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Lead fluoride, PbF2, was investigated experimentally in the laser-heated diamond anvil cell by x-ray diffraction to pressures of 75 GPa at room temperature and to 64.5 GPa and 2430 K, as well as through first-principles density functional theory calculations up to 70 GPa. During room temperature compression, no discontinuous changes in the x-ray diffraction pattern or volume were observed, but the lattice parameters displayed highly anomalous trends between 10-22 GPa with enhanced compressibility along the a direction and reduced or even negative compressibility along b and c. Theoretical calculations of valence electron densities at 22 GPa showed that α-PbF2 underwent a pressure-induced isosymmetric phase transition to a postcotunnite Co2Si structure and also revealed the detailed atomic rearrangements associated with the development of an extra Pb-F bond in the high-pressure phase. Our x-ray results and theoretical calculations are consistent with an isosymmetric phase transition smoothly occurring over 10-22 GPa rather than abruptly as previously suggested. The characteristic values for the cell constants a/c and (a+c)/b, which are used to distinguish among cotunnite-, Co2Si-, and Ni2In-type phases, require modification based on our results. An equation of state fit yields a bulk modulus, K0, of 72(3) GPa for the cotunnite-type, and an ambient-pressure volume, V0, of 182(2)Å3, and K0=81(4)GPa for the Co2Si-type phase when fixing the pressure derivative of the bulk modulus, K0′=4. Upon heating above 1200 K at pressures at or above 25.9 GPa, PbF2 partially transformed to the hexagonal Ni2In-type phase but wholly or partially reverted back to Co2Si-type phase upon temperature quench. From 43-65 GPa, nearly complete transformation to the Ni2In-type PbF2 was observed at high temperature, but the material partially transformed back to the orthorhombic phase upon temperature quench. Our results show that high-pressure behavior of PbF2 is distinct from that of the alkaline earth fluorides with similar ionic radii. Our results also have relevance to understanding the behavior of lanthanide and actinide dioxides, which have been predicted theoretically to exhibit similar isosymmetric transitions at Mbar pressures.

BACKGROUND: Management of combat casualties with severe burns and associated traumatic injuries requires a coordinated interaction of surgical, critical care, and evacuation assets. These patients present enormous challenges to the entire medical system as a result of the severity of injury combined with the great distance required for transport to definitive care. OBJECTIVE: The objective of this study was to review and highlight some of the advances in burn critical care experienced during recent combat operations. This review focuses on initial resuscitation, respiratory support, care of the burn wound, and long range evacuation. DATA SOURCE: The authors conducted a search of the MEDLINE database and manual review of published articles and abstracts from national and international meetings in addition to Institute of Surgical Research Burn Center registry. CONCLUSIONS: Fluid resuscitation during the first 24 to 48 hrs after injury remains a significant challenge for all who manage burn casualties. Guidelines have been developed in an effort to standardize fluid resuscitation during this time. These guidelines along with the standardization of burn wound care and continued provider education have resulted in decreased morbidity and mortality in severely burned patients returning from war zones. This system of care for severely burned patients facilitates the transfer of the burn casualty between healthcare providers and facilities and is now being integrated into the catchment area for the Institute of Surgical Research Burn Center. [ABSTRACT FROM AUTHOR]

Rationale: Cytokines are central mediators of the immune-inflammatory response to injury and subsequent multiple organ dysfunction syndrome (MODS). Although previous studies evaluated cytokine levels after trauma, differences between patients with burn and non-burn trauma have not been assessed systematically.Methods: A prospective database of trauma patients admitted between May 2004 and September 2007 to the burn or surgical intensive care units within 24 h of injury with an anticipated stay of at least 72 h was analyzed. Sequential clinical and laboratory parameters were collected in the first week, including multiplex analysis data for plasma levels of inflammatory cytokines (IL-6, and IL-8). Patients with known pre-injury coagulopathy were excluded. A Marshall score of 10 or greater was defined as MODS.Results: A total of 179 patients were enrolled (67 burn and 112 non-burn). Plasma IL-6 and IL-8 levels were markedly elevated in both burn and non-burn patients compared to healthy volunteers. Burn subjects had higher levels of IL-6 and IL-8 than the non-burn on days 1 through 7 after injury. Subjects with burns and at least 30% total body surface area were older and had a lower injury severity score, a higher prevalence of MODS, and correspondingly higher mortality. Multivariate analysis of injury type, MODS, and time did not demonstrate an influence of MODS.Conclusions: Burns were associated with a greater and more sustained immune-inflammatory response than non-burn trauma as evidenced by elevated plasma IL-6 and IL-8 levels during the first week. There was no association between MODS and plasma cytokine levels. [ABSTRACT FROM AUTHOR]

