Both latent and multidrug-resistant tuberculosis (TB) have been causing significant concern worldwide. A novel drug, pretomanid (PA-824), has shown a potent bactericidal effect against both active and latent forms of Mycobacterium tuberculosis (MTb) and a synergistic effect when combined with pyrazinamide and moxifloxacin. This study aimed to develop triple combination spray dried inhalable formulations composed of antitubercular drugs, pretomanid, moxifloxacin, and pyrazinamide (1:2:8 w/w/w), alone (PaMP) and in combination with an aerosolization enhancer, L-leucine (20 % w/w, PaMPL). The formulation PaMPL consisted of hollow, spherical, dimpled particles (<5 mu m) and showed good aerosolization behaviour with a fine particle fraction of 70 %. Solidstate characterization of formulations with and without L-leucine confirmed the amorphous nature of moxifloxacin and pretomanid and the crystalline nature of pyrazinamide with polymorphic transformation after the spray drying process. Further, the X-ray photoelectron spectroscopic analysis revealed the predominant surface composition of L-leucine on PaMPL dry powder particles. The dose-response cytotoxicity results showed pyrazinamide and moxifloxacin were non-toxic in both A549 and Calu-3 cell lines up to 150 g/mL. However, the cell viability gradually decreased to 50 % when the pretomanid concentration increased to 150 mu g/mL. The in vitro efficacy studies demonstrated that the triple combination formulation had more prominent antibacterial activity with a minimum inhibitory concentration (MIC) of 1 mu g/mL against the MTb H37Rv strain as compared to individual drugs. In conclusion, the triple combination of pretomanid, moxifloxacin, and pyrazinamide as an inhalable dry powder formulation will potentially improve treatment efficacy with fewer systemic side effects in patients suffering from latent and multidrug-resistant TB.

Magnetic skyrmions are topological spin textures with nanoscale size, which have great potential for spintronics applications. However, they are very sensitive to film thicknesses and interfaces in ultrathin films or multilayer heterostructures, and methods to generate and tune skyrmions are needed in order to use them in real-world applications. Electric field gating has been shown to modify the magnetic characteristics of thin films; however, these changes are limited by the low electric fields achievable using solid gate electrodes. In this work, we use ionic liquid gating to modify the magnetic characteristics of perpendicularly magnetized $\mathrm{Mg}\mathrm{O}$/$\mathrm{Mn}$${}_{2}$$\mathrm{Co}\mathrm{Al}$/$\mathrm{Pd}$ ultrathin films, applying a range of voltage sequences to generate skyrmions through both nonvolatile and volatile changes to these films. We achieve a giant anisotropy field tunability of 109.8 mT ${\mathrm{V}}^{\ensuremath{-}1}$ that is nonreversible, which can be ascribed to magneto-ionic effects. Reversible changes to the anisotropy and volatile skyrmion formation are achieved via electrostatic charge accumulation, which could induce an in-plane Rashba field. Our results strongly demonstrate that ionic liquid gating is a versatile method to engineer both nonvolatile and volatile skyrmions by tuning the magnetic characteristics of films to the regimes where they can exist.

Oxygen plasma treatment was applied to atomically flat quartz surfaces in order to study the effect of surface activity on the adsorption of a silyl anchored quaternary ammonium salt biocide. Reduction of contact angle of the quartz surfaces were achieved from 72° to between 14° and 20° by applying oxygen plasma at increasing power between 100 W and 500 W. XPS analysis of the plasma-treated quartz surfaces indicated an increase in the presence of oxygen, implying the conversion of quartz surface siloxane groups into surface hydroxyl groups, consistent with the reduction in contact angle. Surfaces were examined by AFM after adsorption of silyl anchoring quaternary ammonium salts (AQAS). The surface profile of samples indicated an increase in the thickness of the adsorbed AQAS layer from 2.9 ± 0.1 nm for pristine quartz surfaces to 19.0 ± 2.0 nm for oxygen plasma treated surfaces, which is approximately the vertical dimension of 6 oriented molecular layers. The covalently bonded AQAS layer on the quartz surface exhibits a discontinuous film structure consisting of micro-zones of AQAS layers separated by voids or gaps, defined as regions on the quartz surface free of bound AQAS layers. These zones and voids are a consequence of the varying hydrophilicity/adsorption capability of the quartz surface. Plasma treated surfaces also showed a 3-fold reduction of void dimension from 3 µm to 1 µm between the AQAS adsorbed zones on the quartz slide owing to the increased hydrophilicity and adsorption capability of the surface. A leaching study of the AQAS adsorbed-quartz surfaces resulted in the reduction of film thickness from 19.0 ± 2.0 nm to 8 ± 1.0 nm. This reduction indicates the removal of some loosely bound outer layers, but confirms the retention of the surface-anchored layer of AQAS as well as a second and perhaps third layer adsorbed on the anchored first layer.

