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We characterize the transient solvent-dependent OH-stretching frequency shifts of photoacid 2-naphthol hydrogen-bonded with CH3CN in the S0- and S1-states using a combined experimental and theoretical approach, and disentangle specific hydrogen-bonding contributions from nonspecific dielectric response.

Polylactic Acid is a sustainable, compostable bioplastic that requires specific geoenvironmental conditions for degradation. The complexity of managing the PLA waste has limited the scope of its seamless application. There have been a significant number of studies exploring PLA degradation. Majorly they have explored degradability as a material property with limited discussions on the fundamental factors affecting degradation. The knowledge of the influence of biotic and abiotic factors and their complex interplay is critical for enhancing PLA degradation research, specifically accelerated degradation. This understanding is necessary for PLA waste upcycling and generating industrial-scale value-added products. Using the PRISMA framework, a database of articles on PLA degradation (1974-2023) has been created with each entry being annotated with 11 critical parameters depending on the scale and scope of the research. Abiotic hydrolysis, biotic hydrolysis and assimilation of PLA were discussed in detail with information on experiment design analytical techniques and background mechanisms to achieve systematic recommendations. Enzymes responsible for PLA degradation have been categorised and catalogued. The review highlights the need for future research related to PLA degradation in terms of molecular mechanisms of enzymatic degradation, bioengineering enzymes for accelerating degradation, and mathematical models for predicting degradation kinetics in complex environmental conditions., 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 © 2024. Published by Elsevier B.V.)

A seventh blind test of crystal structure prediction has been organized by the Cambridge Crystallographic Data Centre. The results are presented in two parts, with this second part focusing on methods for ranking crystal structures in order of stability. The exercise involved standardized sets of structures seeded from a range of structure generation methods. Participants from 22 groups applied several periodic DFT-D methods, machine learned potentials, force fields derived from empirical data or quantum chemical calculations, and various combinations of the above. In addition, one non-energy-based scoring function was used. Results showed that periodic DFT-D methods overall agreed with experimental data within expected error margins, while one machine learned model, applying system-specific AIMnet potentials, agreed with experiment in many cases demonstrating promise as an efficient alternative to DFT-based methods. For target XXXII, a consensus was reached across periodic DFT methods, with consistently high predicted energies of experimental forms relative to the global minimum (above 4 kJ mol -1 at both low and ambient temperatures) suggesting a more stable polymorph is likely not yet observed. The calculation of free energies at ambient temperatures offered improvement of predictions only in some cases (for targets XXVII and XXXI). Several avenues for future research have been suggested, highlighting the need for greater efficiency considering the vast amounts of resources utilized in many cases., (open access.)

A seventh blind test of crystal structure prediction was organized by the Cambridge Crystallographic Data Centre featuring seven target systems of varying complexity: a silicon and iodine-containing molecule, a copper coordination complex, a near-rigid molecule, a cocrystal, a polymorphic small agrochemical, a highly flexible polymorphic drug candidate, and a polymorphic morpholine salt. In this first of two parts focusing on structure generation methods, many crystal structure prediction (CSP) methods performed well for the small but flexible agrochemical compound, successfully reproducing the experimentally observed crystal structures, while few groups were successful for the systems of higher complexity. A powder X-ray diffraction (PXRD) assisted exercise demonstrated the use of CSP in successfully determining a crystal structure from a low-quality PXRD pattern. The use of CSP in the prediction of likely cocrystal stoichiometry was also explored, demonstrating multiple possible approaches. Crystallographic disorder emerged as an important theme throughout the test as both a challenge for analysis and a major achievement where two groups blindly predicted the existence of disorder for the first time. Additionally, large-scale comparisons of the sets of predicted crystal structures also showed that some methods yield sets that largely contain the same crystal structures., (open access.)

