bluuebunny/crossref_metadata_2025 huggingface dataset:
Stabilization of domain structures in Rb-doped KTiOPO4 for high-temperature processes
Authors: Kianirad Hoda , Lindgren Gustav , Peña Alexandra , Zukauskas Andrius , Ménaert Bertrand , Laurell Fredrik , Boulanger Benoît , Canalias Carlota
Published: February 2019

A way to stabilize the domain structure in periodically poled Rb-doped KTiOPO4 samples at high-temperatures is presented. The domain contraction along the b-crystallographic axis that is observed when crystals are annealed at high temperatures is suppressed when the ends of the domains along the b-axis are diced away. Additionally, the thermal stability of self-assembled domain gratings with a sub-μm average periodicity of 650 ± 200 nm and a domain-width of 225 ± 75 nm in mm-thick samples is investigated, and it is shown that the key factor for the domain stability is the domain width rather than the interdomain distance.
Atomic layer deposition of a MgO barrier for a passivated black phosphorus spintronics platform
Authors: Kern L.-M. , Galceran R. , Zatko V. , Galbiati M. , Godel F. , Perconte D. , Bouamrane F. , Gaufrès E. , Loiseau A. , Brus P. , Bezencenet O. , Martin M.-B. , Servet B. , Petroff F. , Dlubak B. , Seneor P.
Published: February 2019

We demonstrate a stabilized black phosphorus (BP) 2D platform thanks to an ultrathin MgO barrier, as required for spintronic device integration. The in-situ MgO layer deposition is achieved by using a large-scale atomic layer deposition process with high nucleation density. Raman spectroscopy studies show that this layer protects the BP from degradation in ambient conditions, unlocking in particular the possibility to carry out usual lithographic fabrication steps. The resulting MgO/BP stack is then integrated in a device and probed electrically, confirming the tunnel properties of the ultrathin MgO contacts. We believe that this demonstration of a BP material platform passivated with a functional MgO tunnel barrier provides a promising perspective for BP spin transport devices.
New ferrimagnetic film could help speed up spintronic devices
Authors: Patrick Chris
Published: February 2019

The authors grew polycrystalline europium iron garnet films that have perpendicular magnetic anisotropy and potential applications in spintronics.
Community-based case management does not reduce hospital admissions for older people: a systematic review and meta-analysis
Authors: Poupard Nerissa , Tang Clarice Y. , Shields Nora
Published: February 2019

Objective The aim of this study was to investigate the effectiveness of community-based case management in reducing hospital admissions for older people. Methods Five databases were searched from inception to March 2018. Trials were included if: (1) participants were community-dwelling adults aged ≥65 years; (2) intervention was community-based case management for ≥3 months; (3) outcomes related to hospital admissions; and (4) the design included a control group. The quality of evidence was independently assessed by two reviewers using the Physiotherapy Evidence Database (PEDro) scale and the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) approach. Data were analysed descriptively and using meta-analyses where possible. Results Nine trials (n=5468 participants) were included in the analysis. Meta-analysis found community-based case management did not reduce hospital admissions (standard mean difference –0.09; 95% confidence interval (CI) –0.27, 0.10), but did reduce emergency department (ED) presentations (mean difference –0.26; 95% CI –0.51, –0.01). Conclusion Community-based case management intervention may be effective in reducing ED presentations for older people. What is known about the topic? Although community-based case management is common in Australia, little is known about its effectiveness in reducing healthcare utilisation for community-dwelling older people. What does this paper add? The results indicate that community-based case management may decrease the number of ED presentations among older people. What are the implications for practitioners? Patients with high ED presentation rates may benefit from community-based case management to reduce the number of unnecessary ED presentations.
Micro- and macro-scale water retention properties of granular soils: contribution of the X-Ray CT-based voxel percolation method
Authors: Shiota Erika , Mukunoki Toshifumi , Oxarango Laurent , Tinet Anne-Julie , Golfier Fabrice
Published: February 2019

Water retention in granular soils is a key mechanism for understanding transport processes in the vadose zone for various applications from agronomy to hydrological and environmental sciences. The macroscopic pattern of water entrapment is mainly driven by the pore-scale morphology and capillary and gravity forces. In the present study, the drainage water retention curve (WRC) was measured for three different granular materials using a miniaturised hanging column apparatus. The samples were scanned using X-ray micro-computed tomography during the experiment. A segmentation procedure was applied to identify air, water and solid phases in 3D at the pore-scale. A representative elementary volume analysis based on volume and surface properties validated the experimental setup size. A morphological approach, the voxel percolation method (VPM) was used to model the drainage experiment under the assumption of capillary-dominated quasi-static flow. At the macro-scale, the VPM showed a good capability to predict the WRC when compared with direct experimental measurements. An in-depth comparison with image data also revealed a satisfactory agreement concerning both the average volumetric distributions and the pore-scale local topology. Image voxelisation and the quasi-static assumption of VPM are likely to explain minor discrepancies observed at low suctions and for coarser materials.
Forest fuel bed ignitability under marginal fire weather conditions in Eucalyptus forests
Authors: Cawson Jane G. , Duff Thomas J.
Published: February 2019