Flooding affects more people than any other environmental hazard and hinders sustainable development1,2. Investing in flood adaptation strategies may reduce the loss of life and livelihood caused by floods3. Where and how floods occur and who is exposed are changing as a result of rapid urbanization4, flood mitigation infrastructure5 and increasing settlements in floodplains6. Previous estimates of the global flood-exposed population have been limited by a lack of observational data, relying instead on models, which have high uncertainty3,7–11. Here we use daily satellite imagery at 250-metre resolution to estimate flood extent and population exposure for 913 large flood events from 2000 to 2018. We determine a total inundation area of 2.23 million square kilometres, with 255–290 million people directly affected by floods. We estimate that the total population in locations with satellite-observed inundation grew by 58–86 million from 2000 to 2015. This represents an increase of 20 to 24 per cent in the proportion of the global population exposed to floods, ten times higher than previous estimates7. Climate change projections for 2030 indicate that the proportion of the population exposed to floods will increase further. The high spatial and temporal resolution of the satellite observations will improve our understanding of where floods are changing and how best to adapt. The global flood database generated from these observations will help to improve vulnerability assessments, the accuracy of global and local flood models, the efficacy of adaptation interventions and our understanding of the interactions between landcover change, climate and floods. Satellite imagery for the period 2000–2018 reveals that population growth was greater in flood-prone regions than elsewhere, thus exposing a greater proportion of the population to floods.

Cell patterning is becoming increasingly popular in neuroscience because it allows for the control in the location and connectivity of cells. A recently developed cell patterning technology uses patterns of an organic polymer, parylene-C, on a background of SiO2. When cells are cultured on the parylene-C/SiO2 substrate they conform to the underlying parylene-C geometry. Parylene-C is, however, just one member of a family of parylene polymers that have varying chemical and physical properties. In this work, we investigate whether two commercially available mainstream parylene derivatives, parylene-D, parylene-N and a more recent parylene derivative, parylene-HT to determine if they enable higher fidelity hNT astrocyte cell patterning compared to parylene-C. We demonstrate that all parylene derivatives are compatible with the existing laser fabrication method. We then demonstrate that parylene-HT, parylene-D and parylene-N are suitable for use as an hNT astrocyte cell attractive substrate and result in an equal quality of patterning compared to parylene-C. This work supports the use of alternative parylene derivatives for applications where their different physical and chemical properties are more suitable.

A flexible, thermoset and transparent polyurethane (PUR) film with high glass transition temperature, has been deployed as a substrate for anchoring anti-bacterial molecular layers. These layers are formed by adsorbing, from an aqueous solution, a silyl anchoring quaternary ammonium salt (AQAS) with a long alkyl chain (C-18) onto the PUR film surface, followed by thermal curing at 160 degrees C. The presence of AQAS adsorbed on the PUR film surface is confirmed by the appearance of a distinctive N1 s level XPS peak at 402 eV, attributed to quaternary nitrogen (N+). The carbonyl groups on the PUR surface appear to be the main surface binding sites for the adsorbed AQAS molecules. This interpretation is validated by the relative decrease in the intensities observed for the nu (C=O) at 1700 cm(-1) in the infrared spectra, and decreases in the intensity of the Cl s binding energy peak for C=O at 289 eV in the XPS spectra of the PUR following AQAS adsorption. Leaching studies suggest a chemisorbed first layer and several leachable higher layers of oligomeric forms of AQAS. A PUR surface incorporating a blended polydimethylsiloxane additive exhibits similar adsorptive capacity to pristine PUR. However exposing the PUR films to oxygen plasma treatment prior to AQAS adsorption leads to a higher coverage of the adsorbate on the PUR surface. The anchoring quaternary ammonium salt (AQAS) in this current work has established potencies against a wide range of critical organisms. Antibacterial assays adapted from the JIS 2801 wet fomite method confirm the potency (3-log reduction) of these PUR-AQAS films against Staphylococcus aureus and Escherichia coll.