Critical soil suctions (threshold, tipping point, and permanent wilting) corresponding to initial drought response, near-death stage, and complete mortality, respectively; is essential for formulating irrigation schemes of vegetation grown in compacted soil under drought conditions. The effect of soil types on these critical soil suctions are unexplored and is crucial in understanding the soil-specific plant water functions. This study aims to establish the drought response of Axonopus compressus (grass), based on stomatal conductance (g s ) and chlorophyll fluorescence parameters (CI) grown in different soil types. A. compressus were grown in six soil types (2 coarse-grained and 4 fine-grained soils) for 8 weeks, followed by continued drought condition. The g s and CI were monitored along with soil suction and moisture content. Both leaf and root growth were observed to be higher in coarse-grained soils than fine-grained soils, even though the water retention of the coarse-grained soils were comparatively less. Drought stress initiation in plants was captured by ψ threshold from the CI (especially in fine-grained soils) before the g s response. The three critical soil suctions estimated from the correlation between CI and ψ were found to be increasing with higher soil clay fraction. Corresponding plant available water contents (based on v/v volumetric water content) with each of three critical soil suctions were found to be dependent on the relative growth of canopy to root growth that occurred in different soil medias. Especially, plant available water in 'tipping suction' was dependent on the soil clay fraction (i.e., higher fraction could restrict root water uptake) and is presented with a simple empirical correlation for A. compressus., Competing Interests: Declaration of competing interest All authors state that they have no competing interest to declare., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The use of different template surfaces in crystallization experiments can directly influence the nucleation kinetics, crystal growth, and morphology of active pharmaceutical ingredients (APIs). Consequently, templated nucleation is an attractive approach to enhance crystal nucleation kinetics and preferentially nucleate desired crystal polymorphs for solid-form drug molecules, particularly large and flexible molecules that are difficult to crystallize. Herein, we investigate the effect of polymer templates on the crystal nucleation of clotrimazole and ketoprofen with both experiments and computational methods. Crystallization was carried out in toluene solvent for both APIs with a template library consisting of 12 different polymers. In complement to the experimental studies, we developed a computational workflow based on molecular dynamics (MD) and derived descriptors from the simulations to score and rank API-polymer interactions. The descriptors were used to measure the energy of interaction (EOI), hydrogen bonding, and rugosity (surface roughness) similarity between the APIs and polymer templates. We used a variety of machine learning models (14 in total) along with these descriptors to predict the crystallization outcome of the polymer templates. We found that simply rank-ordering the polymers by their API-polymer interaction energy descriptors yielded 92% accuracy in predicting the experimental outcome for clotrimazole and ketoprofen. The most accurate machine learning model for both APIs was found to be a random forest model. Using these models, we were able to predict the crystallization outcomes for all polymers. Additionally, we have performed a feature importance analysis using the trained models and found that the most predictive features are the energy descriptors. These results demonstrate that API-polymer interaction energies are correlated with heterogeneous crystallization outcomes.

