bluuebunny/crossref_metadata_2025 huggingface dataset:
Molecular characteristics of stress overshoot for polymer melts under start-up shear flow
Authors: Jeong Sohdam , Kim Jun Mo , Baig Chunggi
Published: December 2017

Stress overshoot is one of the most important nonlinear rheological phenomena exhibited by polymeric liquids undergoing start-up shear at sufficient flow strengths. Despite considerable previous research, the fundamental molecular characteristics underlying stress overshoot remain unknown. Here, we analyze the intrinsic molecular mechanisms behind the overshoot phenomenon using atomistic nonequilibrium molecular dynamics simulations of entangled linear polyethylene melts under shear flow. Through a detailed analysis of the transient rotational chain dynamics, we identify an intermolecular collision angular regime in the vicinity of the chain orientation angle θ ≈ 20° with respect to the flow direction. The shear stress overshoot occurs via strong intermolecular collisions between chains in the collision regime at θ = 15°–25°, corresponding to a peak strain of 2–4, which is an experimentally well-known value. The normal stress overshoot appears at approximately θ = 10°, at a corresponding peak strain roughly equivalent to twice that for the shear stress. We provide plausible answers to several basic questions regarding the stress overshoot, which may further help understand other nonlinear phenomena of polymeric systems.
Micromagnetic simulation of the ground states of Ce-Fe-B amorphous nanodisks
Authors: Liu D. , Li G. , Zhao X. , Xiong J. F. , Li R. , Zhao T. Y. , Hu F. X. , Sun J. R. , Shen B. G.
Published: December 2017

Using 3D micromagnetics package OOMMF, the ground states of Ce2Fe14B amorphous nanodisks with different dimensions, initial magnetization states and magnetocrystalline anisotropy constants (K) in zero external field were investigated. The simulations indicate that the disk size is the decisive factor in determining magnetic configurations. A diagram is constructed to bring out the dependence of the different equilibrium states on the disk thickness and diameter. When the ratio of thickness (T) to diameter (D) is smaller than 1, the vortex state is energetically more favorable than other states and the eigenfrequency of vortex approximately proportional to (T/D)1/2. A variety of magnetization distributions of ground states for different anisotropy strengths is obtained. The result shows the magnetocrystalline anisotropy not only shrinks or broadens the vortex core but also induces an out-of-plane magnetization component both at the edge and the center of disks. When the K strength reaches a threshold value, there is a transition from vortex state to Bloch-type Skyrmion state which suggests the possibility of Skyrmion in rare-earth materials. In addition, in the system with specific aspect ratio and low intrinsic anisotropy, the vortex domain can always be sustained under various initial conditions. Meanwhile, the existence of stable vortex domain is found by experimentation in amorphous Ce-Fe-B ribbons which is in good agreement with the simulation result.
Broadband cross-polarization conversion by symmetry-breaking ultrathin metasurfaces
Authors: Hu Sha , Yang Shengyan , Liu Zhe , Li Junjie , Gu Changzhi
Published: December 2017

We demonstrate theoretically and experimentally a plasmonic metasurface operating as a broadband polarization converter with adequate efficiency which can transform linearly polarized light into its orthogonal polarization in the near-infrared region. The unit cell of the specifically designed metasurfaces is composed of an asymmetric split-ring resonator (SRR) within a square metallic hole. The adequate polarization conversion rate arises from the enhancement of the cross-polarized electric field and the decrease in the co-polarized electric field induced by the symmetry breaking of the SRR. Furthermore, a broad operating frequency range results from the overlap of multiple polarization rotation responses, which are generated in the combined symmetry-breaking SRRs and square metallic holes. This ultrathin single-layer metasurface avoids the complicated fabrication process of multilayered and tridimensional polarization converters and offers more intriguing possibilities to design high-performance plasmonic metasurfaces for polarization modulation.
Quantum supervaluationism
Authors: Bolotin Arkady
Published: December 2017

As it is known, neither classical logical conjunction “and” nor classical logical alternative “either…or” can replace “+” representing a linear superposition of two quantum states. Therefore, to provide a logical account of the quantum superposition, one must either reconsider the standard interpretation of quantum mechanics (making it fit for classical bivalent logic) or replace the standard logic with a deviant logic suitable for describing the superposition. In this paper, a supervaluation approach to the description of the quantum superposition is considered. In accordance with this approach, the indefinite propositions, which correspond to the superposition states, lack truth-values of any kind, even granting that their compounds (such as logical alternative “either…or”) can have truth-values. As an illustration, the supervaluationist account of the superposition of spin states is presented.
Structural predictor for nonlinear sheared dynamics in simple glass-forming liquids
Authors: Ingebrigtsen Trond S. , Tanaka Hajime
Published: December 2017

Significance

Fluidity is the key dynamical physical property of the liquid state and is characterized by the transport coefficient, viscosity. For slow flow, the viscosity of a liquid is generally independent of the flow rate. For fast flow, however, the behavior can be much more complicated; for example, supercooled liquids are known to exhibit a drastic decrease in viscosity under high flow rates, thus flowing more easily and dissipating less energy. Despite its fundamental and industrial importance, the physical mechanism behind this phenomenon known as “shear thinning” remains unknown. Here, we show that shear thinning is characterized only by the flow-induced change of the liquid structure along the extensional direction of the flow, providing a hint at understanding this long-standing unresolved problem.
For a multidimensional class analysis in Africa
Authors: Noret Joël
Published: December 2017