Objective. Recent literature suggests that astrocytes form organized functional networks and communicate through transient changes in cytosolic Ca2+. Traditional techniques to investigate network activity, such as pharmacological blocking or genetic knockout, are difficult to restrict to individual cells. The objective of this work is to develop cell-patterning techniques to physically manipulate astrocytic interactions to enable the study of Ca2+ in astrocytic networks. Approach. We investigate how an in vitro cell-patterning platform that utilizes geometric patterns of parylene-C on SiO2 can be used to physically isolate single astrocytes and small astrocytic networks. Main results. We report that single astrocytes are effectively isolated on 75  ×  75 µm square parylene nodes, whereas multi-cellular astrocytic networks are isolated on larger nodes, with the mean number of astrocytes per cluster increasing as a function of node size. Additionally, we report that astrocytes in small multi-cellular clusters exhibit spatio-temporal clustering of Ca2+ transients. Finally, we report that the frequency and regularity of Ca2+ transients was positively correlated with astrocyte connectivity. Significance. The significance of this work is to demonstrate how patterning hNT astrocytes replicates spatio-temporal clustering of Ca2+ signalling that is observed in vivo but not in dissociated in vitro cultures. We therefore highlight the importance of the structure of astrocytic networks in determining ensemble Ca2+ behaviour.

This study aimed to develop dry powder particles with surfaces enriched in hydrophobic material by manipulation of spray-drying conditions and to investigate the effect of hydrophobic surface enrichment on aerosolization of hygroscopic drug. The composite dry powder formulations of kanamycin (hygroscopic drug) and rifampicin (hydrophobic drug) were produced by systematically (23 full factorial design) varying the drug ratio, co-solvent composition and inlet temperature using Buchi B-290 Mini Spray-Dryer. All the composite powder particles were inhalable in size (3.1-3.9 µm), wrinkled, flake-shaped and amorphous. X-ray photoelectron spectroscopy and time-of-flight secondary ion mass spectrometry showed that hydrophobic surface enrichment was significantly affected by co-solvent composition. Complete hydrophobic surface enrichment was achieved in one formulation (F7). The aerosolization efficiency by next generation impactor (NGI) showed that the composite formulations had higher fine particle fraction (FPF: >48.0%) than kanamycin-only formulation (FPF: 27.6%). Increase in hydrophobic surface enrichment (from 80.8 to 100%) decreased the powder density and increased FPF (from 48.0 to 77.2%). This is the first systematic study reporting the manipulation of spray-drying conditions for hydrophobic surface enrichment in composite dry powder particles and its effect on aerosolization. The high aerosolization efficiency of the combination formulations may be useful to deliver high doses of these drugs to treat lung infections.

Controlling the spatial distribution of glia and neurons in in vitro culture offers the opportunity to study how cellular interactions contribute to large scale network behaviour. A recently developed approach to cell-patterning uses differential adsorption of animal-serum protein on parylene-C and SiO 2 surfaces to enable patterning of neurons and glia. Serum, however, is typically poorly defined and generates reproducibility challenges. Alternative activation methods are highly desirable to enable patterning without relying on animal serum. We take advantage of the innate contrasting surface chemistries of parylene-C and SiO 2 to enable selective bonding of polyethylene glycol SiO 2 surfaces, i.e. PEGylation, rendering them almost completely repulsive to cell adhesion. As the reagents used in the PEGylation protocol are chemically defined, the reproducibility and batch-to-batch variability complications associated with the used of animal serum are avoided. We report that PEGylated parylene-C/SiO 2 substrates achieve a contrast in astrocyte density of 65:1 whereas the standard serum-immersion protocol results in a contrast of 5.6:1. Furthermore, single-cell isolation was significantly improved on PEGylated substrates when astrocytes were grown on close-proximity parylene-C nodes, whereas isolation was limited on serum-activated substrates due tolerance for cell adhesion on serum-adsorbed SiO 2 surfaces.