Polylactic Acid (PLA) based compostable bioplastic films degrade under thermophilic composting conditions. The purpose of our study was to understand whether sample pre-treatment along with bioaugmentation of the degradation matrix could reduce the biodegradation time under a simulated composting environment. Sepcifically, we also explored whether the commercial composts could be replaced by landfill-mined soil-like fraction (LMSF) for the said application. The effect of pre-treatment on the material was analysed by tests like tensile strength analysis, hydrophobicity analysis, morphological analysis, thermal degradation profiling, etc. Subsequently, the degradation experiment was performed in a simulated composting environment following the ASTM D5338 standard, along with bioaugmentation in selected experimental setups. When the novel approach of material pre-treatment and bioaugmentation were applied in combination, the time necessary for 90% degradation was reduced by 27% using compost and by 23% using LMSF. Beyond the improvement in degradation rate, the water holding capacity increased significantly for the degradation matrices. With pH, C: N ratio and microbial diversity tested to be favourable through 16s metabarcoding studies, material pre-treatment and bioaugmentation allow LMSF to not only replace commercial compost in polymer degradation but also find immense application in the agricultural sector of drought-affected areas (for better water retention) after it has been used for PLA degradation., 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 © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The soil-insect interaction has gathered significant attention in the recent years due to its contribution to bio-cementation. Termites, as a group of cellulose-eating insects, alter physical (texture) and chemical (chemical composition) properties of soil. Conversely, physico-chemical properties of soil also influence termite activities. It is vital to understand the soil-termite interaction and their influence on hydraulic properties and shear strength of soil, which are related to a series of geotechnical engineering problems such as ground water recharge, runoff, erosion and stability of slopes. In this study, an attempt has been made to review the latest developments and research gaps in our understanding of soil-termite interaction within the context of geo-environmental engineering. The hydraulic properties and shear strength of termite modified soil were discussed with respect to soil texture, density and physico-chemical composition. The incorporation of hysteresis effect of soil water characteristic curve, and spatio-temporal variations of hydraulic conductivity and shear strength of termite modified soil is proposed to be considered in geotechnical engineering design and construction. Finally, the challenges and future trends in this research area are presented. The expertise from both geotechnical engineering and entomology is needed to plan future research with an aim to promote use of termites as maintenance engineers in geotechnical infrastructure., 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 © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Crystal structure prediction (CSP) is an invaluable tool in the pharmaceutical industry because it allows to predict all the possible crystalline solid forms of small-molecule active pharmaceutical ingredients. We have used a CSP-based cocrystal prediction method to rank ten potential cocrystal coformers by the energy of the cocrystallization reaction with an antiviral drug candidate, MK-8876, and a triol process intermediate, 2-ethynylglyclerol. For MK-8876, the CSP-based cocrystal prediction was performed retrospectively and successfully predicted the maleic acid cocrystal as the most likely cocrystal to be observed. The triol is known to form two different cocrystals with 1,4-diazabicyclo[2.2.2]octane (DABCO), but a larger solid form landscape was desired. CSP-based cocrystal screening predicted the triol-DABCO cocrystal as rank one, while a triol-l-proline cocrystal was predicted as rank two. Computational finite-temperature corrections enabled determination of relative crystallization propensities of the triol-DABCO cocrystals with different stoichiometries and prediction of the triol-l-proline polymorphs in the free-energy landscape. The triol-l-proline cocrystal was obtained during subsequent targeted cocrystallization experiments and was found to exhibit an improved melting point and deliquescence behavior over the triol-free acid, which could be considered as an alternative solid form in the synthesis of islatravir.

The crystal habit can have a profound influence on the physical properties of crystalline materials, and thus controlling the crystal morphology is of great practical relevance across many industries. Herein, this work investigates the effect of polymer additives on the crystal habit of metformin HCl with both experiments and computational methods with the aim of developing a combined screening approach for crystal morphology engineering. Crystallization experiments of metformin HCl are conducted in methanol and in an isopropanol-water mixture (8:2 V/V). Polyethylene glycol, polyvinylpyrrolidone, Tween80, and hydroxypropyl methylcellulose polymer additives are used in low concentrations (1-2% w/w) in the experiments to study the effect they have on modifying the crystal habit. Additionally, this work has developed computational methods to characterize the morphology "landscape" and quantifies the overall effect of solvent and additives on the predicted crystal habits. Further analysis of the molecular dynamics simulations is used to rationalize the effect of additives on specific crystal faces. This work demonstrates that the effects of additives on the crystal habit are a result of their absorption and interactions with the slow growing {100} and {020} faces., (© 2023 XtalPi Inc and Merck KGaA Darmstadt Germany. Small Methods published by Wiley-VCH GmbH.)