How can we analyse the dynamics of social structure in Africa today? This Debate piece argues that a Bourdieu-inspired, multidimensional class analysis opens promising perspectives for understanding class dynamics in Africa. This implies notably bridging objectivist and subjectivist approaches to class analysis, and working with a multidimensional idea of the social space.
Mannose receptor high, M2 dermal macrophages mediate nonhealing Leishmania major infection in a Th1 immune environment
Authors: Lee Sang Hun , Charmoy Melanie , Romano Audrey , Paun Andrea , Chaves Mariana M. , Cope Frederick O. , Ralph David A. , Sacks David L.
Published: December 2017

The origin and functional specialization of dermal macrophages in cutaneous infections have been little studied. In this paper, we show that a strain of Leishmania major (L. major Seidman [LmSd]) that produces nonhealing cutaneous lesions in conventionally resistant C57BL/6 mice was more efficiently taken up by M2-polarized bone marrow (BM)–derived macrophages (BMDMs) in vitro and by mannose receptor (MR)hi dermal macrophages in vivo compared with a healing strain (L. major Friedlin V1). Both in steady and in T helper type 1 (Th1) cell–driven inflammatory states, the MRhi dermal macrophages showed M2 characteristics. The dermal macrophages were radio resistant and not replaced by monocytes or adult BM-derived cells during infection, but were locally maintained by IL-4 and IL-10. Notably, the favored infection of M2 BMDMs by LmSd in vitro was MR dependent, and genetic deletion of MR or selective depletion of MRhi dermal macrophages by anti–CSF-1 receptor antibody reversed the nonhealing phenotype. We conclude that embryonic-derived, MRhi dermal macrophages are permissive for parasite growth even in a strong Th1-immune environment, and the preferential infection of these cells plays a crucial role in the severity of cutaneous disease.
Voltage modulates halothane-triggered Ca2+ release in malignant hyperthermia-susceptible muscle
Authors: Zullo Alberto , Textor Martin , Elischer Philipp , Mall Stefan , Alt Andreas , Klingler Werner , Melzer Werner
Published: December 2017

Malignant hyperthermia (MH) is a fatal hypermetabolic state that may occur during general anesthesia in susceptible individuals. It is often caused by mutations in the ryanodine receptor RyR1 that favor drug-induced release of Ca2+ from the sarcoplasmic reticulum. Here, knowing that membrane depolarization triggers Ca2+ release in normal muscle function, we study the cross-influence of membrane potential and anesthetic drugs on Ca2+ release. We used short single muscle fibers of knock-in mice heterozygous for the RyR1 mutation Y524S combined with microfluorimetry to measure intracellular Ca2+ signals. Halothane, a volatile anesthetic used in contracture testing for MH susceptibility, was equilibrated with the solution superfusing the cells by means of a vaporizer system. In the range 0.2 to 3%, the drug causes significantly larger elevations of free myoplasmic [Ca2+] in mutant (YS) compared with wild-type (WT) fibers. Action potential–induced Ca2+ signals exhibit a slowing of their time course of relaxation that can be attributed to a component of delayed Ca2+ release turnoff. In further experiments, we applied halothane to single fibers that were voltage-clamped using two intracellular microelectrodes and studied the effect of small (10-mV) deviations from the holding potential (−80 mV). Untreated WT fibers show essentially no changes in [Ca2+], whereas the Ca2+ level of YS fibers increases and decreases on depolarization and hyperpolarization, respectively. The drug causes a significant enhancement of this response. Depolarizing pulses reveal a substantial negative shift in the voltage dependence of activation of Ca2+ release. This behavior likely results from the allosteric coupling between RyR1 and its transverse tubular voltage sensor. We conclude that the binding of halothane to RyR1 alters the voltage dependence of Ca2+ release in MH-susceptible muscle fibers such that the resting membrane potential becomes a decisive factor for the efficiency of the drug to trigger Ca2+ release.
A hybrid-hierarchical genome assembly strategy to sequence the invasive golden mussel, Limnoperna fortunei
Authors: Uliano-Silva Marcela , Dondero Francesco , Dan Otto Thomas , Costa Igor , Lima Nicholas Costa Barroso , Americo Juliana Alves , Mazzoni Camila Junqueira , Prosdocimi Francisco , Rebelo Mauro de Freitas
Published: December 2017

Background

For more than 25 years, the golden mussel, Limnoperna fortunei, has aggressively invaded South American freshwaters, having travelled more than 5000 km upstream across 5 countries. Along the way, the golden mussel has outcompeted native species and economically harmed aquaculture, hydroelectric powers, and ship transit. We have sequenced the complete genome of the golden mussel to understand the molecular basis of its invasiveness and search for ways to control it.

Findings

We assembled the 1.6-Gb genome into 20 548 scaffolds with an N50 length of 312 Kb using a hybrid and hierarchical assembly strategy from short and long DNA reads and transcriptomes. A total of 60 717 coding genes were inferred from a customized transcriptome-trained AUGUSTUS run. We also compared predicted protein sets with those of complete molluscan genomes, revealing an exacerbation of protein-binding domains in L. fortunei.