Context: Femoroacetabular impingement syndrome (FAIS) causes pain and functional limitations. Little is known regarding walking characteristics, volume, and intensity evaluated in laboratory and free-living conditions and whether these measures differ between those with FAIS and uninjured individuals., Objective: To examine the differences in laboratory gait measures and free-living step-based metrics between individuals with FAIS and uninjured control participants., Design: Comparative, cross-sectional study., Patients or Other Participants: We enrolled 25 participants with FAIS and 14 uninjured controls., Main Outcome Measure(s): We evaluated laboratory spatiotemporal gait measures (cadence, velocity, step length, stride length) during self-selected and fast walking speeds using an instrumented walkway. Participants then wore an accelerometer around the waist during waking hours for 7 consecutive days. Free-living step-based metrics included average daily steps, peak 1- and 30-minute cadence, and average daily time spent in walking cadence bands. We compared laboratory gait measures and step-based metrics between groups., Results: The groups did not differ in laboratory spatiotemporal gait measures during both speeds (all P > .05). The FAIS group took fewer daily steps (5346 ± 2141 versus 7338 ± 2787 steps/d; P = .030) and had lower peak 1-minute (92.9 ± 23.9 versus 119.6 ± 16.3 steps/min; P < .001) and 30-minute cadences (60.9 ± 27.1 versus 86.8 ± 22.4 steps/min; P = .003) compared with uninjured controls, respectively. The FAIS group also spent less time in slow (6.0 ± 3.6 versus 10.3 ± 3.4 min/d; P = .001), medium (4.5 ± 4.2 versus 8.9 ± 4.4 min/d; P = .005), and brisk/moderate (4.5 ± 6.2 versus 12.2 ± 10.3; P = .020) cadence bands compared with uninjured controls., Conclusions: Clinical/laboratory gait measures alone may not be representative of real-world walking-related physical activity behavior in individuals with FAIS., (© by the National Athletic Trainers’ Association, Inc.)

Plethysmography is employed in nonhuman primates (NHPs) to calculate respiratory minute volume and determine the exposure time required to deliver an aerosol at the target dose. Anesthetic drugs can impact breathing parameters like steady-state minute volume (SSMV) central to aerosol dosing. Alfaxalone-midazolam mixtures (AM) provide superior parameters for plethysmography in cynomolgus macaques. An obstacle to the use of AM is the volume required to anesthetize via intramuscular injection. A more concentrated formulation of alfaxalone will reduce injection volumes and refine AM protocols. The purpose of this study was to compare AM using the Indexed 10-mg/mL (AM10) formulation compared with an investigational 40-mg/mL (AM40) formulation for IM administration in cynomolgus macaques undergoing plethysmography. We hypothesized that AM10 and AM40 would show no difference in quality of anesthesia (QA), duration of anesthesia, SSMV, accumulated minute volume (AMV), and side effects. We also hypothesized that female macaques would have a longer duration of anesthesia compared with males using both formulations. The study used 15 cynomolgus macaques comprised of 8 females and 7 males. NHPs were compared between 2 separate and randomized anesthetic events no less than one week apart. Each animal served as its own control and animals were randomized by random number generation. Anesthetized NHPs were placed in a sealed plethysmography chamber, and minute volume measurements were calculated every 10 s to determine SSMV. Once SSMV was achieved for 20 min, the trial ended. There were no statistically significant differences between AM10 and AM40 for duration of anesthesia, SSMV, AMV, side effects, or QA. AM40 had a significantly smaller injection volume. Females did not show a significantly longer median duration of anesthesia using either of the alfaxalone formulations. Overall, AM40 offers a more humane anesthetic than AM10 for plethysmography in cynomolgus macaques.

Venezuelan equine encephalitis virus (VEEV) outbreaks occur sporadically. Additionally, VEEV has a history of development as a biothreat agent. Yet, no FDA-approved vaccine or therapeutic exists for VEEV disease. The sporadic outbreaks present a challenge for testing medical countermeasures (MCMs) in humans; therefore, well-defined animal models are needed for FDA Animal Rule licensure. The cynomolgus macaque (CM) model has been studied extensively at high challenge doses of the VEEV Trinidad donkey strain (>1.0 × 10 8 plaque-forming units [PFU]), doses that are too high to be a representative human dose. Based on viremia of two subtypes of VEEV, IC, and IAB, we found the CM infectious dose fifty (ID 50 ) to be low, 12 PFU, and 6.7 PFU, respectively. Additionally, we characterized the pattern of three clinical parameters (viremia, temperature, and lymphopenia) across a range of doses to identify a challenge dose producing consistent signs of infection. Based on these studies, we propose a shift to using a lower challenge dose of 1.0 × 10 3 PFU in the aerosol CM model of VEEV disease. At this dose, NHPs had the highest viremia, demonstrated a fever response, and had a measurable reduction in complete lymphocyte counts-biomarkers that can demonstrate MCM efficacy.

The process of carbon dioxide capture typically requires a large amount of energy for the separation of carbon dioxide from other gases, which has been a major barrier to the widespread deployment of carbon capture technologies. Innovation of carbon dioxide adsorbents is herein vital for the attainment of a sustainable carbon capture process. In this study, we investigated the electrified synthesis and rejuvenation of calcium-based layered double hydroxides (Ca-based LDHs) as solid adsorbents for CO 2 . We discovered that the particle morphology and phase purity of the LDHs, along with the presence of secondary phases, can be controlled by tuning the current density during electrodeposition on a porous carbon substrate. The change in phase composition during carbonation and calcination was investigated to unveil the effect of different intercalated anions on the surface basicity and thermal stability of Ca-based LDHs. By decoupling the adsorption of water and CO 2 , we showed that the adsorbed water largely promoted CO 2 adsorption, most likely through a sequential dissolution and reaction pathway. A carbon capture capacity of 4.3 ± 0.5 mmol/g was measured at 30 °C and relative humidity of 40% using 10 vol % CO 2 in nitrogen as the feed stream. After CO 2 capture occurred, the thermal regeneration step was carried out by directly passing an electric current through the conductive carbon substrate, known as the Joule-heating effect. CO 2 was found to start desorbing from the Ca-based LDHs at a temperature as low as 220 °C as opposed to the temperature above 700 °C required for calcium carbonate that forms as part of the Ca-looping capture process. Finally, we evaluated the cumulative energy demand and environmental impact of the LDH-based capture process using a life cycle assessment. We identified the most environmentally concerning step in the process and concluded that the postcombustion CO 2 capture using LDH could be advantageous compared with existing technologies.