Establishing the absolute configuration of chiral active pharmaceutical ingredients (APIs) is of great importance. Single crystal X-ray diffraction (scXRD) has traditionally been the method of choice for such analysis, but scXRD requires the growth of large crystals, which can be challenging. Here, we present a method for determining absolute configuration that does not rely on the growth of large crystals. By examining microcrystals formed with chiral probes (small chiral compounds such as amino acids), absolute configuration can be unambiguously determined by microcrystal electron diffraction (MicroED). Our streamlined method employs three steps: (1) virtual screening to identify promising chiral probes, (2) experimental cocrystal screening and (3) structure determination by MicroED and absolute configuration assignment. We successfully applied this method to analyze two chiral API molecules currently on the market for which scXRD was not used to determine absolute configuration., (© 2023 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

Growing demand for plastic and increasing plastic waste pollution have led to significant environmental challenges and concerns in today's world. Bioplastics offer exciting new opportunities and possibilities where biodegradable and bio-based plastics are expected to be more eco-friendly and rely on renewable resources. With all its promises, evaluating its real impact and fate on the geoenvironment is paramount for promoting bioplastic use. This paper presents a systematic literature review to understand current bioplastic-soil research and the effects of its residues on the geoenvironment. 632 studies related to bioplastic research in soil since 1973 were identified and categorized into different relevant topics. Publication trend showed bioplastic-soil research grew exponentially after 2010 wherein field studies accounted to 33.1 % of the total studies and only about 9.7 % studied the effects of bioplastic residues on the geoenvironment. Majority of the lab studies were on development and subsequent stability of bioplastics in soil. Short-term studies (in months) dominated the longer-term studies and studies over 4 years were almost non-existent. Lab and field experiments often gave inconsistent results with seasonal, climatic and bio-geographical factors strongly influencing the field results and bioplastic stability in soil. Most existing studies reported significant effects for microbioplastic concentrations at or above 1 % w/w. Bioplastic residues were found to substantially affect soil C/N ratio, impact soil microbial diversity by favouring certain microbial taxa and alter soil physical structure by influencing soil aggregates formation. At higher concentrations, plant health and germination success were also negatively affected. Conclusively, the review found it important to focus more on long-term field experiments to better understand the degree and extent of bioplastic residue impact on soil physico-chemical properties, mechanical properties, soil biology, soil-bioplastic-plant response, nutrients and toxicity. There are also very few studies investigating contaminant transport and migration of micro or nano-bioplastics in soil., 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 © 2022 Elsevier B.V. All rights reserved.)

The function of engineered thermal backfills surrounding underground pipelines of the crude oil industry is to prohibit heat migration for the design period of 25 to 50 years. Biochar is suitable for reconstituting standard thermal backfill material since it is biochemically inert and has a low heat conductivity. However, the preparation of biochar from biomass involves an energy-intensive pyrolysis process. This study aims to make biochar production energy-efficient via optimizing the pyrolysis temperatures, specifically for thermal backfill applications. Ten distinct biochars were prepared by pyrolyzing two waste biomass, i.e., water hyacinth (WH) and sugarcane bagasse (SB), at temperatures ranging from 300 to 700 °C. The biochars were assessed based on their thermal conductivity, energy consumption, yield, and stability in soil for the design period. The thermal conductivity of produced biochars varied in a narrow range of 0.10 to 0.13 W m -1 K -1 with different pyrolysis temperatures, which is possibly due to marginal differences in their microstructure, mineralogy, and physicochemical properties. The findings revealed that the biochar produced at lowest pyrolysis temperature (300 °C) consumed least energy and produced maximum yield. However, it was not suitable for thermal backfill applications due to its inadequate carbon stability in soil. Therefore, the current study recommends a pyrolysis temperature of 400 °C for thermal backfill applications. The recommended pyrolysis temperature was found to be at least 60% energy efficient in comparison to pyrolysis at 700 °C for both the feedstocks. This study provides crucial insight into the role of pyrolysis temperature for tailoring biochar production for intended applications., Competing Interests: Declaration of competing interest The authors declare that there are no competing financial interests., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Sustainable biomaterials such as natural fibers and biochars have been increasingly used in green infrastructures such as landfill covers for its dual-advantages of climate change mitigation and waste management. The existing studies did not systematically discuss the comparison on how biochar (stable carbon) and fiber (likely degradable), influence plant growth and water retention abilities in unsaturated soils. Also, the effect of photochemistry in the amended soils has rarely been investigated. This study addresses the limitations of previous investigations by exploring plant parameters such as photochemical yield, stomatal conductance, root area index, and unsaturated soil hydraulic parameters, including soil water retention curves (SWRC) of amended soils. Pot experiments were conducted in an environmentally controlled greenhouse. Two biochars from different plant-based feedstocks (Eichhornia crassipes, Prosopis juliflora) and one natural fiber (coir pith fiber) were mixed with soil at 5% and 10% application rate (by weight). Grass species of Axonopus compressus was planted to study the effects of different amendment materials and its corresponding plant responses during an applied drought period. The test results show that biochar amended soils increased the shoot growth by up to 100-200%. The stomatal conductance of the grass leaves increased by 54%-101% during the drought period for both biochars and coir amended soil. Furthermore, at low suction, the coir had a high water retention capacity than the biochars, explaining the observed higher stomatal conductance values. Importantly, it was discovered that the plant photochemical quantum yield responses associated with plant wilting was found to vary between 1500 and 1800 kPa for all the soil treatments. The study concludes with a newly developed mathematical expression based on the measurements of plant parameters and soil suction. The new equation could be used to optimize the irrigation frequency in order to apply any informed measures to maintain green infrastructures., 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 © 2021 Elsevier B.V. All rights reserved.)