This study aimed to develop a high payload dry powder inhalation formulation containing a combination of the first line anti-tubercular drug, pyrazinamide, and the second line drug, moxifloxacin HCl. Individual powders of pyrazinamide (PSD) and moxifloxacin (MSD) and combination powders of the two drugs without (PM) and with 10% l-leucine (PML) and 10% DPPC (PMLD) were produced by spray drying. PSD contained >10 μm crystalline particles and showed poor aerosolization behaviour with a fine particle fraction (FPF) of 18.7 ± 3.4%. PM produced spherical hollow particles with aerodynamic diameter < 5 μm and PML showed improved aerosolization with a high FPF of ~70%. However, PMLD showed a significantly reduced FPF (p > 0.05) compared to PML. Solid state studies and surface elemental analysis by X-ray photoelectron spectroscopy and time-of-flight secondary ion mass spectrometry confirmed the surface coating of particles contained amorphous moxifloxacin and both l-leucine and DPPC over crystalline pyrazinamide. Furthermore, pyrazinamide, moxifloxacin, PML and PMLD were found to display low toxicity to both A549 and Calu-3 cell lines even at a concentration of 100 μg/mL. In conclusion, a combination powder formulation of PML has the potential to deliver a high drug dose to the site of infection resulting in efficient treatment.

High dose delivery of drugs to the lung using a dry powder inhaler (DPI) is an emerging approach to combat drug-resistant local infections. To achieve this, highly aerosolizable powders are required. We hypothesized that co-spray-drying kanamycin, a hydrophilic hygroscopic antibiotic, with rifampicin, a hydrophobic antibiotic, would produce inhalable particles with surfaces enriched in rifampicin. Such particles would have higher aerosolization than kanamycin alone, and minimise the mass of powder for inhalation avoiding use of non-active excipients. Kanamycin was co-spray-dried with rifampicin using a Buchi Mini Spray-dryer. All powders were inhalable in size (1.1-5.9 mu m) and noncrystalline. X-ray photoelectron spectroscopy (XPS) and time-of-flight secondary ion mass spectrometry (ToF-SIMS) showed the surface of the combination powder was enriched with rifampicin. In vitro aerosolization (fine particle fraction) determined by next generation impactor (NGI), dramatically improved from 29.5 +/- 0.2% (kanamycin-only) to 78.2 +/- 1.3% (kanamycin-rifampicin combination). The combination powder was flake-shaped in morphology, stable at 15% and 53% RH and 25 +/- 2 degrees C during one-month storage in an open Petri dish, and non-toxic (up to 50 mu g/mL) to human alveolar and bronchial cell-lines. Surface enrichment of kanamycin by hydrophobic rifampicin improves aerosolization, which may help to combat drug-resistant local infections by facilitating high dose delivery to deep lung.

Pharmacotherapy of tuberculosis is potentially more efficient when delivered by the inhaled route than by the current oral and/or parenteral routes due to the higher concentration of drug reaching the primary region of infection in the lungs. This study investigated the influence of the amino acid l-leucine alone and in combination with the phospholipid, 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine (DPPC), on the aerosolization behaviour of the anti-TB drugs, pyrazinamide and moxifloxacin HCl. Spray dried powders of pyrazinamide (P), moxifloxacin (M) alone and in combination with 10% l-leucine (PL and ML) and 10% DPPC (PLD and MLD) were produced. The particle sizes of all powders except P were in the inhalable size range (<5 µm) but differ in their morphology in presence of the excipients. X-ray photoelectron spectroscopy (XPS) and time-of-flight secondary ion mass spectrometry (ToF-SIMS) revealed the migration of surface active l-leucine and DPPC onto the surface of the particles during the spray drying process. The aerosolization from a dry powder inhaler, Aerolizer®, using a Next Generation Impactor revealed fine particle fraction (FPF) values for P, PL and PLD of 18.7 ± 3.4%, 53.0 ± 3.2% and 74.5 ± 5.3% respectively while FPF values for M, ML and MLD were 55.6 ± 3.3%, 74.7 ± 4.7% and 74.1 ± 1.3% respectively. In conclusion, the differences in the aerosolization behaviours of the pyrazinamide and moxifloxacin spray dried powders with and without excipients was a combination of difference in the surface morphology and surface composition.