Delamanid (DLM) is a hydrophobic small molecule therapeutic used to treat drug-resistant tuberculosis (DR-TB). Due to its hydrophobicity and resulting poor aqueous solubility, formulation strategies such as amorphous solid dispersions (ASDs) have been investigated to enhance its aqueous dissolution kinetics and thereby improve oral bioavailability. However, ASD formulations are susceptible to temperature- and humidity-induced phase separation and recrystallization under harsh storage conditions typically encountered in areas with high tuberculosis incidence. Nanoencapsulation represents an alternative formulation strategy to increase aqueous dissolution kinetics while remaining stable at elevated temperature and humidity. The stabilizer layer coating the nanoparticle drug core limits the formation of large drug domains by diffusion during storage, representing an advantage over ASDs. Initial attempts to form DLM-loaded nanoparticles via precipitation-driven self-assembly were unsuccessful, as the trifluoromethyl and nitro functional groups present on DLM were thought to interfere with surface stabilizer attachment. Therefore, in this work, we investigated the nanoencapsulation of DLM via emulsification, avoiding the formation of a solid drug core and instead keeping DLM dissolved in a dichloromethane dispersed phase during nanoparticle formation. Initial emulsion formulation screening by probe-tip ultrasonication revealed that a 1:1 mass ratio of lecithin and HPMC stabilizers formed 250 nm size-stable emulsion droplets with 40% DLM loading. Scale-up studies were performed to produce nearly identical droplet size distribution at larger scale using high-pressure homogenization, a continuous and industrially scalable technique. The resulting emulsions were spray-dried to form a dried powder, and in vitro dissolution studies showed dramatically enhanced dissolution kinetics compared to both as-received crystalline DLM and micronized crystalline DLM, owing to the increased specific surface area and partially amorphous character of the DLM-loaded nanoparticles. Solid-state NMR and dissolution studies showed good physical stability of the emulsion powders during accelerated stability testing (50 °C/75% RH, open vial).

The Oak Ridge National Laboratory is planning to build the Second Target Station (STS) at the Spallation Neutron Source (SNS). STS will host a suite of novel instruments that complement the First Target Station's beamline capabilities by offering an increased flux for cold neutrons and a broader wavelength bandwidth. A novel neutron imaging beamline, named the Complex, Unique, and Powerful Imaging Instrument for Dynamics (CUPI2D), is among the first eight instruments that will be commissioned at STS as part of the construction project. CUPI2D is designed for a broad range of neutron imaging scientific applications, such as energy storage and conversion (batteries and fuel cells), materials science and engineering (additive manufacturing, superalloys, and archaeometry), nuclear materials (novel cladding materials, nuclear fuel, and moderators), cementitious materials, biology/medical/dental applications (regenerative medicine and cancer), and life sciences (plant-soil interactions and nutrient dynamics). The innovation of this instrument lies in the utilization of a high flux of wavelength-separated cold neutrons to perform real time in situ neutron grating interferometry and Bragg edge imaging-with a wavelength resolution of δλ/λ ≈ 0.3%-simultaneously when required, across a broad range of length and time scales. This manuscript briefly describes the science enabled at CUPI2D based on its unique capabilities. The preliminary beamline performance, a design concept, and future development requirements are also presented., (© 2023 Author(s). All article content, except where otherwise noted, is licensed under a Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).)

Biomass pyrolysis within the alkaline molten salt is attractive due to its ability to achieve high hydrogen yield under relatively mild conditions. However, poor contact between biomass, especially the biomass pellet, and hydroxide during the slow heating process, as well as low reaction temperatures, become key factors limiting the hydrogen production. To address these challenges, fast pyrolysis of the algae pellet in molten NaOH-Na 2 CO 3 was conducted at 550, 650, and 750 °C. Algae were chosen as feedstock for their high photosynthetic efficiency and growth rate, and the concept of coupling molten salt with concentrated solar energy was proposed to address the issue of high energy consumption at high temperatures. At 750 °C, the pollutant gases containing Cl and S were completely removed, and the HCN removal rate reached 44.92%. During the continuous pyrolysis process, after a slight increase, the hydrogen yield remained stable at 71.48 mmol/g-algae and constituted 86.10% of the gas products, and a minimum theoretical hydrogen production efficiency of algae can reach 84.86%. Most importantly, the evolution of physicochemical properties of molten NaOH-Na 2 CO 3 was revealed for the first time. Combined with the conversion characteristics of feedstock and gas products, this study provides practical guidance for large-scale application of molten salt including feedstock, operation parameters, and post-treatment process.