Therapeutic options in response to the coronavirus disease 2019 (COVID-19) outbreak are urgently needed. In this communication, we demonstrate how to support selection of a stable solid form of an antiviral drug remdesivir in quick time using the microcrystal electron diffraction (MicroED) technique and a cloud-based and artificial intelligence implemented crystal structure prediction platform. We present the MicroED structures of remdesivir forms II and IV and conclude that form II is more stable than form IV at ambient temperature in agreement with experimental observations. The combined experimental and theoretical study can serve as a template for formulation scientists in the pharmaceutical industry., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

A multi-layered final cover system is constructed over the landfill after it reaches its full capacity to minimize water ingress into the underlying hazardous waste. Three layered landfill cover are designed for areas experiencing very humid climatic conditions. Under the effects of climate change, the occurrences of extreme rainfall events become more frequent and this has resulted in catastrophic floods and hence extreme ponding. This study investigates the seepage characteristics of three-layered capillary barrier cover systems under an extreme ponding condition of 1.5 m water head, through detailed laboratory column tests and finite-element seepage analysis. Four 1.2 m-tall columns having different configurations (C1-C4) were studied. Fly ash (FA) was used to amend the surface and barrier layers in columns C2 and C4, in line with the novel concept of "waste protect waste". Spatiotemporal variations of volumetric water content of the four columns were monitored for three years continuously. With FA amendment in the surface layer and an inclusion of a 0.01 m thick geosynthetic clay liner between the drainage and barrier layers, the onset of basal percolation was significantly delayed until 700 days of ponding, compared to 115 days without FA amendment. Capillary flow dominated the gravitational flow and perched water table was formed as waterfront advanced from the drainage to barrier layers. Further seepage analysis considering a realistic humid climate boundary condition showed that all four configurations were successful in preventing basal percolation for 800 days., Competing Interests: Declaration of competing interest There is no conflict of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Permanent wilting point (PWP) is generally used to ascertain plant resistance against abiotic drought stress and designated as the soil water content (θ) corresponding to soil suction (ψ) at 1500 kPa obtained from the soil water retention curve. Determination of PWP based on only pre-assumed ψ may not represent true wilting condition for soils with contrasting water retention abilities. In addition to ψ, there is a need to explore significance of additional plant parameters (i.e., stomatal conductance and photosynthetic status) in determining PWP. This study introduces a new framework for determining PWP by integrating plant leaf response and ψ during drought. Axonopus compressus were grown in two distinct textured soils (clayey loam and silty sand), after which drought was initiated till wilting. Thereafter, ψ and θ within the root zone were measured along with corresponding leaf stomatal conductance and photosynthetic status. It was found that coarse textured silty sand causes wilting at much lower ψ (≈ 300 kPa) than clayey loam (≈ 1600 kPa). Plant response to drought was dependent on the relative porosity and mineralogy of the soil, which governs the ease at which roots can grow, assimilate soil O 2 , and uptake water. For clay loam, the held water within the soil matrix does not facilitate easy root water uptake by relatively coarse root morphology. Contrastingly, fine root hair formation in silty sand facilitated higher plant water uptake and doubled the plant survival time.