Fires burning under marginal fire-weather conditions tend to be patchy in terms of their spatial coverage. This patchiness is partially driven by variability in the ignitability of the fuel bed. An understanding of fuel-bed ignitability through space and time would help fire managers to more effectively carry out prescribed burns to achieve desired levels of burn coverage in Eucalyptus forests. We sought to identify the key fuel-bed attributes influencing ignitability under marginal weather conditions. We recorded ignition successes and failures at 45 points within 5 operational prescribed burns and used the data to build logistic regression models to predict the probability of ignition as a function of fuel-bed attributes. Models were ranked using an information theoretic approach. The four highest ranked models explained 48–54% of the variance in ignitability. Surface fine-fuel moisture content (FFMC) and overall fuel hazard (i.e. fuel arrangement) were the strongest predictors of ignitability, occurring in all four highest ranking models. Both surface FFMC and overall fuel hazard were negatively related to ignition likelihood, contradicting a commonly assumed positive relationship between fuel hazard and flammability. Our field method to measure ignition success could be applied across more prescribed burns to develop operationally useful models of ignitability.
Musical reward prediction errors engage the nucleus accumbens and motivate learning
Authors: Gold Benjamin P. , Mas-Herrero Ernest , Zeighami Yashar , Benovoy Mitchel , Dagher Alain , Zatorre Robert J.
Published: February 2019

Enjoying music reliably ranks among life’s greatest pleasures. Like many hedonic experiences, it engages several reward-related brain areas, with activity in the nucleus accumbens (NAc) most consistently reflecting the listener’s subjective response. Converging evidence suggests that this activity arises from musical “reward prediction errors” (RPEs) that signal the difference between expected and perceived musical events, but this hypothesis has not been directly tested. In the present fMRI experiment, we assessed whether music could elicit formally modeled RPEs in the NAc by applying a well-established decision-making protocol designed and validated for studying RPEs. In the scanner, participants chose between arbitrary cues that probabilistically led to dissonant or consonant music, and learned to make choices associated with the consonance, which they preferred. We modeled regressors of trial-by-trial RPEs, finding that NAc activity tracked musically elicited RPEs, to an extent that explained variance in the individual learning rates. These results demonstrate that music can act as a reward, driving learning and eliciting RPEs in the NAc, a hub of reward- and music enjoyment-related activity.
Harmonic dynamics of the abelian sandpile
Authors: Lang Moritz , Shkolnikov Mikhail
Published: February 2019

The abelian sandpile is a cellular automaton which serves as the archetypical model to study self-organized criticality, a phenomenon occurring in various biological, physical, and social processes. Its recurrent configurations form an abelian group, whose identity is a fractal composed of self-similar patches. Here, we analyze the evolution of the sandpile identity under harmonic fields of different orders. We show that this evolution corresponds to periodic cycles through the abelian group characterized by the smooth transformation and apparent conservation of the patches constituting the identity. The dynamics induced by second- and third-order harmonics resemble smooth stretchings and translations, respectively, while the ones induced by fourth-order harmonics resemble magnifications and rotations. Based on an extensive analysis of these sandpile dynamics on domains of different size, we conjecture the existence of several scaling limits for infinite domains. Furthermore, we show that the space of harmonic functions provides a set of universal coordinates identifying configurations between different domains, which directly implies that the sandpile group admits a natural renormalization. Finally, we show that the harmonic fields can be induced by simple Markov processes and that the corresponding stochastic dynamics show remarkable robustness. Our results suggest that harmonic fields might split the sandpile group into subsets showing different critical coefficients and that it might be possible to extend the fractal structure of the identity beyond the boundaries of its domain.
A novel molten wire tungsten inert gas welding process
Authors: Liu Aiguo , Zhang Xingpin , Zheng Chengbo , Han Xue
Published: February 2019

A novel molten wire tungsten inert gas welding process was presented. In this process, a welding arc is used to melt the workpiece, and a melting arc is used to melt the feeding wire. Metal transfer is separated from the melting of the wire and the workpiece, and the arcs are stable no matter the droplet transfer mode is spraying or globular. The spatter rate in the process is close to zero. Mechanical properties of low carbon steel joint bonded with this process are superior to those bonded with the metal inert gas welding process.
Staying in touch: Taking a closer look at ER–Golgi contact sites
Authors: Sassano Maria Livia , Agostinis Patrizia
Published: February 2019

ER–Golgi contact sites regulate lipid homeostasis and trafficking across the trans-Golgi network. However, their molecular nature is elusive. In this issue, Venditti et al. (2019. J. Cell Biol. https://doi.org/10.1083/jcb.201812020 and https://doi.org/10.1083/jcb.201812021) shine new light on the molecular determinants coupling lipid exchange and cargo exit with maintenance of ER–Golgi contacts.
When Art Can’t Lie
Authors: Cooke Brandon
Published: February 2019

Pre-philosophically, an artwork can lie in virtue of some (perhaps successfully realized) authorial intention that the audience comes to accept as true something that the author believes to be false. This thought forces a confrontation with the debate about the relation between the interpretation of a work and the intentions of its author. Anti-intentionalist theories of artwork meaning, which divorce work meaning from the actual author’s intentions, cannot license the judgment that an artwork lies. But if artwork lying is a genuine possibility, then anti-intentionalism must be rejected as false.
Lying with Pictures
Authors: Viebahn Emanuel
Published: February 2019