Understanding the mechanism of iron-catalyzed graphitization of biomass is an important step for the large-scale synthesis of green graphene. Although iron is known to be the most active transition metal for the catalytic graphitization of cellulose-derived biochar, the direct effect of the iron molecular structure on the formation of highly graphitic carbon remains elusive. Here, biochar was produced from pyrolysis of iron-impregnated cellulose at three different temperatures (1000, 1400, and 1800 °C). X-ray diffraction, X-ray photoelectron spectroscopy, and magnetic measurements were used to probe changes in biochar nanostructure catalyzed by the inclusion of iron. An increase of pyrolysis temperature led to an increase in the iron particle size and the degree of iron reduction, as well as the formation of larger graphitic carbon crystallite sizes, and these two attributes of iron were seen to positively affect the biochar graphitization usually challenging under 2000 °C., (© 2022 The Authors. ChemSusChem published by Wiley-VCH GmbH.)

Plethysmography is used in nonhuman primates (NHPs) to measure minute volume before aerosol exposure to an agent to calculate total time necessary in the exposure chamber. The consistency of respiratory parameters during the entire exposure time is paramount to ensuring dosing accuracy. Our study sought to validate an alfaxalone-midazolam (AM) anesthetic combination for use in aerosol studies. We hypothesized that AM would provide an adequate duration of anesthesia, achieve and maintain steady state minute volume (SSMV) for 20 min, and have anesthetic quality and side effects comparable to or better than either tiletamine-zolazepam (TZ) and ketamine-acepromazine (KA), the most common anesthetics used for this purpose currently. Two groups of NHPs, one consisting of 15 cynomolgus macaques and one of 15 rhesus macaques, received 3 intramuscular anesthetic combinations (AM, TZ, and KA), no less than one week apart. Anesthetized NHPs were placed in a plethysmograph chamber and their minute volumes were measured every 10 s to determine whether they had achieved SSMV and maintained it for at least 20 consecutive min. Achieving and reliably maintaining an SSMV for at least 20 min facilitates precise aerosol dosing of a challenge agent. Quality of anesthesia, based on the NHP's ability to achieve and maintain SSMV, was higher with AM compared with TZ and KA in both species, and AM had a longer duration of SSMV as compared with TZ and KA in cynomolgus macaques. Average SSMV was larger with AM compared with TZ in cynomolgus macaques, but larger with KA compared with AM in rhesus macaques. Duration of anesthesia was sufficient with all combinations but was longer for TZ than both AM and KA in both species. These results suggest that the AM anesthetic combination would produce the most accurate dosing for an aerosol challenge.

The purpose of this study was to evaluate the effects of the route of administration on the immunogenicity and efficacy of a combined western, eastern, and Venezuelan equine encephalitis (WEVEE) virus-like replicon particle (VRP) vaccine in cynomolgus macaques. The vaccine consisted of equal amounts of WEEV, EEEV, and VEEV VRPs. Thirty-three animals were randomly assigned to five treatment or control groups. Animals were vaccinated with two doses of WEVEE VRPs or the control 28 days apart. Blood was collected 28 days following primary vaccination and 21 days following boost vaccination for analysis of the immune response to the WEVEE VRP vaccine. NHPs were challenged by aerosol 28 or 29 days following second vaccination with WEEV CBA87. Vaccination with two doses of WEVEE VRP was immunogenic and resulted in neutralizing antibody responses specific for VEEV, EEEV and WEEV. None of the vaccinated animals met euthanasia criteria following aerosol exposure to WEEV CBA87. However, one NHP control (total of 11 controls) met euthanasia criteria after infection with WEEV CBA87. Statistically significant differences in median fever hours were noted in control NHPs compared to vaccinated NHPs, providing a quantitative measure of infection and efficacy of the vaccine against a WEEV challenge. Alterations in lymphocytes, monocytes, and neutrophils were observed. Lymphopenia was observed in control NHPs.

More than 70% of the population without access to safe drinking water lives in remote and off-grid areas. Inspired by natural plant transpiration, we designed and tested in this study an array of scalable three-dimensional (3D) engineered trees made of natural wood for continuous water desalination to provide affordable and clean drinking water. The trees took advantage of capillary action in the wood xylems and lifted water more than 1 foot off the ground with or without solar irradiation. This process overcame some major challenges of popular solar-driven water evaporation and water harvesting, such as intermittent operation, low water production rate, and system scaling. The trade-off between energy transfer and system footprint was tackled by optimizing the interspacing between the trees. The scaled system has a ratio of surface area (vapor generation) to project area (water transport) up to 118, significantly higher than the prevailing flat-sheet design. The extensive surface area evaporated water at a temperature cooler than the surrounding air, drawing on multiple environmental energy sources including solar, wind, or ambient heat in the air and realized continuous operation. The total energy for evaporation reached over 300% of the one-sun irradiance, enabling a freshwater production rate of 4.8 L m -2 h -1 from an array of 16 trees in an enclosed room and 14 L m -2 h -1 under a 3 m/s airflow. Furthermore, we found that the ambient heat in the air contributed 60%-70% of the total latent heat of vaporization when energy sources were decoupled. During long-term desalination tests, the engineered trees demonstrated a self-cleaning mechanism with daily cycles of salt accumulation and dissolution. Combining the quantification from an evaporation model and meteorology data covering the globe, we also demonstrated that the 3D engineered trees can be of particular interest for sustainable desalination in the Middle East and North Africa (MENA) regions.

