (DSF) to detect and quantify the initiation and progression of the damage in the structure under ambient vibrations. The outcome of both the DSFs corroborate with the experimental investigation, thereby improving the robustness of the algorithm by avoiding false damage alarms.
Characterization of a pulsed low pressure argon discharge in a cylindrical magnetron reactor by plasma diagnostic and 3D plasma modeling
Authors: Mathioudaki Stella , Vandenabeele Cédric , Tonneau Romain , Pflug Andreas , Lucas Stéphane
Published: March 2019

This work describes a combined experimental and numerical study of a low pressure argon plasma in a cylindrical magnetron reactor. The plasma properties are first investigated experimentally using optical emission spectroscopy as a function of the position in the reactor and the applied power, for two excitation modes (pulsed direct current and pulsed bipolar) at a constant pressure of 10 Pa. Langmuir probe measurements are also performed to complement the plasma diagnostic. The results are compared with three-dimensional particle-in-cell simulations combined with a Monte Carlo Collision scheme. A consistent agreement occurs between the experimentally measured and numerically calculated electron temperatures, enabling one to validate the numerical model and to explain the influence of the magnetic field on the spatial variations of the electron temperature. The aim of this work is to pave the way for more complex simulations, such as the modeling of a plasma enhanced chemical vapor deposition process. In a future article, we will investigate both experimentally and numerically the plasma polymerization of cyclopropylamine in the same reactor.
Has a second person with HIV been cured?
Authors: Cohen Jon
Published: March 2019

Long-term disappearance of virus after a stem cell transplant may guide less drastic cures.
Magneto-Seebeck tunneling on the atomic scale
Authors: Friesen Cody , Osterhage Hermann , Friedlein Johannes , Schlenhoff Anika , Wiesendanger Roland , Krause Stefan
Published: March 2019

Mapping out the magneto-Seebeck coefficient

In the Seebeck effect, a temperature difference across a device generates voltage. If the thermal gradient is imposed across a magnetic tunnel junction—with two magnetized layers separated by an insulating tunnel barrier—the magnitude of the generated voltage depends on the relative orientation of the magnetization in the two layers. Transport measurements of this so-called magneto-Seebeck tunneling typically reveal only the signal averaged over the device. Friesen
et al.
created an atomic-scale version of this experiment by using a scanning tunneling microscope with a spin-polarized tip that they scanned across the surface of a magnetic sample. By heating the tip, they were able to map out the spatial dependence of the spin-resolved Seebeck coefficient.

Science
, this issue p.
1065
Cascading impacts of large-carnivore extirpation in an African ecosystem
Authors: Atkins Justine L. , Long Ryan A. , Pansu Johan , Daskin Joshua H. , Potter Arjun B. , Stalmans Marc E. , Tarnita Corina E. , Pringle Robert M.
Published: March 2019

Ecosystems feel war's effects

War ravages human lives and landscapes, but nonhuman victims are no less affected. The Mozambican Civil War resulted in the rapid decline of predators in Gorongosa National Park and led to a trophic cascade that shifted prey behaviors and plant communities. Atkins
et al.
monitored this shift and found that the absence of wild dogs and leopards resulted in a change in habitat use and plant consumption by bushbuck, which are forest-dwelling antelopes. Experiments further showed that changes in prey behavior were reversible when signs of predator activity were introduced, supporting the impact of the predator loss. These results confirm patterns seen elsewhere and go further in providing mechanistic detail about the importance of the “landscape of fear” perceived by prey animals.

Science
, this issue p.
173
Stoichiometry controls activity of phase-separated clusters of actin signaling proteins
Authors: Case Lindsay B. , Zhang Xu , Ditlev Jonathon A. , Rosen Michael K.
Published: March 2019

Organized for action

It is becoming increasingly clear that biomolecular condensates, which are concentrations of macromolecules not surrounded by a membrane, are a key organizational structure in eukaryotic cells (see the Perspective by Martin and Mittag). Now, two papers show how such condensates function in actin assembly or in a Ras signaling pathway. In both cases, the condensates form at the plasma membrane and increase the activity of signaling proteins by increasing their membrane dwell times. Case
et al.
show that the dwell time is dependent on cluster stoichiometry, so that stoichiometry of regulatory proteins can control actin assembly. Huang
et al.
demonstrate that the longer dwell time allows kinetic proofreading in receptor-mediated activation of Ras.