Pictures are notably absent from the current debate about how to define lying. Theorists in this debate tend to focus on linguistic means of communication and do not consider the possibility of lying with photographs, drawings and other kinds of pictures. The aim of this paper is to show that such a narrow focus is misguided: there is a strong case to be made for the possibility of lying with pictures and this possibility allows for insights concerning the question of how lying should be defined.
Movement of juvenile tuna deduced from parasite data
Authors: Moore Bradley R , Lestari Pratiwi , Cutmore Scott C , Proctor Craig , Lester Robert J G
Published: February 2019

The movements, and hence stock structures, of bigeye tuna, Thunnus obesus, and yellowfin tuna, Thunnus albacares, remain poorly defined despite their importance to food security, livelihoods and government revenue in many nations. We examined the parasite fauna of juvenile bigeye tuna and juvenile yellowfin tuna from areas within and outside Indonesia to determine how far they may have moved since metamorphosis and acquisition of a piscivorous diet. Patterns in parasite data between collection areas were consistent between the two tuna species. Fish from two outlier areas, Maldives and the Solomon Islands, harboured a distinct parasite fauna from those from adjacent Indonesian areas, although occasionally showed similarity with those from within the Indonesian archipelago. Within Indonesia, the parasite data indicated that few juvenile fish moved west from the Pacific Ocean into the archipelago and few moved west from the archipelago into the eastern Indian Ocean. While sampling of adult fish is required to fully resolve the stock structure of both tuna species, the results provide a necessary first-step in examining structuring of the two tuna species in Indonesia and indicate that juveniles of both species may have more restricted movement than is recognized in current management arrangements.
Indirect Effect of Azithromycin Use on the Intestinal Microbiome Diversity of Untreated Children: A Randomized Trial
Authors: Oldenburg Catherine E , Sié Ali , Coulibaly Boubacar , Ouermi Lucienne , Dah Clarisse , Tapsoba Charlemagne , Bärnighausen Till , Lebas Elodie , Arzika Ahmed M , Cummings Milo E , Zhong Lina , Lietman Thomas M , Keenan Jeremy D , Doan Thuy
Published: February 2019

Cohabiting children may share components of their intestinal microbiome. We evaluated whether receipt of azithromycin in one sibling confers changes to the intestinal microbiome in an untreated sibling compared with placebo in a randomized controlled trial. We found no evidence of an indirect effect of antibiotic use in cohabiting children.

Clinical Trials Registrations: NCT03187834.
A Quantitative Assessment of the Accuracy and Reliability of Robotically Guided Percutaneous Pedicle Screw Placement: Technique and Application Accuracy
Authors: Godzik Jakub , Walker Corey T , Hartman Cory , de Andrada Bernardo , Morgan Clinton D , Mastorakos George , Chang Steven , Turner Jay , Porter Randall W , Snyder Laura , Uribe Juan
Published: February 2019

BACKGROUND

Minimally invasive surgery (MIS) and anterior (ALIF), transforaminal (TLIF), or lateral lumbar interbody fusion (LLIF) often require percutaneous pedicle screw fixation (PSF) to achieve circumferential fusion. Robotic guidance technology may augment workflow to improve screw placement and decrease operative time.

OBJECTIVE

To report surgical experience with robotically assisted percutaneous screw placement following LLIF.

METHODS

Data from fusions with robotically assisted PSF in prone or lateral decubitus positions was reviewed. A CT-guided robotic guidance arm was used for screw placement (Excelsius GPS™, Globus Medical Inc, Audubon, Pennsylvania). Postoperative CT imaging facilitated screw localization. 3-dimensional and 2-dimensional coordinates of the screw tip and tail were calculated and compared with a target trajectory to calculate targeting errors. Breach was defined as a violation of the lateral or medial pedicle wall.

RESULTS

Robotic-guided screw placement was successful in 28/31 patients. In those patients, 116/116 screws were successfully implanted. The breach rate was 3.4% (4/116). Across 17 patients (70 screws), mean 3-D accuracy was 5.0 ± 2.4 mm, mean 2-D accuracy was 2.6 ± 1.1 mm, and mean angular offset was 5.6 ± 4.3° with corresponding intraclass correlation coefficients (ICC) of 0.775 and 0.693. 3-dimensional accuracy correlated with age (R = 0.306, P = .011) and BMI (R = 0.252, P = .038). Accuracy did not significantly differ among vertebral body levels (P > .22). Mean operative time for MIS-TLIF and percutaneous screws was 277 ± 52 and 183 ± 54 min, respectively. Operative time did not significantly decrease across either group (P > .187).