Synthesizing nanopores which mimic the functionality of ion-selective biological channels has been a challenging yet promising approach to advance technologies for precise ion-ion separations. Inspired by the facilitated fluoride (F - ) permeation in the biological fluoride channel, we designed a highly fluoride-selective TiO 2 film using the atomic layer deposition (ALD) technique. The subnanometer voids within the fabricated TiO 2 film (4 Å < d < 12 Å, with two distinct peaks at 5.5 and 6.5 Å), created by the hindered diffusion of ALD precursors ( d = 7 Å), resulted in more than eight times faster permeation of sodium fluoride compared to other sodium halides. We show that the specific Ti-F interactions compensate for the energy penalty of F - dehydration during the partitioning of F - ions into the pore and allow for an intrapore accumulation of F - ions. Concomitantly, the accumulation of F - ions on the pore walls also enhances the transport of sodium (Na + ) cations due to electrostatic interactions. Molecular dynamics simulations probing the ion concentration and mobility within the TiO 2 pore further support our proposed mechanisms for the selective F - transport and enhanced Na + permeation in the TiO 2 film. Overall, our work provides insights toward the design of ion-selective nanopores using the ALD technique.

We evaluated anthropogenic Pb deposition along a west-east transect from the Adirondack Mountains, New York, USA (ADIR) region, the Vermont-New Hampshire-Maine, USA (VT-NH-ME) region, and Nova Scotia, Canada (NS) region using 47 210 Pb-dated lake sediment records. We used focus-corrected Pb inventories to evaluate cumulative deposition and breakpoint analysis to evaluate possible differences in timings among regions. Peak Pb concentrations decreased from west to east (ADIR region: 52-378 mg kg -1 , VT-NH-ME region: 54-253 mg kg -1 , NS: 38-140 mg kg -1 ). Cumulative deposition of anthropogenic Pb also decreased from west to east (ADIR region: 791-1344 mg m -2 , VT-NH-ME region: 209-1206 mg m -2 , NS: 52-421 mg m -2 ). The initiation of anthropogenic Pb deposition occurred progressively later along the same transect (ADIR region: 1869-1900, VT-NH-ME region: 1874-1905, NS region: 1901-1930). Previous lead isotope studies suggest that eastern Canadian Pb deposition over the past ~150 years has originated from a mix of both Canadian and U.S. sources. The results of this study indicate that anthropogenic Pb from sources west of the ADIR region were deposited in lesser amounts from west to east and/or Pb sources reflect less population density from west to east. The timing of the initiation of anthropogenic Pb deposition in the NS region suggests that Pb from gasoline may be an important source in this region., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

There are no FDA licensed vaccines or therapeutics for Venezuelan equine encephalitis virus (VEEV) which causes a debilitating acute febrile illness in humans that can progress to encephalitis. Previous studies demonstrated that murine and macaque monoclonal antibodies (mAbs) provide prophylactic and therapeutic efficacy against VEEV peripheral and aerosol challenge in mice. Additionally, humanized versions of two neutralizing mAbs specific for the E2 glycoprotein, 1A3B-7 and 1A4A-1, administered singly protected mice against aerosolized VEEV. However, no studies have demonstrated protection in nonhuman primate (NHP) models of VEEV infection. Here, we evaluated a chimeric antibody 1A3B-7 (c1A3B-7) containing mouse variable regions on a human IgG framework and a humanized antibody 1A4A-1 containing a serum half-life extension modification (Hu-1A4A-1-YTE) for their post-exposure efficacy in NHPs exposed to aerosolized VEEV. Approximately 24 hours after exposure, NHPs were administered a single bolus intravenous mAb. Control NHPs had typical biomarkers of VEEV infection including measurable viremia, fever, and lymphopenia. In contrast, c1A3B-7 treated NHPs had significant reductions in viremia and lymphopenia and on average approximately 50% reduction in fever. Although not statistically significant, Hu-1A4A-1-YTE administration did result in reductions in viremia and fever duration. Delay of treatment with c1A3B-7 to 48 hours post-exposure still provided NHPs protection from severe VEE disease through reductions in viremia and fever. These results demonstrate that post-exposure administration of c1A3B-7 protected macaques from development of severe VEE disease even when administered 48 hours following aerosol exposure and describe the first evaluations of VEEV-specific mAbs for post-exposure prophylactic use in NHPs. Viral mutations were identified in one NHP after c1A3B-7 treatment administered 24 hrs after virus exposure. This suggests that a cocktail-based therapy, or an alternative mAb against an epitope that cannot mutate without resulting in loss of viral fitness may be necessary for a highly effective therapeutic., Competing Interests: JWF, MLP, KM, JK, YV, and PJG have filled a patent application on c1A3B-7. CLM and JE are employees of Mapp Biopharmaceutical. LZ is an employee and co-owner of Mapp. This does not alter our adherence to all PLOS Pathogens policies on sharing data and materials.