Science
, this issue p.
1093
, p.
1098
; see also p.
1036
Exotic states in a simple network of nanoelectromechanical oscillators
Authors: Matheny Matthew H. , Emenheiser Jeffrey , Fon Warren , Chapman Airlie , Salova Anastasiya , Rohden Martin , Li Jarvis , Hudoba de Badyn Mathias , Pósfai Márton , Duenas-Osorio Leonardo , Mesbahi Mehran , Crutchfield James P. , Cross M. C. , D’Souza Raissa M. , Roukes Michael L.
Published: March 2019

Quickly exploring weakly coupled oscillators

Synchronizing oscillators have been useful models for exploring coupling in dynamic systems. However, many macroscopic platforms such as pendula evolve on slow time scales, which can limit the observation of states that emerge after many cycles. Matheny
et al.
fabricated a ring of eight nanoelectromechanical oscillators resonating at ∼2.2 megahertz with quality factors of ∼4000 that could be rapidly controlled and read out. Analysis of these large datasets revealed exotic synchronization states with complex dynamics and broken symmetries. Theoretical modeling showed that emergent higher-order interactions (such as biharmonic and next-nearest neighbor) stabilized complex dynamics, despite the network having weak nearest-neighbor coupling.

Science
, this issue p.
eaav7932
The therapeutic promise of apoptosis
Authors: Fuchs Yaron
Published: March 2019

Programmed stem cell death appears to play a role in wound healing and tissue regeneration
Dwelling at membranes promotes decisive signaling
Authors: Martin Erik W. , Mittag Tanja
Published: March 2019

Membrane receptor clustering and phase separation enable noise filtering in signaling
The southern amplifier
Authors: Menviel Laurie
Published: March 2019

Greater Southern Ocean stratification may have lowered the atmospheric CO
2
concentration and prolonged ice ages
Analysis of the
Pseudomonas aeruginosa
Aminoglycoside Differential Resistomes Allows Defining Genes Simultaneously Involved in Intrinsic Antibiotic Resistance and Virulence
Authors: Sanz-García Fernando , Alvarez-Ortega Carolina , Olivares-Pacheco Jorge , Blanco Paula , Martínez José Luis , Hernando-Amado Sara
Published: March 2019

High-throughput screening of transposon insertion libraries is a useful strategy for unveiling bacterial genes whose inactivation results in an altered susceptibility to antibiotics. A potential drawback of these studies is they are usually based on just one model antibiotic for each structural family, under the assumption that the results can be extrapolated to all members of said family.
In Vitro
Activities of Omadacycline against Rapidly Growing Mycobacteria
Authors: Shoen Carolyn , Benaroch David , Sklaney Mary , Cynamon Michael
Published: March 2019

The
in vitro
activity of omadacycline, a new tetracycline derivative, was evaluated against isolates of
Mycobacterium abscessus
,
Mycobacterium chelonae
, and
Mycobacterium fortuitum
using a broth microtiter dilution assay. Omadacycline had MIC
90
values of 2 μg/ml, 0.25 μg/ml, and 0.5 μg/ml, respectively.
Control of Klebsiella pneumoniae Infection in Mice by Using Dissolving Microarray Patches Containing Gentamicin
Authors: Rodgers Aoife M. , McCrudden Maelíosa T. C. , Courtenay Aaron J. , Kearney Mary-Carmel , Edwards Katherine L. , Ingram Rebecca J. , Bengoechea Jose , Donnelly Ryan F.
Published: March 2019

Using a murine model of
Klebsiella pneumoniae
bacterial infection, we demonstrate that gentamicin dissolving microarray patches, applied to murine ears, could control
K. pneumoniae
infection. Mice treated with microarray patches had reduced bacterial burden in the nasal-associated lymphoid tissue and lungs compared with their untreated counterparts.
Potential for Microbially Mediated Natural Attenuation of Diluted Bitumen on the Coast of British Columbia (Canada)
Authors: Schreiber Lars , Fortin Nathalie , Tremblay Julien , Wasserscheid Jessica , Elias Miria , Mason Jennifer , Sanschagrin Sylvie , Cobanli Susan , King Thomas , Lee Kenneth , Greer Charles W.
Published: March 2019