Conclusions

We built one of the best bivalve genome assemblies available using a cost-effective approach using Illumina paired-end, mate-paired, and PacBio long reads. We expect that the continuous and careful annotation of L. fortunei's genome will contribute to the investigation of bivalve genetics, evolution, and invasiveness, as well as to the development of biotechnological tools for aquatic pest control.
Global leaf nitrogen and phosphorus stoichiometry and their scaling exponent
Authors: Tian Di , Yan Zhengbing , Niklas Karl J , Han Wenxuan , Kattge Jens , Reich Peter B , Luo Yongkai , Chen Yahan , Tang Zhiyao , Hu Huifeng , Wright Ian J , Schmid Bernhard , Fang Jingyun
Published: December 2017

Leaf nitrogen (N) and phosphorus (P) concentrations constrain photosynthetic and metabolic processes, growth and the productivity of plants. Their stoichiometry and scaling relationships regulate the allocation of N and P from subcellular to organism, and even ecosystem levels, and are crucial to the modelling of plant growth and nutrient cycles in terrestrial ecosystems. Prior work has revealed a general biogeographic pattern of leaf N and P stoichiometric relationships and shown that leaf N scales roughly as two-thirds the power of P. However, determining whether and how leaf N and P stoichiometries, especially their scaling exponents, change with functional groups and environmental conditions requires further verification. In this study, we compiled a global data set and documented the global leaf N and P concentrations and the N:P ratios by functional group, climate zone and continent. The global overall mean leaf N and P concentrations were 18.9 mg g−1 and 1.2 mg g−1, respectively, with significantly higher concentrations in herbaceous than woody plants (21.72 mg g−1 vs. 18.22 mg g−1 for N; and 1.64 mg g−1 vs. 1.10 mg g−1 for P). Both leaf N and P showed higher concentrations at high latitudes than low latitudes. Among six continents, Europe had the highest N and P concentrations (20.79 and 1.54 mg g−1) and Oceania had the smallest values (10.01 and 0.46 mg g−1). These numerical values may be used as a basis for the comparison of other individual studies. Further, we found that the scaling exponent varied significantly across different functional groups, latitudinal zones, ecoregions and sites. The exponents of herbaceous and woody plants were 0.659 and 0.705, respectively, with significant latitudinal patterns decreasing from tropical to temperate to boreal zones. At sites with a sample size ≥10, the values fluctuated from 0.366 to 1.928, with an average of 0.841. Several factors including the intrinsic attributes of different life forms, P-related growth rates and relative nutrient availability of soils likely account for the inconstant exponents of leaf N vs. P scaling relationships.
Pharmacodynamics and Pharmacokinetics of Lidocaine in a Rodent Model of Diabetic Neuropathy
Authors: ten Hoope Werner , Hollmann Markus W. , de Bruin Kora , Verberne Hein J. , Verkerk Arie O. , Tan Hanno L. , Verhamme Camiel , Horn Janneke , Rigaud Marcel , Picardi Susanne , Lirk Philipp
Published: December 2017

Background

Clinical and experimental data show that peripheral nerve blocks last longer in the presence of diabetic neuropathy. This may occur because diabetic nerve fibers are more sensitive to local anesthetics or because the local anesthetic concentration decreases more slowly in the diabetic nerve. The aim of this study was to investigate both hypotheses in a rodent model of neuropathy secondary to type 2 diabetes.

Methods

We performed a series of sciatic nerve block experiments in 25 Zucker Diabetic Fatty rats aged 20 weeks with a neuropathy component confirmed by neurophysiology and control rats. We determined in vivo the minimum local anesthetic dose of lidocaine for sciatic nerve block. To investigate the pharmacokinetic hypothesis, we determined concentrations of radiolabeled (14C) lidocaine up to 90 min after administration. Last, dorsal root ganglia were excised for patch clamp measurements of sodium channel activity.

Results

First, in vivo minimum local anesthetic dose of lidocaine for sciatic nerve motor block was significantly lower in diabetic (0.9%) as compared to control rats (1.4%). Second, at 60 min after nerve block, intraneural lidocaine was higher in the diabetic animals. Third, single cell measurements showed a lower inhibitory concentration of lidocaine for blocking sodium currents in neuropathic as compared to control neurons.

Conclusions

We demonstrate increased sensitivity of the diabetic neuropathic nerve toward local anesthetics, and prolonged residence time of local anesthetics in the diabetic neuropathic nerve. In this rodent model of neuropathy, both pharmacodynamic and pharmacokinetic mechanisms contribute to prolonged nerve block duration.
Cost-Effective Hearing Conservation: Regulatory and Research Priorities
Authors: Dobie Robert A.
Published: December 2017

Hearing conservation programs (HCPs) mandated by the US Occupational Safety and Health Administration (OSHA) cost about $350/worker/year. Are they cost-effective? A cross-sectional model of the US adult population with and without HCPs incorporates (1) the American Medical Association’s method for estimating binaural hearing impairment and whole-person impairment; (2) the model of the International Organization for Standardization (ISO) for estimating both age-related and noise-induced hearing loss; and (3) an acceptable cost of $50,000 per quality-adjusted life year. The ISO model’s outputs were audiometric thresholds for groups of people with different age, sex, and noise exposure history. These thresholds were used to estimate cost per quality-adjusted life year saved for people in HCPs with different noise exposure levels. Model simulations suggest that HCPs may be cost-effective only when time-weighted average (TWA) noise exposures are ≥ 90 dBA. Enforcing existing regulations, requiring engineering noise control at high exposure levels, and using new methods that can document hearing protection device performance could improve cost-effectiveness. If the OSHA action level remains at 85 dBA-TWA, reducing the permissible exposure limit to the same level would simplify management and slightly improve cost-effectiveness. Research should evaluate employer compliance across industries, determine whether workers currently excluded from HCP regulations are at risk of noise-induced hearing loss, and develop cost-effective HCPs for mobile workers in construction, agriculture, and oil and gas drilling and servicing. Research on HCP cost-effectiveness could be extended to incorporate sensitivity analyses of the effects of a wider range of assumptions.
Effect of Boarding on Mortality in ICUs
Authors: Stretch Robert , Della Penna Nicolás , Celi Leo Anthony , Landon Bruce E.
Published: December 2017

Objectives:

Hospitals use a variety of strategies to maximize the availability of limited ICU beds. Boarding, which involves assigning patients to an open bed in a different subspecialty ICU, is one such practice employed when ICU occupancy levels are high, and beds in a particular unit are unavailable. Boarding disrupts the normal geographic colocation of patients and care teams, exposing patients to nursing staff with different training and expertise to those caring for nonboarders. We analyzed whether medical ICU patients boarding in alternative specialty ICUs are at increased risk of mortality.