CONCLUSION

The Excelsius GPS™ robotic guidance system allows accurate PSF in most cases with 2 mm 2-D accuracy. Future studies are needed to demonstrate the utility of this novel guidance system and workflow improvement.
THC intoxication in a 16-month-old child
Authors: Burrows Kim , Williams Jennifer Ann
Published: February 2019

A 16-month-old previously healthy child with normal development presented with decreased level of consciousness, apneas, and seizure requiring intubation and treatment for status epilepticus. Investigations revealed no evidence of infection or trauma, normal head CT scan, and urine positive for tetrahydrocannabinol (THC) and negative for other substances. This report outlines the clinical presentation, approach to treatment, and potential seriousness of THC intoxication in young children. Mandatory reporting and monitoring of THC intoxication in children is recommended. The need for effective education of parents about the risks of unintentional THC poisoning and measures to safeguard young children is discussed.
Connectome-Based Patterns of First-Episode Medication-Naïve Patients With Schizophrenia
Authors: Cui Long-Biao , Wei Yongbin , Xi Yi-Bin , Griffa Alessandra , De Lange Siemon C , Kahn René S , Yin Hong , Van den Heuvel Martijn P
Published: February 2019

Emerging evidence indicates that a disruption in brain network organization may play an important role in the pathophysiology of schizophrenia. The neuroimaging fingerprint reflecting the pathophysiology of first-episode schizophrenia remains to be identified. Here, we aimed at characterizing the connectome organization of first-episode medication-naïve patients with schizophrenia. A cross-sectional structural and functional neuroimaging study using two independent samples (principal dataset including 42 medication-naïve, previously untreated patients and 48 healthy controls; replication dataset including 39 first-episode patients [10 untreated patients] and 66 healthy controls) was performed. Brain network architecture was assessed by means of white matter fiber integrity measures derived from diffusion-weighted imaging (DWI) and by means of structural-functional (SC-FC) coupling measured by combining DWI and resting-state functional magnetic resonance imaging. Connectome rich club organization was found to be significantly disrupted in medication-naïve patients as compared with healthy controls (P = .012, uncorrected), with rich club connection strength (P = .032, uncorrected) and SC-FC coupling (P < .001, corrected for false discovery rate) decreased in patients. Similar results were found in the replication dataset. Our findings suggest that a disruption of rich club organization and functional dynamics may reflect an early feature of schizophrenia pathophysiology. These findings add to our understanding of the neuropathological mechanisms of schizophrenia and provide new insights into the early stages of the disorder.
How (not) to change the (un)changeable?
Authors: Ronovská Kateřina , Pihera Vlastimil
Published: February 2019

The aim of this article is to outline how the current Czech legal doctrine deals with one of the most problematic issues in foundation law, namely the issue of making ex post facto changes to foundation deeds, including a change of purpose. When dealing with this topic, we need to consider the lack of clarity of the current regulation, which was inspired by various (sometimes antithetical) conceptual approaches. It is likely that the direction of the entire Czech foundation law will be dependent upon how such legal issues are addressed. With a view to the general nature of the issue, an analysis of the Czech situation is relevant for other countries as well. For that reason, the discussion is based on the general framework of the current trends in the development of foundation law in Europe.
Molecular epidemiology of Marek’s disease virus in central Pennsylvania, USA
Authors: Bell Andrew S , Kennedy David A , Jones Matthew J , Cairns Christopher L , Pandey Utsav , Dunn Patricia A , Szpara Moriah L , Read Andrew F
Published: February 2019

The evolution of Marek’s disease virus (MDV, Gallid herpesvirus 2) has threatened the sustainability of poultry farming in the past and its continued evolution remains a concern. Genetic diversity is key to understanding evolution, yet little is known about the diversity of MDV in the poultry industry. Here, we investigate the diversity of MDV on 19 Pennsylvanian poultry farms over a 3-year period. Using eight polymorphic markers, we found that at least twelve MDV haplotypes were co-circulating within a radius of 40 km. MDV diversity showed no obvious spatial clustering nor any apparent clustering by bird line: all of the virus haplotypes identified on the commercial farms could be found within a single, commonly reared bird line. On some farms, a single virus haplotype dominated for an extended period of time, while on other farms the observed haplotypes changed over time. In some instances, multiple haplotypes were found simultaneously on a farm, and even within a single dust sample. On one farm, co-occurring haplotypes clustered into phylogenetically distinct clades, putatively assigned as high and low virulence pathotypes. Although the vast majority of our samples came from commercial poultry farms, we found the most haplotype diversity on a noncommercial backyard farm experiencing an outbreak of clinical Marek’s disease. Future work to explore the evolutionary potential of MDV might therefore direct efforts toward farms that harbor multiple virus haplotypes, including both backyard farms and farms experiencing clinical Marek’s disease.
Spatial Distribution of Soybean Cyst Nematode in Research Plots
Authors: Poromarto Susilo H. , del Río Mendoza Luis E. , Nelson Berlin D.
Published: February 2019

Soybean cyst nematode (SCN; Heterodera glycines Ichinohe) is a major pathogen of soybean [Glycine max (L.) Merr.] in the United States. The spatial distribution of SCN in 10 naturally infested research sites in North Dakota was examined between 2006 and 2009. Egg densities were measured in plots and expressed as arithmetic means or grouped into classes using two categorical scales based on the effect of SCN on yield. Data were used to determine spatial distribution, egg cluster sizes, minimum plot sizes, and replications in field experiments. SCN populations varied among plots from undetected to 25,800 eggs/100 cm3 of soil, and differences between adjacent plots were as high as sixfold. Mean to median ratios and Lloyd’s index of patchiness suggested an aggregated distribution in nine of the 10 sites. SCN cluster sizes varied in five of the 10 sites and optimum plot size over all sites varied depending on calculation methods. The minimum number of replications needed to detect specific differences among plots varied between field sites. Grouping data into either of the two categories generally increased the ability to detect differences between plots. The spatial distribution of SCN can be a critical factor affecting design and outcomes of field experiments.
The Effect of Fhb1 and Fhb5 Quantitative Trait Loci in Hard Red Spring Wheat Does Not Depend on Fungicide Use for Managing Fusarium Head Blight in Wheat
Authors: Brar Gurcharn S. , Hnatowich Garry , Peng Gary , Hucl Pierre J. , Kutcher Hadley R.
Published: February 2019