Western Canada hosts large petroleum deposits, which ultimately enter the market in the form of dilbit. Tanker-based shipping represents the primary means to transport dilbit to international markets. With anticipated increases in production to meet global energy needs, the risk of a dilbit spill is expected to increase. This study investigated the potential of microbial communities naturally present in the waters of a potential dilbit shipping lane to mitigate the effects of a spill. Here we show that microbial degradation of dilbit was mostly limited to
n
-alkanes, while the overall concentration of polycyclic aromatic hydrocarbons, which represent the most toxic fraction of dilbit, decreased only slightly within the time frame of our experiments. We further investigated the effect of the oil dispersant Corexit 9500A on microbial dilbit degradation. Our results highlight the fact that dispersant-associated growth stimulation, and not only increased bioavailability of hydrocarbons and inhibition of specific genera, contributes to the overall effect of dispersant addition.
Unique Interferon Pathway Regulation by the Andes Virus Nucleocapsid Protein Is Conferred by Phosphorylation of Serine 386
Authors: Simons Matthew J. , Gorbunova Elena E. , Mackow Erich R.
Published: March 2019

ANDV contains virulence determinants that uniquely permit it to spread person to person and cause highly lethal HPS in immunocompetent hamsters. We discovered that ANDV S386 and an ANDV-specific hypervariable domain permit ANDV N to inhibit IFN induction and that IFN regulation is directed by phosphomimetic S386D substitutions in ANDV N. In addition, MAPV N proteins containing D386 and ANDV HVD gained the ability to inhibit IFN induction. Validating these findings, mass spectroscopy analysis revealed that S386 of ANDV N protein is uniquely phosphorylated during ANDV infection. Collectively, these findings reveal new paradigms for ANDV N protein as a phosphoprotein and IFN pathway regulator and suggest new mechanisms for hantavirus regulation of cellular kinases and signaling pathways. Our findings define novel IFN-regulating virulence determinants of ANDV, identify residues that can be modified to attenuate ANDV for vaccine development, and suggest the potential for kinase inhibitors to therapeutically restrict ANDV replication.
Thermostability of the Foot-and-Mouth Disease Virus Capsid Is Modulated by Lethal and Viability-Restoring Compensatory Amino Acid Substitutions
Authors: López-Argüello Silvia , Rincón Verónica , Rodríguez-Huete Alicia , Martínez-Salas Encarnación , Belsham Graham J. , Valbuena Alejandro , Mateu Mauricio G.
Published: March 2019

This study provides novel insights into the little-known structural determinants of the balance between thermal stability and instability in the capsid of foot-and-mouth disease virus and into the relationship between capsid stability and virus infectivity. The results provide new guidelines for the development of thermostabilized empty capsid-based recombinant vaccines against foot-and-mouth disease, one of the economically most important animal diseases worldwide.
Interaction between Intracellular Bacterial Pathogens and Host Cell Mitochondria
Authors: Spier Anna , Stavru Fabrizia , Cossart Pascale
Published: March 2019

Mitochondria are essential and highly dynamic organelles whose morphology is determined by a steady-state balance between fusion and fission. Mitochondrial morphology and function are tightly connected. Because they are involved in many important cellular processes, including energy production, cell-autonomous immunity, and apoptosis, mitochondria present an attractive target for pathogens. Here, we explore the relationship between host cell mitochondria and intracellular bacteria, with a focus on mitochondrial morphology and function, as well as apoptosis. Modulation of apoptosis can allow bacteria to establish their replicative niche or support bacterial dissemination. Furthermore, bacteria can manipulate mitochondrial morphology and function through secreted effector proteins and can also contribute to the establishment of a successful infection, e.g., by favoring access to nutrients and/or evasion of the immune system.
Type I Secretion Systems—One Mechanism for All?
Authors: Spitz Olivia , Erenburg Isabelle N. , Beer Tobias , Kanonenberg Kerstin , Holland I. Barry , Schmitt Lutz
Published: March 2019

Type I secretion systems (T1SS) are widespread in Gram-negative bacteria, especially in pathogenic bacteria, and they secrete adhesins, iron-scavenger proteins, lipases, proteases, or pore-forming toxins in the unfolded state in one step across two membranes without any periplasmic intermediate into the extracellular space. The substrates of T1SS are in general characterized by a C-terminal secretion sequence and nonapeptide repeats, so-called GG repeats, located N terminal to the secretion sequence. These GG repeats bind Ca
2+
ions in the extracellular space, which triggers folding of the entire protein. Here we summarize our current knowledge of how Gram-negative bacteria secrete these substrates, which can possess a molecular mass of up to 1,500 kDa. We also describe recent findings that demonstrate that the absence of periplasmic intermediates, the “classic” mode of action, does not hold true for all T1SS and that we are beginning to realize modifications of a common theme.
Upper Windermere Supergroup and the transition from rifting to continent-margin sedimentation, Nadaleen River area, northern Canadian Cordillera
Authors: Moynihan David P. , Strauss Justin V. , Nelson Lyle L. , Padget Colin D.
Published: March 2019