Design:

Retrospective cohort study using an instrumental variable analysis to control for unmeasured confounding. A semiparametric bivariate probit estimation strategy was employed for the instrumental model. Propensity score matching and standard logistic regression (generalized linear modeling) were used as robustness checks.

Setting:

The medical ICU of a tertiary care nonprofit hospital in the United States between 2002 and 2012.

Patients:

All medical ICU admissions during the specified time period.

Interventions:

None.

Measurements and Main Results:

The study population consisted of 8,429 patients of whom 1,871 were boarders. The instrumental variable model demonstrated a relative risk of 1.18 (95% CI, 1.01–1.38) for ICU stay mortality for boarders. The relative risk of in-hospital mortality among boarders was 1.22 (95% CI, 1.00–1.49). GLM and propensity score matching without use of the instrument yielded similar estimates. Instrumental variable estimates are for marginal patients, whereas generalized linear modeling and propensity score matching yield population average effects.

Conclusions:

Mortality increased with boarding of critically ill patients. Further research is needed to identify safer practices for managing patients during periods of high ICU occupancy.
Comparison of Hyaluronic Acid Gel With (HARDL) and Without Lidocaine (HAJUP) in the Treatment of Moderate-To-Severe Nasolabial Folds: A Randomized, Evaluator-Blinded Study
Authors: Baumann Leslie , Weiss Robert A. , Grekin Steven , Narins Rhoda , Gold Michael , Donofrio Lisa , Nogueira Alessandra , Shawcross Heather , Brown Sarah , Mashburn Jay H.
Published: December 2017

BACKGROUND

Injectable fillers, such as those containing hyaluronic acid (HA), are increasingly used to smooth age-related facial creases and wrinkles.

OBJECTIVE

To compare efficacy and safety of a HA gel with lidocaine formulated by XpresHAn Technology (HARDL) with a HA gel without lidocaine produced by Hylacross technology (HAJUP) in the treatment of moderate-to-severe nasolabial folds.

MATERIALS AND METHODS

Subjects (n = 162) received initial and touch-up injections with HARDL and HAJUP on either side of the face. Investigator- and subject-assessed wrinkle severity was measured up to 48 weeks after final injection.

RESULTS

Mean (SD) Wrinkle Severity Rating Scale was improved by 1.1 (0.75) and 1.1 (0.68) with HARDL and HAJUP, respectively, at 24 weeks; improvements were sustained up to Week 48 with both treatments. Noninferiority of HARDL was demonstrated (mean difference −0.09 [95% confidence interval: −0.18 to −0.01], p = .032) at 24 weeks. Adverse events were reported in 43% subjects, 12% were treatment related, with a similar distribution for both treatments.

CONCLUSION

Effectiveness and safety profiles of HARDL and HAJUP were comparable.
Moving Pulmonary Rehabilitation Into the Home
Authors: Garvey Chris , Singer Jonathan P. , Bruun Allan Murphy , Soong Allison , Rigler Julia , Hays Steven
Published: December 2017

Pulmonary rehabilitation (PR) is the standard of care for persons with chronic, symptomatic lung disease. The availability of PR is limited, particularly in rural areas. In addition, barriers to PR include the lack of transportation, patient inconvenience, inadequate insurance coverage, and cost. Technology has the potential to overcome several barriers to PR by enhancing the availability and uptake of PR principles through the development of technology-supported, home-based PR programs. For technology-supported, home-based PR, or telehealth PR, to be effective, key components of traditional PR must be present including appropriate individualized exercise prescription, self-management education, outcome measurements, and patient support. This clinical review summarizes the current practice of PR, describes limitations to the availability of PR, describes key principles that technology should feature to ensure best practices are met, and proposes current and future technology options as an emerging strategy for home delivery of PR and its components.
Transcatheter Aortic Valve Replacement
Authors: Goel Kashish , Holmes David R.
Published: December 2017