Fusarium head blight (FHB), caused by Fusarium graminearum, is one of the most damaging diseases that affect wheat in Canada. The disease is best managed by integrating host resistance and fungicides, mainly demethylation inhibitors. Research has shown that the effect of fungicides may be dependent on the level of resistance of the cultivar. However, whether the performance of genotypes carrying specific Sumai 3-derived major FHB quantitative trait loci is dependent on fungicide application has not been explored. In our study, the performance of near-isogenic lines (NILs; <1.0% genome/alleles from the resistance donor), carrying Fhb1 and Fhb5 in a hard red spring wheat cultivar CDC Go background compared with a moderately susceptible (MS) genotype, was evaluated with and without one application of metconazole during full flowering. Field experiments were conducted at five site-years in Saskatchewan, Canada, between 2016 and 2017. In both the individual and combined analysis (all trials), we found that the effect of NILs and metconazole in suppressing FHB symptoms and deoxynivalenol (DON) accumulation in the grain was additive. FHB severity was generally low and fungicide efficacy levels, relative to the untreated control, were increased in the MS cultivar than in the NILs carrying Fhb1 and Fhb5, which were least affected by the disease. The results confirm the importance of integrating fungicides with cultivar resistance to reduce FHB and DON, regardless of the presence of those well-characterized resistant genes.
Crp-Like Protein Plays Both Positive and Negative Roles in Regulating the Pathogenicity of Bacterial Pustule Pathogen Xanthomonas axonopodis pv. glycines
Authors: Guo Wei , Gao Jie , Chen Qingshan , Ma Bojun , Fang Yuan , Liu Xia , Chen Gongyou , Liu Jian-Zhong
Published: February 2019

The global regulator Crp-like protein (Clp) is positively involved in the production of virulence factors in some of the Xanthomonas spp. However, the functional importance of Clp in X. axonopodis pv. glycines has not been investigated previously. Here, we showed that deletion of clp led to significant reduction in the virulence of X. axonopodis pv. glycines in soybean, which was highly correlated with the drastic reductions in carbohydrates utilization, extracellular polysaccharide (EPS) production, biofilm formation, cell motility, and synthesis of cell wall degrading enzymes (CWDEs). These significantly impaired properties in the clp mutant were completely rescued by a single-copy integration of the wild-type clp into the mutant chromosome via homologous recombination. Interestingly, overexpression of clp in the wild-type strain resulted in significant increases in cell motility and synthesis of the CWDEs. To our surprise, significant reductions in carbohydrates utilization, EPS production, biofilm formation, and the protease activity were observed in the wild-type strain overexpressing clp, suggesting that Clp also plays a negative role in these properties. Furthermore, quantitative reverse transcription polymerase chain reaction analysis suggested that clp was positively regulated by the diffusible signal factor-mediated quorum-sensing system and the HrpG/HrpX cascade. Taken together, our results reveal that Clp functions as both activator and repressor in multiple biological processes in X. axonopodis pv. glycines that are essential for its full virulence.
Effects of Mesenchymal Stem Cell Treatment on Systemic Cytokine Levels in a Phase 1 Dose Escalation Safety Trial of Septic Shock Patients*
Authors: Schlosser Kenny , Wang Jia-Pey , dos Santos Claudia , Walley Keith R. , Marshall John , Fergusson Dean A. , Winston Brent W. , Granton John , Watpool Irene , Stewart Duncan J. , McIntyre Lauralyn A. , Mei Shirley H. J. ,   on behalf of the Canadian Critical Care Trials Group and the Canadian Critical Care Translational Biology Group
Published: February 2019

Objectives:

Cellular Immunotherapy for Septic Shock is the first-in-human clinical trial evaluating allogeneic mesenchymal stem/stromal cells in septic shock patients. Here, we sought to determine whether plasma cytokine profiles may provide further information into the safety and biological effects of mesenchymal stem/stromal cell treatment, as no previous study has conducted a comprehensive analysis of circulating cytokine levels in critically ill patients treated with mesenchymal stem/stromal cells.

Design:

Phase 1 dose-escalation trial.

Patients:

The interventional cohort (n = 9) of septic shock patients received a single dose of 0.3, 1.0, or 3.0 million mesenchymal stem/stromal cells/kg body weight (n = 3 per dose). The observational cohort received no mesenchymal stem/stromal cells (n = 21).

Interventions:

Allogeneic bone marrow-derived mesenchymal stem/stromal cells.

Measurements and Main Results:

Serial plasma samples were collected at study baseline prior to mesenchymal stem/stromal cell infusion (0 hr), 1 hour, 4 hours, 12 hours, 24 hours, and 72 hours after mesenchymal stem/stromal cell infusion/trial enrollment. Forty-nine analytes comprised mostly of cytokines along with several biomarkers were measured. We detected no significant elevations in a broad range of pro-inflammatory cytokines and biomarkers between the interventional and observational cohorts. Stratification of the interventional cohort by mesenchymal stem/stromal cell dose further revealed patient-specific and dose-dependent perturbations in cytokines, including an early but transient dampening of pro-inflammatory cytokines (e.g., interleukin-1β, interleukin-2, interleukin-6, interleukin-8, and monocyte chemoattractant protein 1), suggesting that mesenchymal stem/stromal cell treatment may alter innate immune responses and underlying sepsis biology.