Securing water in the soil through suitable amendments is one of the methods for drought management in arid regions. In this study, a poor water sorbing fly ash was transformed into a high water-absorbing material for improving soil water retention during the drought period. The fly ash water absorbent (FAWA) exhibited high water-absorbing capacity (WAC) of 310 g/g at par with commercially available superabsorbent hydrogel (SAH). The FAWA showed excellent re-swelling behavior for more than eight alternate wetting-drying cycles. The WAC of FAWA was sensitive to salt type, pH, and ionic strength of the solution. At maximum salinity level permitted for plant growth, the WAC of FAWA was 80 g/g indicating its suitability for drought management. There was only a marginal WAC variation in the range of pH (5.5-7.5) considered most suitable for plant growth. The drying characteristics of FAWA amended soil exhibited an increase in desaturation time by 3.3, 2.2, and 1.5 times for fine sand, silt loam, and clay loam, respectively. The study demonstrates the success of using a low rate of FAWA for drought management with the advantage of offering a non-toxic and eco-friendly solution to mass utilization of industrial solid waste for agricultural applications.

Multi-layered engineered landfill consists of the bottom liner layer (mainly bentonite clay (B)) upon which the hazardous wastes are dumped. In current practice, sand (S) is mixed with bentonite to mitigate the adverse effects of using bentonite alone in the liner layer. Incorporation of waste and unutilized fly ash (FA) as an amendment material to B has been explored in terms of its hydro-mechanical properties, but not gauged its adsorption potential. Indian subcontinent primarily relies on the thermal power source, and FA dumps have already reached its full capacity. The objective of this study is to explore the adsorption characteristics of four B-FA composite mixes sourced within India, considering Pb 2+ as a model contaminant. The effect of fly ash type, fly ash amendment rate and adsorbate concentration was explored in the current study and juxtaposed with B-S mixes, based on 960 batch adsorption tests. Both B-FA and B-S mixes reached equilibrium adsorption capacity within 65 min. At higher adsorbate concentrations (commonly observed in the liner), B-FA mixes exhibited superior adsorption capacity, mainly one mixed with Neyvelli fly ash (NFA). The effect of higher amendment rate had little impact on the adsorption capacity at different concentration, but gradually decreased the percentage removal of Pb 2+ . The B-S mix showed a drastic decrease in percentage removal at higher adsorbate concentration among all tested mixes. Systematic characterization including geotechnical properties, microstructure and chemical analysis was also done to interpret the obtained results. Both Freundlich and Langmuir models fitted the isotherm data well for all B-FA mixes. The maximum adsorption capacity from the isotherm was correlated to easily measurable Atterberg limits by two empirical relationships., Competing Interests: Declaration of competing interest The authors declare no competing financial interests., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Low hydraulic conductivity and high chemical immobilization are the two characteristics that make bentonite a mandatory construction material for hazardous waste containment applications. We performed a comprehensive batch sorption study on Barmer bentonite (BB), an exclusive construction clay mined in India, using lead (Pb 2+ ) as a model contaminant. The maximum adsorption capacity of BB was obtained as 55 mg g -1 at pH 5 and 27 ± 2℃. Adsorption was extremely rapid, with equilibrium attained <5 min for the BB. Increased adsorbent dosage resulted in higher Pb 2+ percentage removal, while adsorption capacity decreased. Ionic strength, salt concentration, valency and ionic radius played a critical role in suppressing the adsorption of Pb 2+ . Clay fabric change was observed to be dispersed at low ionic strength and gradually attained aggregated face-to-face structures at high ionic strength. The simultaneous presence of other metals/salts strongly influenced Pb 2+ removal by BB, while divalent salt exhibited high suppression of adsorptive reaction at low concentrations. Sorption isotherm and kinetic modeling results indicated the possibility of chemisorption of Pb 2+ on BB. Based on the thermodynamic analysis, it was noted that Pb 2+ adsorption on BB is exothermic, spontaneous and adsorption reaction is less favorable at a higher temperature., Competing Interests: Declaration of Competing Interest The authors declare that there are no competing financial interests., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Proteorhodopsin (PR) is a light-driven proton pump that is most notable for ushering in the discovery of an ever-increasing number of microbial retinal proteins that are at the forefront of fields such as optogenetics. Two variants, blue (BPR) and green (GPR) proteorhodopsin, have evolved to harvest light at different depths of the ocean. The color-tuning mechanism in PR is controlled by a single residue at position 105: in BPR it is a glutamine, whereas in GPR it is a leucine. Although the majority of studies on the spectral tuning mechanism in PR have focused on GPR, detailed understanding of the electronic environment responsible for spectral tuning in BPR is lacking. In this work, several BPR models were investigated using quantum mechanics/molecular mechanics (QM/MM) calculations to obtain fundamental insights into the color tuning mechanism of BPR. We find that the molecular mechanism of spectral tuning in BPR depends on two geometric parameters, the bond length alternation and the torsion angle deviation of the all-trans-retinyl chromophore. Both parameters are influenced by the strength of the hydrogen-bonded networks in the chromophore-binding pocket, which shows how BPR is different from other microbial rhodopsins.