Transcatheter aortic valve replacement (TAVR) has been approved in the United States for intermediate and high-risk patients with severe symptomatic aortic stenosis. More than 80 000 TAVR procedures have been performed in the United States and the number is growing every year. Two valve designs are approved in the United States including the balloon expandable Edwards Sapien prosthesis and self-expanding CoreValve prosthesis. The PARTNER trial of the Sapien valve, involving patients who were considered inoperable, reported a 19% absolute risk reduction in mortality compared with medical therapy, with a number needed to treat of 5. Randomized controlled trials in patients with high and intermediate risk of inhospital mortality based on the Society of Thoracic Surgeons score showed noninferiority of TAVR compared with surgical aortic valve replacement. Major complications associated with TAVR include a 2% to 3% risk of stroke at 30 d, 8% to 25% risk of permanent pacemaker implantation depending on valve design, and 6% risk of major vascular complications. There are some concerns regarding valve durability as this technology is extended to younger patients with lower risk. Five-year follow-up data from the initial PARTNER trials noted appropriate valve performance and hemodynamics in survivors; however, longer follow-up is required to assess the true incidence of structural deterioration. Approximately one-third of TAVR patients are transferred to a transitional care facility after TAVR, and more than 50% of the patients are frail. Cardiac rehabilitation has been reported to be safe in post-TAVR patients and was associated with significant improvements in exercise capacity, functional independence, and frailty.
Mesenchymal stem cell-derived extracellular vesicles attenuate pulmonary vascular permeability and lung injury induced by hemorrhagic shock and trauma
Authors: Potter Daniel R. , Miyazawa Byron Y. , Gibb Stuart L. , Deng Xutao , Togaratti Padma P. , Croze Roxanne H. , Srivastava Amit K. , Trivedi Alpa , Matthay Michael , Holcomb John B. , Schreiber Martin A. , Pati Shibani
Published: December 2017

BACKGROUND

Mesenchymal stem cells (MSCs) have been shown to mitigate vascular permeability in hemorrhagic shock (HS) and trauma-induced brain and lung injury. Mechanistically, paracrine factors secreted from MSCs have been identified that can recapitulate many of the potent biologic effects of MSCs in animal models of disease. Interestingly, MSC-derived extracellular vesicles (EVs), contain many of these key soluble factors, and have therapeutic potential independent of the parent cells. In this study we sought to determine whether MSC-derived EVs (MSC EVs) could recapitulate the beneficial therapeutic effects of MSCs on lung vascular permeability induced by HS in mice.

METHODS

Mesenchymal stem cell EVs were isolated from human bone marrow-derived MSCs by ultracentrifugation. A mouse model of fixed pressure HS was used to study the effects of shock, shock + MSCs and shock + MSC EVs on lung vascular endothelial permeability. Mice were administered MSCs, MSC EVs, or saline IV. Lung tissue was harvested and assayed for permeability, RhoA/Rac1 activation, and for differential phosphoprotein expression. In vitro, human lung microvascular cells junctional integrity was evaluated by immunocytochemistry and endothelial cell impedance assays.

RESULTS

Hemorrhagic shock-induced lung vascular permeability was significantly decreased by both MSC and MSC EV infusion. Phosphoprotein profiling of lung tissue revealed differential activation of proteins and pathways related to cytoskeletal rearrangement and regulation of vascular permeability by MSCs and MSC EVs. Lung tissue from treatment groups demonstrated decreased activation of the cytoskeletal GTPase RhoA. In vitro, human lung microvascular cells, MSC CM but not MSC-EVs prevented thrombin-induced endothelial cell permeability as measured by electrical cell-substrate impedance sensing system and immunocytochemistry of VE-cadherin and actin.

CONCLUSION

Mesenchymal stem cells and MSC EVs modulate cytoskeletal signaling and attenuate lung vascular permeability after HS. Mesenchymal stem cell EVs may potentially be used as a novel “stem cell free” therapeutic to treat HS-induced lung injury.
Beta blockers in critically ill patients with traumatic brain injury: Results from a multicenter, prospective, observational American Association for the Surgery of Trauma study
Authors: Ley Eric J. , Leonard Samuel D. , Barmparas Galinos , Dhillon Navpreet K. , Inaba Kenji , Salim Ali , O'Bosky Karen R. , Tatum Danielle , Azmi Hooman , Ball Chad G. , Engels Paul T. , Dunn Julie A. , Carrick Matthew M. , Meizoso Jonathan P. , Lombardo Sarah , Cotton Bryan A. , Schroeppel Thomas J. , Rizoli Sandro , Chang David S. J. , de León Luis Alejandro , Rezende-Neto Joao , Jacome Tomas , Xiao Jimmy , Mallory Gina , Rao Krishnamurti , Widdel Lars , Godin Samuel , Coates Angela , Benedict Leo Andrew , Nirula Raminder , Kaul Sanjeev , Li Tong
Published: December 2017

BACKGROUND

Beta blockers, a class of medications that inhibit endogenous catecholamines interaction with beta adrenergic receptors, are often administered to patients hospitalized after traumatic brain injury (TBI). We tested the hypothesis that beta blocker use after TBI is associated with lower mortality, and secondarily compared propranolol to other beta blockers.

METHODS

The American Association for the Surgery of Trauma Clinical Trial Group conducted a multi-institutional, prospective, observational trial in which adult TBI patients who required intensive care unit admission were compared based on beta blocker administration.

RESULTS

From January 2015 to January 2017, 2,252 patients were analyzed from 15 trauma centers in the United States and Canada with 49.7% receiving beta blockers. Most patients (56.3%) received the first beta blocker dose by hospital day 1. Those patients who received beta blockers were older (56.7 years vs. 48.6 years, p < 0.001) and had higher head Abbreviated Injury Scale scores (3.6 vs. 3.4, p < 0.001). Similarities were noted when comparing sex, admission hypotension, mean Injury Severity Score, and mean Glasgow Coma Scale. Unadjusted mortality was lower for patients receiving beta blockers (13.8% vs. 17.7%, p = 0.013). Multivariable regression determined that beta blockers were associated with lower mortality (adjusted odds ratio, 0.35; p < 0.001), and propranolol was superior to other beta blockers (adjusted odds ratio, 0.51, p = 0.010). A Cox-regression model using a time-dependent variable demonstrated a survival benefit for patients receiving beta blockers (adjusted hazard ratio, 0.42, p < 0.001) and propranolol was superior to other beta blockers (adjusted hazard ratio, 0.50, p = 0.003).