Purpose: A novel automatic discontinuation policy implemented within an antimicrobial stewardship program (ASP) is described, and results of an evaluation of the policy's effects on antibiotic usage are reported., Methods: A retrospective, before-and-after study was conducted at an 800-bed, tertiary care, academic teaching hospital to evaluate selected antibiotic usage outcomes in both intensive care unit (ICU) and non-ICU adult patients targeted for ASP interventions before and after implementation of an automatic discontinuation of antibiotics policy (ADAP) authorizing the ASP team to automatically halt antibiotic therapy in cases involving inappropriate duplicate antimicrobial coverage or excess duration of therapy. The primary outcome was total days of antibiotic therapy. Secondary outcomes included excess days of therapy and rates of 30-day readmission, Clostridioides difficile infection, and multidrug-resistant infection., Results: There were no statistically significant differences in group demographics or clinical characteristics. The most common indication for antibiotics was hospital-acquired pneumonia, and the most common reason for ASP intervention was excess duration of therapy. The mean total number of antibiotic days per patient was reduced from 7.6 days in the pre-ADAP group to 6.6 days in the post-ADAP group (p < 0.05). The mean number of excess days of antibiotics was similarly reduced, from 2.3 days to 1.5 days, after implementation of the ADAP (p < 0.05)., Conclusion: Adoption of an ADAP-a more active approach to ASP interventions-was effective in reducing overall antibiotic usage and improving the efficiency of the ASP., (© American Society of Health-System Pharmacists 2019. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The legume endosymbiont Sinorhizobium meliloti can utilize a broad range of carbon compounds to support its growth. The linear, six-carbon polyol galactitol is abundant in vascular plants and is metabolized in S. meliloti by the contribution of two loci SMb21372-SMb21377 and SMc01495-SMc01503 which are found on pSymB and the chromosome, respectively. The data suggest that several transport systems, including the chromosomal ATP-binding cassette (ABC) transporter smoEFGK, contribute to the uptake of galactitol, while the adjacent gene smoS encodes a protein for oxidation of galactitol into tagatose. Subsequently, genes SMb21374 and SMb21373, encode proteins that phosphorylate and epimerize tagatose into fructose-6-phosphate, which is further metabolized by the enzymes of the Entner-Doudoroff pathway. Of note, it was found that SMb21373, which was annotated as a 1,6-bis-phospho-aldolase, is homologous to the E. coli gene gatZ, which is annotated as encoding the non-catalytic subunit of a tagatose-1,6-bisphosphate aldolase heterodimer. When either of these genes was introduced into an Agrobacterium tumefaciens strain that carries a tagatose-6-phosphate epimerase mutation, they are capable of complementing the galactitol growth deficiency associated with this mutation, strongly suggesting that these genes are both epimerases. Phylogenetic analysis of the protein family (IPR012062) to which these enzymes belong, suggests that this misannotation is systemic throughout the family. S. meliloti galactitol catabolic mutants do not exhibit symbiotic deficiencies or the inability to compete for nodule occupancy.

We assessed factory-calibrated field-portable X-ray fluorescence (pXRF) data quality for use with minimally-prepared aquatic sediments, including the precision of replicate pXRF measurements, accuracy of factory-calibrated pXRF values as compared to total digestion/ICP-OES concentrations, and comparability of calibrated pXRF values to extractable concentrations. Data quality levels for precision, accuracy, and comparability were not equivalent for element/analyzer combinations. All analyses of elements that were assessed for precision and accuracy on a single analyzer were both precise (<10% relative standard deviation) and accurate (r 2  > 0.85) for K, Ca, Ti, Mn, Fe, and Zn. Calibrated pXRF values for Al, K, Ca, Ti, Mn, Fe, Cu, Zn, and Pb were within ∼10% relative difference of total digestion/ICP-OES concentrations. Calibrated pXRF values for Fe, Cu, Zn, As, and Pb were within ∼20% relative difference of extractable concentrations. Some elements had a higher level of data quality using specific analyzers, but in general, no pXRF analyzer had the highest level of data quality in all categories. Collectively, our data indicate that a wide range of factory-calibrated pXRF units are capable of providing high-quality total concentrations for the analysis of aquatic sediments., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

In this study, in situ quasi-elastic neutron scattering (QENS) has been employed to probe the water dynamics and reaction mechanisms occurring during the formation of NaOH- and Na2SiO3-activated slags, an important class of low-CO2 cements, in conjunction with isothermal conduction calorimetry (ICC), Fourier transform infrared spectroscopy (FTIR) analysis and N2 sorption measurements. We show that the single ICC reaction peak in the NaOH-activated slag is accompanied with a transformation of free water to bound water (from QENS analysis), which directly signals formation of a sodium-containing aluminum-substituted calcium-silicate-hydrate (C-(N)-A-S-H) gel, as confirmed by FTIR. In contrast, the Na2SiO3-activated slag sample exhibits two distinct reaction peaks in the ICC data, where the first reaction peak is associated with conversion of constrained water to bound and free water, and the second peak is accompanied by conversion of free water to bound and constrained water (from QENS analysis). The second conversion is attributed to formation of the main reaction product (i.e., C-(N)-A-S-H gel) as confirmed by FTIR and N2 sorption data. Analysis of the QENS, FTIR and N2 sorption data together with thermodynamic information from the literature explicitly shows that the first reaction peak is associated with the formation of an initial gel (similar to C-(N)-A-S-H gel) that is governed by the Na+ ions and silicate species in Na2SiO3 solution and the dissolved Ca/Al species from slag. Hence, this study exemplifies the power of in situ QENS, when combined with laboratory-based characterization techniques, in elucidating the water dynamics and associated chemical mechanisms occurring in complex materials, and has provided important mechanistic insight on the early-age reactions occurring during formation of two alkali-activated slags.