Neoproterozoic–Cambrian rocks of the Windermere Supergroup and overlying units record the breakup of Rodinia and formation of the northwestern Laurentian ancestral continental margin. Understanding the nature and timing of this transition has been hampered by difficulty correlating poorly dated sedimentary successions from contrasting depositional settings across Mesozoic structures. Here we present new litho- and chemo-stratigraphic data from a Cryogenian–lower Cambrian succession in east-central Yukon (Canada), establish correlations between proximal and distal parts of the upper Windermere Supergroup and related strata in the northern Canadian Cordillera, and consider implications for the formation of the northwestern Laurentian margin. The newly defined Nadaleen Formation hosts the first appearance of Ediacaran macrofossils, while the overlying Gametrail Formation features a large negative carbon isotope anomaly with δ13Ccarb values as low as –13‰ that correlates with the globally developed Shuram-Wonoka anomaly. We also define the Rackla Group, which includes the youngest (Ediacaran) portions of the Windermere Supergroup in the northern Cordillera. The top of the Windermere Supergroup is marked by an unconformity above the Risky Formation that passes into a correlative conformity in the Nadaleen River area. This surface has been interpreted to mark the top of the rift-related succession, but we draw attention to evidence for tectonic instability through the early-middle Cambrian and argue that the transition from rifting to post-rift thermal subsidence is marked by a widespread unconformity that underlies upper Cambrian carbonate rocks. This is younger than the interpreted age of the rift to post-rift transition elsewhere along the ancestral western Laurentian continental margin.
Nivolumab-induced hypophysitis leading to hypopituitarism and secondary empty sella syndrome in a patient with non-small cell lung cancer
Authors: Chang Jeremy , Tran Jeffrey , Kamel Dina , Basu Arnab
Published: March 2019

We describe the clinical course of a 64-year-old woman with stage IVa lung adenocarcinoma who presented with over 1 month of fatigue, unintentional weight loss and emesis. She initiated treatment with nivolumab immunotherapy 1 year prior and had been tolerating the treatment well. A comprehensive workup revealed multiple endocrinological abnormalities consistent with hypophysitis leading to hypopituitarism in the form of central adrenal insufficiency and hypogonadism as well as a partially empty sella on imaging. This case demonstrates that while receiving novel forms of treatment such as immunotherapy, patients should be monitored closely for a wide range of adverse effects.
Autoinflammatory constrictive pericarditis and chronic myelomonocytic leukaemia: when one speciality is not enough
Authors: Varian Frances , Kaur Harpreet , Carter Stuart , Gunn Julian
Published: March 2019

We present a case of constrictive pericarditis with concomitant blood and bone marrow appearances of chronic myelomonocytic leukaemia (CMML). Despite surgical treatment with pericardiectomy, the patient deteriorated into multiorgan failure. Pericardial histology disclosed a typical inflammatory picture with no evidence of monocytic or malignant infiltrate. Following intensive collaboration between cardiologists, haematologists and rheumatologists via daily email exchanges, a diagnosis was reached of autoinflammatory constrictive pericarditis with a non-infiltrative coexisting CMML. The key to achieving a rapid and sustained response was a trial of high-dose steroids followed by intravenous immunoglobulins. This achieved restoration of cardiac function, resolution of symptoms and near normalisation of inflammatory markers. A diagnosis of concurrent CMML was confirmed at 3 months. The patient remains well, taking colchicine and steroids.
How is implementation research applied to advance health in low-income and middle-income countries?
Authors: Alonge Olakunle , Rodriguez Daniela Cristina , Brandes Neal , Geng Elvin , Reveiz Ludovic , Peters David H
Published: March 2019

This paper examines the characteristics of implementation research (IR) efforts in low-income and middle-income countries (LMICs) by describing how key IR principles and concepts have been used in published health research in LMICs between 1998 and 2016, with focus on how to better apply these principles and concepts to support large-scale impact of health interventions in LMICs. There is a stark discrepancy between principles of IR and what has been published. Most IR studies have been conducted under conditions where the researchers have considerable influence over implementation and with extra resources, rather than in ‘real world’ conditions. IR researchers tend to focus on research questions that test a proof of concept, such as whether a new intervention is feasible or can improve implementation. They also tend to use traditional fixed research designs, yet the usual conditions for managing programmes demand continuous learning and change. More IR in LMICs should be conducted under usual management conditions, employ pragmatic research paradigm and address critical implementation issues such as scale-up and sustainability of evidence-informed interventions. This paper describes some positive examples that address these concerns and identifies how better reporting of IR studies in LMICs would include more complete descriptions of strategies, contexts, concepts, methods and outcomes of IR activities. This will help practitioners, policy-makers and other researchers to better learn how to implement large-scale change in their own settings.
Dog ownership and cardiovascular risk factors: a nationwide prospective register-based cohort study
Authors: Mubanga Mwenya , Byberg Liisa , Egenvall Agneta , Sundström Johan , Magnusson Patrik Karl Erik , Ingelsson Erik , Fall Tove
Published: March 2019