CONCLUSION

Administration of beta blockers after TBI was associated with improved survival, before and after adjusting for the more severe injuries observed in the treatment cohort. This study provides a robust evaluation of the effects of beta blockers on TBI outcomes that supports the initiation of a multi-institutional randomized control trial.

LEVEL OF EVIDENCE

Therapeutic/care management, level III.
Benchmarking clinical outcomes and the immunocatabolic phenotype of chronic critical illness after sepsis in surgical intensive care unit patients
Authors: Stortz Julie A. , Mira Juan C. , Raymond Steven L. , Loftus Tyler J. , Ozrazgat-Baslanti Tezcan , Wang Zhongkai , Ghita Gabriela L. , Leeuwenburgh Christiaan , Segal Mark S. , Bihorac Azra , Brumback Babette A. , Mohr Alicia M. , Efron Philip A. , Moldawer Lyle L. , Moore Frederick A. , Brakenridge Scott C.
Published: December 2017

BACKGROUND

A growing number of patients survive sepsis but remain chronically critically ill. We sought to define clinical outcomes and incidence of chronic critical illness (CCI) after sepsis and to determine whether selected biomarkers of inflammation, immunosuppression, and catabolism differ between these patients and those that rapidly recover (RAP).

METHODS

This 3-year prospective observational cohort study (NCT02276417) evaluated 145 surgical intensive care unit patients with sepsis for the development of CCI (≥14 days of intensive care unit resource utilization with persistent organ dysfunction). Patient clinical demographics, outcomes, and serial serum/urine samples were collected for plasma protein and urinary metabolite analyses.

RESULTS

Of 145 sepsis patients enrolled, 19 (13%) died during their hospitalization and 71 (49%) developed CCI. The CCI patients were significantly older (mean, 63 ± 15 vs. 58 ± 13 years, p = 0.006) and more likely to be discharged to long-term acute care facilities (32% vs. 3%, p < 0.0001), whereas those with RAP were more often discharged to home or a rehabilitation facility. Six-month mortality was significantly higher in CCI as compared with RAP cohort (37% vs. 2%; p < 0.01). Multivariate logistic regression modeling revealed delayed onset sepsis (>48 hours after admission; odds ratio [OR], 10.93; 95% confidence interval [CI], 4.15–28.82]), interfacility transfer (OR, 3.58; 95% CI, 1.43–8.96), vasopressor-dependent septic shock (OR, 3.75; 95% CI, 1.47–9.54), and Sequential Organ Failure Assessment score of 5 or greater at 72 hours (OR, 5.03; 95% CI, 2.00–12.62) as independent risk factors for the development of CCI. The CCI patients also demonstrated greater elevations in inflammatory cytokines (IL-6, IL-8, IL-10), and biomarker profiles are consistent with persistent immunosuppression (absolute lymphocyte count and soluble programmed death ligand 1) and catabolism (plasma insulin-like growth factor binding protein 3 and urinary 3-methylhistidine excretion).

CONCLUSION

The development of CCI has become the predominant clinical trajectory in critically ill surgical patients with sepsis. These patients exhibit biomarker profiles consistent with an immunocatabolic phenotype of persistent inflammation, immunosuppression, and catabolism.

LEVEL OF EVIDENCE

Prognostic, level II.
Microparticles formed during storage of red blood cell units support thrombin generation
Authors: Bouchard Beth A. , Orfeo Thomas , Keith Hollis N. , Lavoie Elizabeth M. , Gissel Matthew , Fung Mark , Mann Kenneth G.
Published: December 2017

BACKGROUND

Intact red blood cells (RBCs) appear to support thrombin generation in in vitro models of blood coagulation. During storage of RBC units, biochemical, structural, and physiological changes occur including alterations to RBC membranes and release of microparticles, which are collectively known as storage lesion. The clinical consequences of microparticle formation in RBC units are unclear. This study was performed to assess thrombin generation via the prothrombinase complex by washed RBCs and RBC-derived microparticles as a function of RBC unit age.

METHODS

Well-characterized kinetic and flow cytometric assays were used to quantify and characterize microparticles isolated from leukocyte-reduced RBC units during storage for 42 days under standard blood banking conditions.

RESULTS

Stored RBCs exhibited known features of storage lesion including decreasing pH, cell lysis, and release of microparticles demonstrated by scanning electron microscopy. The rate of thrombin formation by RBC units linearly increased during storage, with the microparticle fraction accounting for approximately 70% of the prothrombinase activity after 35 days. High-resolution flow cytometric analyses of microparticle isolates identified phosphatidylserine-positive RBC-derived microparticles; however, their numbers over time did not correlate with thrombin formation in that fraction.

CONCLUSION

Red blood cell-derived microparticles capable of supporting prothrombinase function accumulate during storage, suggesting an increased potential of transfused units as they age to interact in unplanned ways with ongoing hemostatic processes in injured individuals, especially given the standard blood bank practice of using the oldest units available.
A retrospective analysis of the respiratory adjusted shock index to determine the presence of occult shock in trauma patients
Authors: Caputo Nicholas , Reilly James , Kanter Marc , West Jason
Published: December 2017

BACKGROUND

The shock index (SI), calculated as hear rate/systolic blood pressure, is a simple hemodynamic marker that may be used to assess for the presence of occult shock in trauma patients. The normal range for a healthy adult patient is 0.5 to 0.7. Recently, studies have demonstrated that tachypnea is the most important predictor of cardiac arrest in hospital wards and is an important indicator of derangements across multiple organ systems. As such, we have sought to determine whether the inclusion of the patient’s respiratory rate (RR) to the already existing SI (called the Respiratory Adjusted Shock Index [RASI]), calculated as hear rate/systolic blood pressure*(RR/10), will improve the overall diagnostic accuracy of detecting patients in early occult shock.