Background: OZ439 is a new chemical entity which is active against drug-resistant malaria and shows potential as a single-dose cure. However, development of an oral formulation with desired exposure has proved problematic, as OZ439 is poorly soluble (BCS Class II drug). In order to be feasible for low and middle income countries (LMICs), any process to create or formulate such a therapeutic must be inexpensive at scale, and the resulting formulation must survive without refrigeration even in hot, humid climates. We here demonstrate the scalability and stability of a nanoparticle (NP) formulation of OZ439. Previously, we applied a combination of hydrophobic ion pairing and Flash NanoPrecipitation (FNP) to formulate OZ439 NPs 150 nm in diameter using the inexpensive stabilizer hydroxypropyl methylcellulose acetate succinate (HPMCAS). Lyophilization was used to process the NPs into a dry form, and the powder's in vitro solubilization was over tenfold higher than unprocessed OZ439., Methods: In this study, we optimize our previous formulation using a large-scale multi-inlet vortex mixer (MIVM). Spray drying is a more scalable and less expensive operation than lyophilization and is, therefore, optimized to produce dry powders. The spray dried powders are then subjected to a series of accelerated aging stability trials at high temperature and humidity conditions., Results: The spray dried OZ439 powder's dissolution kinetics are superior to those of lyophilized NPs. The powder's OZ439 solubilization profile remains constant after 1 month in uncapped vials in an oven at 50 °C and 75% RH, and for 6 months in capped vials at 40 °C and 75% RH. In fasted-state intestinal fluid, spray dried NPs achieved 80-85% OZ439 dissolution, to a concentration of 430 µg/mL, within 3 h. In fed-state intestinal fluid, 95-100% OZ439 dissolution is achieved within 1 h, to a concentration of 535 µg/mL. X-ray powder diffraction and differential scanning calorimetry profiles similarly remain constant over these periods., Conclusions: The combined nanofabrication and drying process described herein, which utilizes two continuous unit operations that can be operated at scale, is an important step toward an industrially-relevant method of formulating the antimalarial OZ439 into a single-dose oral form with good stability against humidity and temperature.

More than 40% of newly developed drug molecules are highly hydrophobic and, thus, suffer from low bioavailability. Kinetically trapping the drug as a nanoparticle in an amorphous state enhances solubility. However, enhanced solubility can be compromised by subsequent recrystallization from the amorphous state during drying processes. We combine Flash NanoPrecipitation (FNP) to generate nanoparticles with spray-drying to produce stable solid powders. We demonstrate that the continuous nanofabrication platform for nanoparticle synthesis and recovery does not compromise the dissolution kinetics of the drug. Lumefantrine, an anti-malaria drug, is highly hydrophobic with low bioavailability. Increasing the bioavailability of lumefantrine has the potential to reduce the dose and number of required administrations per treatment, thus reducing cost and increasing patient compliance. The low melting temperature of lumefantrine (Tm = 130 °C) makes the drying of amorphous nanoparticles at elevated temperatures potentially problematic. Via FNP, we produced 200-400 nm nanoparticles using hydroxypropyl methylcellulose acetate succinate (HPMCAS), lecithin phospholipid, and zein protein stabilizers. Zein nanoparticles were spray-dried at 100 °C and 120 °C to study the effect of the drying temperature. For zein powders, at two hours the dissolution kinetics under fasted conditions reached 85% release for the 100 °C sample, but only 60% release for the 120 °C sample. Powder X-ray diffraction, differential scanning calorimetry, and solid state nuclear magnetic resonance indicate that the lumefantrine in the nanoparticle core is amorphous for samples spray-dried at 100 °C. Dissolution under fed state conditions showed similar release kinetics for both temperatures, with 90-95% release at two hours. Zein and HPMCAS nanoparticles spray-dried at 100 °C showed release profiles in fasted and fed state media that are identical to those of lyophilized samples, i.e. those dried at cryogenic conditions where no transformation to the crystalline state can occur. Thus, spray drying 30 °C below the melting transition of lumefantrine is sufficient to maintain the amorphous state. These inexpensive formulations have potential to be developed into future therapies for malaria, and the results also highlight the potential of combining FNP and spray-drying as a versatile platform to assemble and rapidly recover amorphous nanoparticles in a solid dosage form.

In several retinal degenerative disease pathologies, such as dry age-related macular degeneration (AMD), the retinal pigment epithelium (RPE) cell monolayer becomes dysfunctional. Promising tissue engineering treatment approaches implant RPE cells on scaffolds into the subretinal space. However, these approaches are not without challenges. Two major challenges that must be addressed are RPE dedifferentiation and the inflammatory response to cell/scaffold implantation. Design and optimization of scaffold cues for the purpose of RPE transplantation remain relatively unexplored, specifically the mechanical properties of the scaffolds. Prior work from our group indicated that by varying substrate moduli significant differences could be induced in cell cytoskeleton structure, cellular activity, and expression of inflammatory markers. We hypothesized that Activin A would provide rescue effects for cells demonstrating dedifferentiated characteristics. Results demonstrated that for cells on low modulus scaffolds, the mechanical environment was the dominating factor and Activin A was unable to rescue these cells. However, Activin A did demonstrate rescue effects for cells on high modulus scaffolds. This finding indicates that when cultured on scaffolds with an appropriate modulus, exogenous factors, such as Activin A, can improve RPE cell expression, morphology, and activity, while an inappropriate scaffold modulus can have devastating effects on RPE survival regardless of chemical stimulation. These findings have broad implications for the design and optimization of scaffolds for long-term successful RPE transplantation. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 2871-2880, 2018., (© 2018 Wiley Periodicals, Inc.)