Conclusions:

A single infusion of up to 3 million cells/kg of allogeneic mesenchymal stem/stromal cells did not exacerbate elevated cytokine levels in plasma of septic shock patients, consistent with a safe response. These data also offer insight into potential biological mechanisms of mesenchymal stem/stromal cell treatment and support further investigation in larger randomized controlled trials.
Nevi and Breslow thickness in melanoma: sex differences?
Authors: De Giorgi Vincenzo , Scarfì Federica , Gori Alessia , Maida Pierandrea , Trane Luciana , Silvestri Flavia , Portelli Francesca , Massi Daniela , Covarelli Piero , Gandini Sara
Published: February 2019

A large body of evidence in the scientific literature suggests that the numbers of common and atypical nevi are strong, independent risk factors for the occurrence of cutaneous malignant melanoma. Furthermore, some studies recently found an association between high nevus counts and an improved melanoma prognosis. The aim of this study was to investigate a possible relationship between the number of common and atypical nevi and melanoma prognostic factors. We carried out a retrospective analysis of patients with a histopathologically confirmed diagnosis of melanoma. These patients were treated at the Dermatology Clinic of the University of Florence from January 2000 to December 2013. The main analysis investigated the association of common and atypical nevi with Breslow thickness and ulceration. The number of nevi was investigated as a continuous variable and a categorical variable considering the median number of common nevi, given the skewness of the distribution of common nevi. We analyzed 818 melanoma patients treated from January 2000 to December 2013. We found a sex and nevi interaction: among women, thick melanomas occur more frequently in patients with a low common nevi count (<10); no association was found in men. This sex and nevi interaction was also found considering the association with very thick melanomas (Breslow > 4 mm). Moreover, the presence of an increasing number of atypical nevi was associated with increased risk of ulceration in both sexes. These data provide new perspectives in the differential sex-related biological behavior of melanoma among females and males.
Multicolumn spinal cord stimulation for predominant back pain in failed back surgery syndrome patients: a multicenter randomized controlled trial
Authors: Rigoard Philippe , Basu Surajit , Desai Mehul , Taylor Rod , Annemans Lieven , Tan Ye , Johnson Mary Jo , Van den Abeele Carine ,   PROMISE Study Group, North Richard
Published: February 2019

Despite optimal medical management (OMM), low back pain (LBP) can be disabling, particularly after spinal surgery. Spinal cord stimulation (SCS) is effective in reducing neuropathic leg pain; however, evidence is limited for LBP. This prospective, open-label, parallel-group trial randomized (1:1) failed back surgery syndrome (FBSS) patients with predominant LBP to SCS plus OMM (SCS group) or OMM alone (OMM group) at 28 sites in Europe and the Americas. If trial stimulation was successful, a multicolumn SCS system was implanted. Outcomes were assessed at baseline (before randomization) and at 1, 3, 6, and 12 months after randomization. Patients could change treatment groups at 6 months. The primary outcome was the proportion of patients with ≥50% reduction in LBP (responder) at 6 months. Secondary outcomes included change in pain intensity, functional disability, and health-related quality of life (HRQoL). The results are posted at ClinicalTrials.gov under registration number NCT01697358. In the intent-to-treat analysis, there were more responders in the SCS group than in the OMM group (13.6%, 15/110 vs 4.6%, 5/108, difference 9% with 95% confidence interval 0.6%-17.5%, P = 0.036) at 6 months. The SCS group improved in all secondary outcomes compared with the OMM group. The OMM group only improved in HRQoL. In the SCS group, 17.6% (18/102) experienced SCS-related adverse events through 6 months, with 11.8% (12/102) requiring surgical reintervention. Adding multicolumn SCS to OMM improved pain relief, HRQoL, and function in a traditionally difficult-to-treat population of failed back surgery syndrome patients with predominant LBP. Improvements were sustained at 12 and 24 months.
The role of Nav1.7 in human nociceptors: insights from human induced pluripotent stem cell–derived sensory neurons of erythromelalgia patients
Authors: Meents Jannis E. , Bressan Elisangela , Sontag Stephanie , Foerster Alec , Hautvast Petra , Rösseler Corinna , Hampl Martin , Schüler Herdit , Goetzke Roman , Le Thi Kim Chi , Kleggetveit Inge Petter , Le Cann Kim , Kerth Clara , Rush Anthony M. , Rogers Marc , Kohl Zacharias , Schmelz Martin , Wagner Wolfgang , Jørum Ellen , Namer Barbara , Winner Beate , Zenke Martin , Lampert Angelika
Published: February 2019