Objective

To study the association between dog ownership and cardiovascular risk factors.

Design

A nationwide register–based cohort study and a cross-sectional study in a subset.

Setting

A cohort of 2 026 865 participants was identified from the Register of the Total Population and linked to national registers for information on dog ownership, prescribed medication, hospital admissions, education level, income and country of birth. Participants were followed from 1 October, 2006, to the end of the study on 31 December, 2012, assessing medication for a cardiovascular risk factor, emigration and death. Cross-sectional associations were further assessed in 10 110 individuals from the TwinGene study with additional adjustment for professional level, employment status, Charlson comorbidity index, disability and tobacco use.

Participants

All Swedish residents aged 45–80 years on 1 October, 2006.

Main outcome measures

Initiation of medication for hypertension, dyslipidaemia and diabetes mellitus.

Results

After adjustment for confounders, the results indicated slightly higher likelihood of initiating antihypertensive (HR, 1.02; 95% CI, 1.01 to 1.03) and lipid-lowering treatment (HR, 1.02; 95% CI, 1.01 to 1.04) in dog owners than in non-owners, particularly among those aged 45–60 years and in those owning mixed breed or companion/toy breed dogs. No association of dog ownership with initiation of treatment for diabetes was found in the overall analysis (HR, 0.98; 95% CI, 0.95 to 1.01). Sensitivity analyses in the TwinGene cohort indicated confounding of the association between dog ownership and prevalent treatment for hypertension, dyslipidaemia and diabetes mellitus, respectively, from factors not available in the national cohort, such as employment status and non cardiovascularchronic disease status.

Conclusions

In this large cohort study, dog ownership was associated with a minimally higher risk of initiation of treatment for hypertension and dyslipidaemia implying that the previously reported lower risk of cardiovascular mortality among dog owners in this cohort is not explained by reduced hypertension and dyslipidaemia. These observations may suffer from residual confounding despite access to multiple important covariates, and future studies may add valuable information.
Towards a decision support tool for intensive care discharge: machine learning algorithm development using electronic healthcare data from MIMIC-III and Bristol, UK
Authors: McWilliams Christopher J , Lawson Daniel J , Santos-Rodriguez Raul , Gilchrist Iain D , Champneys Alan , Gould Timothy H , Thomas Mathew JC , Bourdeaux Christopher P
Published: March 2019

Objective

The primary objective is to develop an automated method for detecting patients that are ready for discharge from intensive care.

Design

We used two datasets of routinely collected patient data to test and improve on a set of previously proposed discharge criteria.

Setting

Bristol Royal Infirmary general intensive care unit (GICU).

Patients

Two cohorts derived from historical datasets: 1870 intensive care patients from GICU in Bristol, and 7592 from Medical Information Mart for Intensive Care (MIMIC)-III.

Results

In both cohorts few successfully discharged patients met all of the discharge criteria. Both a random forest and a logistic classifier, trained using multiple-source cross-validation, demonstrated improved performance over the original criteria and generalised well between the cohorts. The classifiers showed good agreement on which features were most predictive of readiness-for-discharge, and these were generally consistent with clinical experience. By weighting the discharge criteria according to feature importance from the logistic model we showed improved performance over the original criteria, while retaining good interpretability.

Conclusions

Our findings indicate the feasibility of the proposed approach to ready-for-discharge classification, which could complement other risk models of specific adverse outcomes in a future decision support system. Avenues for improvement to produce a clinically useful tool are identified.
Training non-physician anaesthetists in sub-Saharan Africa: a qualitative investigation of providers’ perspectives
Authors: Edgcombe Hilary , Baxter Linden S , Kudsk-Iversen Soren , Thwaites Victoria , Bulamba Fred
Published: March 2019

Objectives

To explore the views of non-physician anaesthesia providers (NPAPs) and their colleagues regarding the effectiveness of NPAP training programmes in three contrasting sub-Saharan African countries.