METHODS

A retrospective chart review over a 4-year period (2012–2016) at an urban, Level I trauma center was performed. All patients admitted to hospital for trauma were included in the study. Exclusion criteria were patients in traumatic arrest or in overt shock. Charts were reviewed for triage vital signs and point of care lactate drawn within 30 minutes of presentation. A lactate greater than 2 mmol/L was used to determine presence of hypoperfusion. The upper limit of normal for the RASI was calculated by multiplying the upper limit of the SI by 1.9 (RR of 19 divided by 10) and validated internally.

RESULTS

A total of 3,093 patients were included in this study. There was no difference in SI for patients discharged versus patients admitted, 0.6 (95% CI, 0.5–0.7) versus 0.7 (95% CI, 0.5–0.8) and a significant difference between the same groups of patients (discharged vs. admitted) for the RASI, 1.1 (95% CI, 1.04–1.18) versus 1.46 (95% CI, 1.35–1.55), respectively. Area under the curve for SI was 0.58 and for the RASI score was 0.94.

CONCLUSION

The RASI score improves diagnostic accuracy for detecting early occult shock in trauma patients when compared to the SI.

LEVEL OF EVIDENCE

Diagnostic, level II.
Transcriptomic changes following valproic acid treatment promote neurogenesis and minimize secondary brain injury
Authors: Nikolian Vahagn C. , Dennahy Isabel S. , Higgins Gerald A. , Williams Aaron M. , Weykamp Michael , Georgoff Patrick E. , Eidy Hassan , Ghandour Mohamed H. , Chang Panpan , Alam Hasan B.
Published: December 2017

BACKGROUND

Early treatment with valproic acid (VPA) has demonstrated benefit in preclinical models of traumatic brain injury, including smaller brain lesion size, decreased edema, reduced neurologic disability, and faster recovery. Mechanisms underlying these favorable outcomes are not fully understood. We hypothesized that VPA treatment would upregulate genes involved in cell survival and proliferation and downregulate those associated with cell death and the inflammatory response.

METHODS

Ten female swine were subjected to a protocol of traumatic brain injury and hemorrhagic shock. They were assigned to two groups (n = 5): normal saline (NS; 3× volume of shed blood), or NS + VPA (150 mg/kg). Following 6 hours of observation, brain tissue was harvested to evaluate lesion size and edema. Brain tissue was processed for RNA sequencing. Gene set enrichment and pathway analysis was performed to determine the differential gene expression patterns following injury.

RESULTS

Animals treated with VPA were noted to have a 46% reduction in brain lesion size and a 57% reduction in ipsilateral brain edema. Valproic acid significantly upregulated genes involved in morphology of the nervous system, neuronal development and neuron quantity. The VPA treatment downregulated pathways related to apoptosis, glial cell proliferation, and neuroepithelial cell differentiation. Ingenuity Pathway Analysis identified VPA as the top upstream regulator of activated transcription, supporting it as a direct cause of these transcriptional changes. Master transcriptional regulator NEUROD1 was also significantly upregulated, suggesting that VPA may induce additional transcription factors.

CONCLUSION

Administration of VPA attenuated brain lesion size, reduced brain edema, and induced significant changes in the transcriptome of injured brain within 6 hours. Patterns of differential expression were consistent with the proposed neurogenic and prosurvival effects of VPA treatment.
Human adipose-derived stem cell treatment modulates cellular protection in both in vitro and in vivo traumatic brain injury models
Authors: Kappy Nikolas S. , Chang Shaohua , Harris William M. , Plastini Michael , Ortiz Telisha , Zhang Ping , Hazelton Joshua P. , Carpenter Jeffrey P. , Brown Spencer A.
Published: December 2017

BACKGROUND

Traumatic brain injury (TBI) is a common cause of morbidity and mortality in the civilian population. The purpose of this study was to examine the effect(s) of adipose-derived stem cell (ASC) treatment on cellular and functional recovery in TBI via both in vitro and in vivo methods.

METHODS

Cultured neuroblastoma cells, SH-SY5Y, were scratched to mimic TBI in an in vitro model. The effect of ASC-conditioned medium (CM) on cell death, mitochondrial function, and expression of inflammatory cytokines (tumor necrosis factor α [TNF-α], interleukin 1β [IL-1β], and IL-6), as well as apoptosis marker FAS, was measured. In our in vivo model, Sprague-Dawley rats underwent TBI via a frontal, closed-head injury model. Animals randomly received either intravenous human-derived ASCs or intravenous saline within 3 hours of injury and were compared with a sham group. Functional recovery was evaluated via accelerating Rotarod method. On post-TBI Day 3, brain tissue was harvested and assessed for cellular damage via enzyme-linked immunosorbent assay for TNF-α, as well as immunohistochemical staining for β-amyloid precursor protein (β-APP).