The development of a sustained-release biocide system, involving an anchored quaternary ammonium salt (AQAS) embedded in expanded perlite (EP) substrate, is reported. Scanning electron microscopy (SEM) images reveal the well-defined honeycomb cells that are a feature of EP. These honeycomb cells exhibit a variety of polygon shapes, which are filled with the AQAS molecules as evidenced by SEM data. The aqueous leaching of the AQAS from the EP honeycomb cells is monitored by the Fourier transform infrared CH stretching absorbance maxima at 2920 and 2850 cm-1. Solid-state NMR data indicate the formation of three dominant oligomeric forms of the AQAS biocide molecules formed within the EP network by condensation reactions at curing temperatures (160 °C). The various oligomeric species involve different numbers of SiO chains bonded to a central Si atom within the AQAS anchoring groups. Assays confirm the potency of the AQAS oligomers against Staphylococcus aureus and Escherichia coli bacteria.

A siloxane surface-anchored quaternary ammonium salt (AQAS: BIOSAFE HM4100 in this study) has been chemisorbed onto a quartz substrate. The aim of this study is to elucidate, using atomic force microscopy (AFM) and X-ray photoelectron spectroscopy (XPS), the structure of the chemisorbed AQAS layers. The AQAS biocide includes a C18 alkyl chain previously invoked in lysis potency. The AQAS coverage appears in zones on the surface, which include a first layer (2.6 ± 0.1 nm) and multilayering that were explored using AFM. The XPS data exhibited two N 1s signals at about 402 and 399 eV, with only the former exhibiting angular dependence. This signal at 402 eV was assigned to the first anchored layer with perpendicular orientation determined by the AQAS anchoring to the surface. In preliminary AFM studies of bacteria on these AQAS surfaces, perturbations on the Staphylococcus aureus cells and the degradation of Escherichia coli cells suggest lysis potency.

Background: Kanamycin, an injectable agent, is currently used to treat drug-resistant tuberculosis (TB). Parenteral kanamycin causes high systemic toxicity which could be avoided by direct delivery to the lungs. This study focused on producing a highly aerosolizable dry-powder of hygroscopic kanamycin by spray-drying with L-leucine.Methods: Kanamycin powders were prepared with different concentrations (0, 5,10,15 and 20% w/w) of L-leucine using the Buchi B-290 Mini Spray-Dryer. In vitro aerosolization efficiency, particle size, morphology, crystallinity, surface composition, drug-excipient interaction and moisture content of the powders were characterized by a Next Generation Impactor (NGI), laser diffraction, scanning electron microscopy, X-ray diffractometry, XPS, ATR-FTIR and thermogravimetric analysis. The physicochemical and aerosolization stability of the powders were investigated after one-month storage at 25 +/- 2 degrees C/15% RH and 25 +/- 2 degrees C/75% RH. The cytotoxicity on Calu-3 and A549 cells of the kanamycin powders was evaluated by MTT assay.Results: The spray-dried powder particles were in the inhalable size range (<6.1 mu m). The powders with L-leucine were wrinkled in shape, amorphous in nature and had low moisture content (<5.0%). Kanamycin with 5% (w/w) of L-leucine showed the best aerosolization efficiency of 73.0 +/- 2.5%. The powders remained stable during storage at 25 +/- 2 degrees C/15% RH and tolerated by respiratory cell lines.Conclusion: L-leucine improved the aerosolization of kanamycin by surface modification, which may be helpful for the effective treatment of drug-resistant tuberculosis. (C) 2017 Elsevier B.V. All rights reserved.