Design

This was a qualitative exploratory descriptive study. Semistructured interviews were conducted online, recorded, transcribed and analysed thematically using NVivo.

Setting

Participants’ homes or workplaces in Sierra Leone, Somaliland and Uganda.

Participants

15 NPAPs, physician anaesthetists and surgeons working in the countries concerned.

Results

Three major themes were identified: (1) discrepancy between urban training and rural practice, (2) prominent development of attitudes outside the curricular set during training, including approaches to learning and clinical responsibility and (3) the importance of interprofessional relationships developed during training for later practice.

Conclusions

Anaesthesia providers in different cadres and very different country contexts in sub-Saharan Africa describe common themes in training which appear to be significant for their later practice. Not all these issues are explicitly planned for in current training programmes, although they are important in the view of providers. Subsequent programme development should consider these themes with a view to enhancing the safety and quality of anaesthesia practice in this context.
Injury incidence and risk factors: a cohort study of 706 8-km or 16-km recreational runners
Authors: Dallinga Joan , Van Rijn Rogier , Stubbe Janine , Deutekom Marije
Published: March 2019

Objectives

To report (1) the injury incidence in recreational runners in preparation for a 8-km or 16-km running event and (2) which factors were associated with an increased injury risk.

Methods

Prospective cohort study in Amsterdam, the Netherlands. Participants (n=5327) received a baseline survey to determine event distance (8 km or 16 km), main sport, running experience, previous injuries, recent overuse injuries and personal characteristics. Three days after the race, they received a follow-up survey to determine duration of training period, running distance per week, training hours, injuries during preparation and use of technology. Univariate and multivariate regression models were applied to examine potential risk factors for injuries.

Results

1304 (24.5%) participants completed both surveys. After excluding participants with current health problems, no signed informed consent, missing or incorrect data, we included 706 (13.3%) participants. In total, 142 participants (20.1%) reported an injury during preparation for the event. Univariate analyses (OR: 1.7, 95% CI 1.1 to 2.4) and multivariate analyses (OR: 1.7, 95% CI 1.1 to 2.5) showed that injury history was a significant risk factor for running injuries (Nagelkerke R-square=0.06).

Conclusion

An injury incidence for recreational runners in preparation for a running event was 20%. A previous injury was the only significant risk factor for running-related injuries.
Educational concussion module for professional footballers: from systematic development to feasibility and effect
Authors: Gouttebarge Vincent , Cowie Charlotte , Goedhart Edwin , Kemp Simon P T , Kerkhoffs Gino M M J , Patricios Jon , Stokes Keith A
Published: March 2019

Objectives

To describe: (1) how we developed a concussion module and (2) whether the concussion module is feasible (in terms of relevance, added value and suitability) and enhances knowledge and changes attitude of professional footballers about concussion.

Developing the concussion module

We developed the concussion module based on two structured and systematic processes. First, our needs assessment (questionnaire and interviews) in professional football (especially players) revealed that a 5–10 min concussion module was needed, ideally disseminated during club visits. Second, the objectives were defined (from published literature and by experts) as to disseminate essential information about what concussion is (definition), how to recognise it and the importance of removing a player with (suspected) concussion from the football field. We included an introductory video featuring a high-profile professional footballer and an animated educational component on defining concussion, recognising it and removing affected players from the field.

Feasibility and effect

A quasiexperimental study (pretest post-test design) was conducted among 61 professional footballers. These players were asked to complete two questionnaires related to knowledge about and attitude towards concussion and feasibility of the module: one before and one after viewing the concussion module. Potential increase in knowledge and attitude was explored by comparing the pretest and post-test scores of the Rosenbaum Concussion Knowledge and Attitudes Survey with the non-parametric Wilcoxon signed-rank test (p<0.05). The mean knowledge score of the participants was stable between tests (Z=213; p=0.16), while mean attitude score increased significantly (Z=331; p=0.01). Nearly all participants (85%–100%) were positive about the relevance, added value, duration and form of the concussion module.

Conclusion

The developed educational concussion module leads to better attitude of professional footballers towards concussion.
G-Eye: ocular manifestations of gastrointestinal disease
Authors: Imam Lema , Haboubi Hasan Nadim
Published: March 2019

Extraintestinal manifestations of gastrointestinal disease can form an important aspect of the diagnosis, monitoring and management in these diseases. Ocular manifestations in particular are often disregarded and can, albeit rarely, present as an emergency.