Hazardous wastes disposed of in engineered landfills interact with rainwater, generate harmful leachate and may contaminate groundwater. To minimize this, a suitable multi-layered cover system (MLCS) is constructed over the buried waste. Field assessment of complex moisture dynamics in unsaturated MLCS and its long-term hydraulic efficiency has not been investigated in detail for extremely humid conditions (annual rainfall >1000 mm). Therefore, the overarching purpose of this study was to investigate the long-term hydraulic performance of a three-layered hydraulic barrier cover system under humid Indian conditions. The field cover setup was exposed to natural weather condition in the Northeast Indian state of Assam, for 800 days. The MLCS was instrumented to measure continuous variation of volumetric water content and matric suction as function of time and depth. The field measurements were used to determine the appropriate input hydraulic parameters and evapotranspiration model that can be used for numerical modeling. The results showed that simulation using drying van Genuchten soil-water characteristic curve parameters and Penman-Monteith evapotranspiration model matched the field observations. Events of the highest precipitation and extreme drought (cause for desiccation) did not lead to percolation in the drainage layer (60 cm) and barrier layer (100 cm). Numerical analyses performed for 87 years by considering the climate data of two different humid locations (Eastern and Western part) of India revealed that the progressive saturation of barrier layer occurred within 18 to 20 years. However, when geosynthetic clay liner was incorporated as additional barrier material, the saturation time increased by two-fold (42 to 44 years)., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Interest is growing in the use of macrocycles in pharmaceutical discovery. Macrocylization may provide a gateway to an expanded chemical space for small-molecule drug discovery, and this could be beneficial in prosecuting difficult targets, e.g., protein-protein interactions. Most, but not all, macrocycle drugs are derived from natural products. Studies on synthetic drug-like small-molecule macrocycles are limited, and our current understanding of macrocycle drugs is similarly limited. Following some background discussion, we review several examples of the structure-based design of synthetic macrocycles. Our opinion is that in conformationally suitable systems macrocycles are an analog class worthy of consideration. We then summarize an approach for the initial evaluation of molecules as candidates for macrocyclization.