The chronic pain syndrome inherited erythromelalgia (IEM) is attributed to mutations in the voltage-gated sodium channel (NaV) 1.7. Still, recent studies targeting NaV1.7 in clinical trials have provided conflicting results. Here, we differentiated induced pluripotent stem cells from IEM patients with the NaV1.7/I848T mutation into sensory nociceptors. Action potentials in these IEM nociceptors displayed a decreased firing threshold, an enhanced upstroke, and afterhyperpolarization, all of which may explain the increased pain experienced by patients. Subsequently, we investigated the voltage dependence of the tetrodotoxin-sensitive NaV activation in these human sensory neurons using a specific prepulse voltage protocol. The IEM mutation induced a hyperpolarizing shift of NaV activation, which leads to activation of NaV1.7 at more negative potentials. Our results indicate that NaV1.7 is not active during subthreshold depolarizations, but that its activity defines the action potential threshold and contributes significantly to the action potential upstroke. Thus, our model system with induced pluripotent stem cell–derived sensory neurons provides a new rationale for NaV1.7 function and promises to be valuable as a translational tool to profile and develop more efficacious clinical analgesics.
Cisplatin educates CD8+ T cells to prevent and resolve chemotherapy-induced peripheral neuropathy in mice
Authors: Laumet Geoffroy , Edralin Jules D. , Dantzer Robert , Heijnen Cobi J. , Kavelaars Annemieke
Published: February 2019

The mechanisms responsible for the persistence of chemotherapy-induced peripheral neuropathy (CIPN) in a significant proportion of cancer survivors are still unknown. Our previous findings show that CD8+ T cells are necessary for the resolution of paclitaxel-induced mechanical allodynia in male mice. In this study, we demonstrate that CD8+ T cells are not only essential for resolving cisplatin-induced mechanical allodynia, but also to normalize spontaneous pain, numbness, and the reduction in intraepidermal nerve fiber density in male and female mice. Resolution of CIPN was not observed in Rag2
−/− mice that lack T and B cells. Reconstitution of Rag2
−/− mice with CD8+ T cells before cisplatin treatment normalized the resolution of CIPN. In vivo education of CD8+ T cells by cisplatin was necessary to induce resolution of CIPN in Rag2

−/−
mice because adoptive transfer of CD8+ T cells from naive wild-type mice to Rag2
−/− mice after completion of chemotherapy did not promote resolution of established CIPN. The CD8+ T-cell-dependent resolution of CIPN does not require epitope recognition by the T-cell receptor. Moreover, adoptive transfer of cisplatin-educated CD8+ T cells to Rag2
−/− mice prevented CIPN development induced by either cisplatin or paclitaxel, indicating that the activity of the educated CD8+ T is not cisplatin specific. In conclusion, resolution of CIPN requires in vivo education of CD8+ T cells by exposure to cisplatin. Future studies should examine whether ex vivo CD8+ T cell education could be applied as a therapeutic strategy for treating or preventing CIPN in patients.
Nociceptin/orphanin FQ receptor modulates painful and fatigue symptoms in a mouse model of fibromyalgia
Authors: Dagnino Ana Paula Aquistapase , da Silva Rodrigo Braccini Madeira , Chagastelles Pedro Cesar , Pereira Talita Carneiro Brandão , Venturin Gianina Teribele , Greggio Samuel , Costa da Costa Jaderson , Bogo Maurício Reis , Campos Maria Martha
Published: February 2019

Generalized pain and fatigue are both hallmarks of fibromyalgia, a syndrome with an indefinite etiology. The treatment options for fibromyalgia are currently limited, probably because of its intricate pathophysiology. Thus, further basic and clinical research on this condition is currently needed. This study investigated the effects of nociceptin/orphanin FQ (N/OFQ) receptor (NOPr) ligands and the modulation of the NOP system in the preclinical mouse model of reserpine-induced fibromyalgia. The effects of administration of the natural agonist N/OFQ and the selective NOPr antagonists (UFP-101 and SB-612111) were evaluated in fibromyalgia-related symptoms in reserpine-treated mice. The expression of prepronociceptin/orphanin FQ and NOPr was assessed in central and peripheral sites at different time points after reserpine administration. Nociceptin/orphanin FQ displayed dual effects in the behavioral changes in the reserpine-elicited fibromyalgia model. The peptide NOPr antagonist UFP-101 produced analgesic and antifatigue effects, by preventing alterations in brain activity and skeletal muscle metabolism, secondary to fibromyalgia induction. The nonpeptide NOPr antagonist SB-612111 mirrored the favorable effects of UFP-101 in painful and fatigue alterations induced by reserpine. A time-related up- or downregulation of prepronociceptin/orphanin FQ and NOPr was observed in supraspinal, spinal, and peripheral sites of reserpine-treated mice. Our data shed new lights on the mechanisms underlying the fibromyalgia pathogenesis, supporting a role for N/OFQ-NOP receptor system in this syndrome.
Experimental evaluation of central pain processes in young women with primary dysmenorrhea
Authors: Payne Laura A. , Seidman Laura C. , Sim Myung-Shin , Rapkin Andrea J. , Naliboff Bruce D. , Zeltzer Lonnie K.
Published: February 2019