RESULTS

Our in vitro data show that ASC treatment imparted reduced cell death (ratio to control: 1.21 ± 0.066 vs. 1.01 ± 0.056, p = 0.017), increased cell viability (ratio to control: 0.86 ± 0.009 vs. 1.09 ± 0.01, p = 0.0001), increased mitochondrial function (percentage of control: 78 ± 6% vs. 68 ± 3%), and significantly decreased levels of inflammatory cytokine IL-1β. In our in vivo study, compared with TBI alone, ASC-treated animals showed no difference in functional recovery, lower levels of expressed TNF-α (ratio to total protein, 0.47 ± 0.01 vs. 0.67 ± 0.04; p < 0.01), and lower levels of β-amyloid precursor protein (fluorescence ratio, 0.43 ± 0.05 vs. 0.69 ± 0.03; p < 0.01).

CONCLUSIONS

Adipose-derived stem cell treatment results in improved cell survival, decreased inflammatory marker release, and decreased evidence of neural injury. No difference in functional recovery was seen. These data suggest the potential for ASC treatment to aid in cellular protection and recovery in neural cells following TBI.
Simulating a virtual population's sensitivity to salt and uninephrectomy
Authors: Clemmer John S. , Hester Robert L. , Pruett W. Andrew
Published: December 2017

Salt sensitivity, with or without concomitant hypertension, is associated with increased mortality. Reduced functional renal mass plays an important role in causing salt-sensitive hypertension for many individuals. Factors that are important in the condition of decreased renal mass and how they affect blood pressure (BP) or salt sensitivity are unclear. We used HumMod, an integrative mathematical model of human physiology, to create a heterogeneous population of 1000 virtual patients by randomly varying physiological parameters. We examined potential physiological mechanisms responsible for the change in BP in response to high-salt diet (8× change in salt intake for three weeks) with full kidney mass and again after the removal of one kidney in the same group of virtual patients. We used topological data analysis (TDA), a clustering algorithm tool, to analyse the large dataset and separate patient subpopulations. TDA distinguished five unique clusters of salt-sensitive individuals (more than 15 mmHg change in BP with increased salt). While these clusters had similar BP responses to salt, different collections of variables were responsible for their salt sensitivity, e.g. greater reductions in glomerular filtration rate (GFR) or impairments in the renin–angiotensin system. After simulating uninephrectomy in these virtual patients, the three most salt-sensitive clusters were associated with a blunted increase in renal blood flow (RBF) and higher increase in loop and distal sodium reabsorption when compared with the salt-resistant population. These data suggest that the suppression of sodium reabsorption and renin–angiotensin system is key for salt resistance, and RBF in addition to GFR may be an important factor when considering criteria for kidney donors. Here, we show that in our model of human physiology, different derangements result in the same phenotype. While these concepts are known in the experimental community, they were derived here by considering only the data obtained from our virtual experiments. These methodologies could potentially be used to discover patterns in patient sensitivity to dietary change or interventions and could be a revolutionary tool in personalizing medicine.
A model for the optimization of anti-inflammatory treatment with chemerin
Authors: Laranjeira Simao , Regan-Komito Daniel , Iqbal Asif J. , Greaves David R. , Payne Stephen J. , Orlowski Piotr
Published: December 2017

Routine treatment of mild to moderate pain with a combination of non-steroidal anti-inflammatory drugs such as paracetamol in combination with corticoid opioids can lead to severe complications including death from gastrointestinal injury or to drug dependence. There is a need for the development of new safer drugs. Chemerin is a mediator promoting resolution of inflammation and it is then a promising candidate for a new treatment. A pilot experimental work using the zymosan-induced peritonitis model has found that injecting extra chemerin resulted in an approximately 1% reduction in the total number of inflammatory cells recruited. This paper combines and adapts existing mathematical models of inflammation to reproduce these results and to explore the therapeutic potential of chemerin through simulations. Analysis of the model predicts that the injection of chemerin at a concentration of 2000 ng ml
−1
within the first 5 min of inflammation onset leads to maximal inflammation inhibition. The degree of inhibition is shown to be sensitive to data used for the fit with a mean inhibition of 22 ± 3.7% for a series of remove-one bootstrap tests, whereas optimal chemerin injection parameters were not. Overall sensitivity analysis identifies parameters of the model that need to be measured more accurately or with increased sampling rate to improve model robustness and confirm chemerin's therapeutic potential.
TheEscherichia coliCpxAR system does not sense surface contact
Authors: Kimkes Tom Eric Pieter , Heinemann Matthias
Published: December 2017

For proper biofilm formation, bacteria must have mechanisms in place to sense adhesion to surfaces. InEscherichia coli, the CpxAR and RcsCDB systems have been reported to sense surfaces. The CpxAR system is widely considered to be responsible for sensing attachment, to specifically hydrophobic surfaces. Here, using both single-cell and population-level analyses, we confirm RcsCDB activation upon surface contact, but find that the CpxAR system is not activated, in contrast to what had earlier been reported. Thus, the role of CpxAR in surface sensing and initiation of biofilm formation needs to be reconsidered.

Significance statement

E. coliis capable of forming medically problematic biofilms, which are surface-associated microbial communities, protected by an exopolymeric matrix and with increased antibiotic tolerance. How these bacteria sense physical contact with a surface, which may lead to initiation of the biofilm formation process, is largely elusive. The signal transduction systems CpxAR and RcsCDB have previously been found to activate upon surface contact. Here, we confirm that RcsCDB is a surface sensing system, immediately responding to attachment. In contrast, using two different experimental approaches, we found that the CpxAR system does not perceive surface contact. Thus, contrary to the current view, the CpxAR system does not play a signaling role in the first step of biofilm initiation.