For in situ neutron scattering experiments on cementitious materials, it is of great interest to have access to a robust device which can induce uniaxial load on a given solid sample. Challenges involve selection of materials making up the apparatus that are both weak neutron scatterers and yet adequately strong to induce loads of up to a few kilonewtons on the sample. Here, the design and experimental commissioning of a novel load frame is provided with the intended use as a neutron scattering sample environment enabling time-dependent stress-induced changes to be probed in an engineering material under compression. The frame is a scaled down version of a creep apparatus, which is typically used in the laboratory to measure deformation due to creep in concrete. Components were optimized to enable 22 MPa of compressive stress to be exerted on a 1 cm diameter cement cylinder. To minimize secondary scattering signals from the load frame, careful selection of the metal components was needed. Furthermore, due to the need to maximize the wide angular detector coverage and signal to noise for neutron total scattering measurements, the frame was designed specifically to minimize the size and required number of support posts while matching sample dimensions to the available neutron beam size.

While the formulation of nanoparticle (NP) suspensions has been widely applied in materials and life science, the recovery of NPs from such a suspension into a solid state is practically important to confer long-term storage stability. However, solidification, while preserving the original nanoscale properties, remains a formidable challenge in the pharmaceutical and biomedical applications of NPs. Herein we combined flash nanoprecipitation (FNP) and spray-drying as a nanofabrication platform for NP formulation and recovery without compromising the dissolution kinetics of the active ingredient. Clofazimine was chosen to be the representative drug, which has been recently repurposed as a potential treatment for cryptosporidiosis. Clofazimine was encapsulated in NPs with low-cost surface coatings, hypromellose acetate succinate (HPMCAS) and lecithin, which were required by the ultimate application to global health. Spray-drying and lyophilization were utilized to produce dried powders with good long-term storage stability for application in hot and humid climatic zones. The particle morphology, yield efficiency, drug loading, and clofazimine crystallinity in the spray-dried powders were characterized. The in vitro release kinetics of spray-dried NP powders were compared to analogous dissolution profiles from standard lyophilized NP samples, crystalline clofazimine powder, and the commercially available formulation Lamprene. The spray-dried powders showed a supersaturation level of up to 60 times the equilibrium solubility and remarkably improved dissolution rates. In addition, the spray-dried powders with both surface coatings showed excellent stability during aging studies with elevated temperature and humidity, in view of the dissolution and release in vitro. Considering oral delivery for pediatric administration, the spray-dried powders show less staining effects with simulated skin than crystalline clofazimine and may be made into minitablets without additional excipients. These results highlight the potential of combining FNP and spray-drying as a feasible and versatile platform to design and rapidly recover amorphous NPs in a solid dosage form, with the advantages of satisfactory long-term storage stability, low cost, and easy scalability., Competing Interests: The authors declare no competing financial interest.

Background: Given the significant public health burden of pulmonary diseases and the vital role pharmacists play in management across the continuum of care (and within transitions in care), an elective course for pharmacy students focused on pulmonary diseases was developed., Educational Activity: A month-long elective course for third-year pharmacy students consisting of 12 class sessions delivered in two-hour periods three times per week, was implemented. The course was delivered using the team-based learning (TBL) format in addition to hands-on skills and simulation sessions. Knowledge and skills assessments were administered before and after completion of the course. Student perceptions of self-confidence and ability regarding management of pulmonary diseases pre- and post-course and their perceptions of the course and TBL as a teaching strategy for this course were evaluated upon course completion., Critical Analysis: Nine students completed the course. Mean scores on knowledge and skills assessment significantly improved after completion of the course (54.5% pre-course vs. 79.3% post-course; p < 0.05% and 60.3% pre-course vs. 93.2% post-course; p < 0.05, respectively). Student perceptions of their ability to care for patients with pulmonary diseases significantly increased, compared to pre-assessments, in all areas taught in the course (p< 0.05). Additionally, students' confidence in managing specific disease states significantly improved in all areas (p < 0.05) except for spirometry (p = 0.06). Students' knowledge, skills, and confidence regarding management of common pulmonary disease states improved following this month-long elective course delivered using a combination of TBL activities and hands-on skills sessions., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Conventional drying of colloidal materials and gels (including cement) can lead to detrimental effects due to the buildup of internal stresses as water evaporates from the nano/microscopic pores. However, for these gel materials the underlying nanoscopic alterations that are, in part, responsible for macroscopically-measured strain values (especially at low relative humidity) remain a topic of open debate in the literature. In this study, sodium-based calcium-alumino-silicate-hydrate (C-(N)-A-S-H) gel, the major binding phase of silicate-activated blast furnace slag (one type of low-CO2 cement), is investigated from a drying perspective, since it is known to suffer extensively from drying-induced microcracking. By employing in situ synchrotron X-ray total scattering measurements and pair distribution function (PDF) analysis we show that the significant contributing factor to the strain development in this material at extremely low relative humidity (0%) is the local atomic structural rearrangement of the C-(N)-A-S-H gel, including collapse of interlayer spacing and slight disintegration of the gel. Moreover, analysis of the medium range (1.0-2.2 nm) ordering in the PDF data reveals that the PDF-derived strain values are in much closer agreement (same order of magnitude) with the macroscopically measured strain data, compared to previous results based on reciprocal space X-ray diffraction data. From a mitigation standpoint, we show that small amounts of ZrO2 nanoparticles are able to actively reinforce the structure of silicate-activated slag during drying, preventing atomic level strains from developing. Mechanistically, these nanoparticles induce growth of a silica-rich gel during drying, which, via density functional theory calculations, we show is attributed to the high surface reactivity of tetragonal ZrO2.