Primary dysmenorrhea (PD; menstrual pain without an underlying medical condition) is associated with enhanced pain sensitivity and temporal summation (TS) in adult women, which may reflect the presence of central pain processes. Research in this area has been limited by focusing on only adult populations and incomplete assessments of central sensitization. The current study explored both excitatory and inhibitory measures of pain processing in girls and young adult women with and without PD. Thirty-two young women with PD and 34 healthy controls underwent laboratory pain testing during each of 3 menstrual cycle phases (menstrual, ovulatory, and midluteal), which included measures of pain tolerance and threshold, TS, and conditioned pain modulation. Results indicated enhanced pain sensitivity in young women with PD as measured by heat pain tolerance and Average Pain50 (P50), compared with healthy controls. These group differences were evident at all phases of the menstrual cycle. No group differences in cold pain tolerance, TS, or conditioned pain modulation were evident at any phase of the menstrual cycle. These data suggest some evidence of central sensitization in young women with PD, although no evidence of enhanced excitatory or deficient inhibitory mechanisms were observed. Future research should focus on identifying other potential phenotypes for PD to determine those at risk of developing other pain problems.
Donor-Specific Human Leukocyte Antigen Antibody Formation After Distal Tibia Allograft and Subsequent Graft Resorption
Authors: Liwski Christopher R. , Dillman Daryl , Liwski Robert S. , Wong Ivan H.
Published: February 2019

The association between donor-specific human leukocyte antigen (HLA) antibody formation and small bone allograft resorption has not been studied. We present the case of a patient treated for glenoid bone loss using a distal tibial allograft with Bankart repair who formed donor-specific HLA antibodies against the allograft and had subsequent graft resorption. X-ray and computed tomography (CT) scans were performed before and after surgery at standard checkpoints. Patient blood and serum samples were collected before and after surgery for HLA typing and HLA antibody testing. Human leukocyte antigen antibodies against the donor-specific HLA-A2 antigens were identified 6 weeks after surgery and were still detected at 5 months after surgery. At 6 months after surgery, a CT arthrogram revealed significant graft resorption. This case shows a temporal correlation between HLA antibody formation and clinical findings, potentially suggesting an association between HLA antibody formation and graft resorption. Further study is required to confirm this.
Liver fibrosis is associated with risk for colorectal adenoma in patients with nonalcoholic fatty liver disease
Authors: Kim Min Cheol , Park Jung Gil , Jang Byung Ik , Lee Heon Ju , Lee Won Kee
Published: February 2019

Nonalcoholic fatty liver disease (NAFLD) is associated with risks for developing colorectal adenoma. This study aimed to evaluate the association between advanced fibrosis in NAFLD and the risk for colorectal adenoma.

We retrospectively analyzed the data of 6332 adults who underwent abdominal ultrasound and 1st-time colonoscopy on the same day in a health screening program at a single center. We evaluated the presence of advanced fibrosis in NAFLD using various noninvasive score, which also analyzed the detection rate of colorectal adenoma according to the presence of advanced fibrosis in NAFLD.

The subjects with NAFLD had a higher prevalence of colorectal adenoma. In the multivariate analysis, NAFLD was an independent risk factor for colorectal adenoma (adjusted odds ratio [OR], 1.15; 95% confidence interval [CI], 1.02–1.30), advanced adenoma (adjusted OR, 1.50; 95% CI, 1.12–2.01), and multiple adenomas (adjusted OR, 1.32; 95% CI, 1.01–1.73). When NAFLD was further stratified based on the stage of fibrosis using the noninvasive score models, the subjects with NAFLD and advanced fibrosis had a significantly higher risk for colorectal adenoma, advanced adenoma, and multiple adenomas than those with NAFLD without advanced fibrosis.

NAFLD with advanced fibrosis might be risk factor for colorectal adenoma compared with NAFLD without advanced fibrosis.
Herbal medicine (Zhengan Xifeng Decoction) for essential hypertension protocol for a systematic review and meta-analysis
Authors: Huang Yonglian , Chen Yanhong , Cai Hairong , Chen Dongjie , He Xiaoming , Li Zhixiong , Cai Xiaojing , Peng Xiaohong , Huang Yaxiu , Li Shaoping , Cao Qifeng , Wang Ping , Chen Bojun
Published: February 2019

Background:

Essential hypertension is one of the most common chronic diseases worldwide, as well as a leading risk factor for cardiocerebrovascular diseases. Zhengan Xifeng Decoction (ZGXFD) has been widely used to treat essential hypertension, but there is no systematic review by assessing efficacy and safety of ZGXFD on essential hypertension. Therefore, we aim to perform systematic review and meta-analysis to evaluate the efficacy and safety of ZGXFD in the treatment of essential hypertension.

Methods:

This systematic review and meta-analysis will be performed by means of electronic databases, including EMBASE, Cochrane Center Registration Controlled trials (Cochrane Library), Web of Science (WOS), World Health Organization International Clinical Trials Registry Platform, PubMed, China Biomedical Literature Database (CBM), China National Knowledge Infrastructure (CNKI), Chinese Scientific Journal Database (VIP), and Wan-fang database. The electronic databases will be searched from their inception to October 2018. This systemic review will include only published English and Chinese articles randomized controlled trials (RTCs) of ZGXFD on essential hypertension. The primary outcome is Efficacy and blood pressure (BP), blood lipid and adverse reactions will be accepted as secondary outcomes. All statistical analyses will be conducted using RevMan V.5.3.5 software.

Results:

This systematic review and meta-analysis will provide high-quality evidence from several aspects, including for efficacy, blood pressure, blood lipid and adverse effects to evaluate the efficacy and safety of ZGXFD on EHTN.

Conclusion:

This systematic review will determine whether or not ZGXFD is an effective intervention for essential hypertension.