This work reports the fabrication of a biosensing chip surface designed for plasmonic detection, and features a layer of noble metal nanoparticles encapsulated as a sandwich within amine-functionalized polysiloxane layers formed by plasma-enhanced chemical vapour deposition. The collective surface plasmon resonance (CSPR) phenomenon characteristic of a dense particle layer is demonstrated for encapsulated gold nanoparticles of different diameters. Biomolecular immobilization is carried out through the amine functional groups that are part of the encapsulating layer. The detection of biomolecular binding events at the sensor surface is demonstrated both by a shift in resonance wavelength at constant angle of incidence using SPR-enhanced spectroscopic ellipsometry and by detecting the angular shift in resonance in a commercial SPR instrument (Biacore®). Taken with other results, this work shows how a complete SPR chip can be assembled by a rapid sequence of operations in a single plasma chamber.

Metal roofing material is commonly used for residential and industrial roofs in volcanically active areas. Increased corrosion of metal roofing from chemically reactive volcanic ash following ash deposition post-eruption is a major concern due to decreasing the function and stability of roofs. Currently, assessment of ash-induced corrosion is anecdotal, and quantitative data are lacking. Here, we systematically evaluate the corrosive effects of volcanic ash, specifically ash leachates, on a variety of metal roofing materials (i.e. weathered steel, zinc, galvanized steel, and Colorsteel©) utilizing weathering chamber experiments and direct acid treatments. Weathering chamber tests were carried out for up to 30 days, and visual, chemical, and surface analyses did not definitively identify significant corrosion in any of the test roofing metal samples. Direct concentrated acid treatments with hydrochloric (HCl), sulphuric (H2SO4), and hydrofluoric (HF) acids demonstrate that roofing materials are chemically resilient. Our experimental results suggest that ash-leachate-related corrosion is a longer-term process (>1 month), potentially related to a multitude of factors including increased ash leachate concentrations, the dissolution of the glass matrix of the ash, moisture retention at the ash-surface boundary, and potential reactions involving photo-oxidation. Overall, corrosion is not a simple process related to the short-term release of acid and/or salt leachates from the ash surface, but a product of dynamic interactions involving ash and water at the surface of metal roofing material for extended periods.

Cell patterning commonly employs photolithographic methods for the micro fabrication of structures on silicon chips. These require expensive photo-mask development and complex photolithographic processing. Laser based patterning of cells has been studied in vitro and laser ablation of polymers is an active area of research promising high aspect ratios. This paper disseminates how 800 nm femtosecond infrared (IR) laser radiation can be successfully used to perform laser ablative micromachining of parylene-C on SiO2 substrates for the patterning of human hNT astrocytes (derived from the human teratocarcinoma cell line (hNT)) whilst 248 nm nanosecond ultra-violet laser radiation produces photo-oxidization of the parylene-C and destroys cell patterning. In this work, we report the laser ablation methods used and the ablation characteristics of parylene-C for IR pulse fluences. Results follow that support the validity of using IR laser ablative micromachining for patterning human hNT astrocytes cells. We disseminate the variation in yield of patterned hNT astrocytes on parylene-C with laser pulse spacing, pulse number, pulse fluence and parylene-C strip width. The findings demonstrate how laser ablative micromachining of parylene-C on SiO2 substrates can offer an accessible alternative for rapid prototyping, high yield cell patterning with broad application to multi-electrode arrays, cellular micro-arrays and microfluidics.

This paper describes the use of 800nm femtosecond infrared (IR) and 248nm nanosecond ultraviolet (UV) laser radiation in performing ablative micromachining of parylene-C on SiO2 substrates for the patterning of human hNT astrocytes. Results are presented that support the validity of using IR laser ablative micromachining for patterning human hNT astrocytes cells while UV laser radiation produces photo-oxidation of the parylene-C and destroys cell patterning. The findings demonstrate how IR laser ablative micromachining of parylene-C on SiO2 substrates can offer a low cost, accessible alternative for rapid prototyping, high yield cell patterning.