Clinically, erythropoietin (EPO) is known to increase systemic vascular resistance and arterial blood pressure. However, EPO stimulates the production of the potent vasodilator, nitric oxide (NO), in culture endothelial cells. The mechanism by which EPO causes vasoconstriction despite stimulating NO production may be dependent on its ability to activate two receptor complexes, the homodimeric EPO (EPOR 2 ) and the heterodimeric EPOR/β-common receptor (βCR). The purpose of this study was to investigate the contribution of each receptor to the vasoactive properties of EPO. First-order, mesenteric arteries were isolated from 16-week-old male C57BL/6 mice, and arterial function was studied in pressure arteriographs. To determine the contribution of each receptor complex, EPO-stimulating peptide (ESP), which binds and activates the heterodimeric EPOR/βCR complex, and EPO, which activates both receptors, were added to the arteriograph chamber 20 min prior to evaluation of endothelium-dependent (acetylcholine, bradykinin, A23187) and endothelium-independent (sodium nitroprusside) vasodilator responses. Only ACh-induced vasodilation was impaired in arteries pretreated with EPO or ESP. EPO and ESP pretreatment abolished ACh-induced vasodilation by 100% and 60%, respectively. EPO and ESP did not affect endothelium-independent vasodilation by SNP. Additionally, a novel βCR inhibitory peptide (βIP), which was computationally developed, prevented the impairment of acetylcholine-induced vasodilation by EPO and ESP, further implicating the EPOR/βCR complex. Last, pretreatment with either EPO or ESP did not affect vasoconstriction by phenylephrine and KCl. Taken together, these findings suggest that acute activation of the heterodimeric EPOR/βCR in endothelial cells leads to a selective impairment of ACh-mediated vasodilator response in mouse mesenteric resistance arteries., (© 2018 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)

In short-term animal models of ischemia, erythropoietin (EPO) signaling through the heterodimeric EPO receptor (EPOR)/β-common receptor (βCR) is believed to elicit tissue protective effects. However, large, randomized, controlled trials demonstrate that targeting a higher hemoglobin level by administering higher doses of EPO, which are more likely to activate the heterodimeric EPOR/βCR, is associated with an increase in adverse cardiovascular events. Thus, inhibition of long-term activation of the βCR may have therapeutic implications. This study aimed to design and evaluate the efficacy of novel computationally designed βCR inhibitory peptides (βIP). These novel βIPs were designed based on a truncated portion of Helix-A from EPO, specifically residues 11-26 (VLERYLLEAKEAEKIT). Seven novel peptides (P1 to P7) were designed. Peptide 7 (P7), VLERYLHEAKHAEKIT, demonstrated the most robust inhibitory activity. We also report here the ability of P7 to inhibit βCR-induced nitric oxide (NO) production and angiogenesis in human umbilical vein endothelial cells (HUVECs). Specifically, we found that P7 βIP completely abolished EPO-induced NO production. The inhibitory effect could be overcome with super physiological doses of EPO, suggesting a competitive inhibition. βCR-induced angiogenesis in HUVEC's was also abolished with treatment of P7 βIP, but P7 βIP did not inhibit vascular endothelial growth factor (VEGF)-induced angiogenesis. In addition, we demonstrate that the novel P7 βIP does not inhibit EPO-induced erythropoiesis with use of peripheral blood mononuclear cells (PBMCs). These results, for the first time, describe a novel, potent βCR peptide inhibitor that inhibit the actions of the βCR without affecting erythropoiesis., (Published by Elsevier Inc.)

Understanding olfaction at the molecular level is challenging due to the lack of crystallographic models of odorant receptors (ORs). To better understand the molecular mechanism of OR activation, we focused on chiral ( R )-muscone and other musk-smelling odorants due to their great importance and widespread use in perfumery and traditional medicine, as well as environmental concerns associated with bioaccumulation of musks with estrogenic/antiestrogenic properties. We experimentally and computationally examined the activation of human receptors OR5AN1 and OR1A1, recently identified as specifically responding to musk compounds. OR5AN1 responds at nanomolar concentrations to musk ketone and robustly to macrocyclic sulfoxides and fluorine-substituted macrocyclic ketones; OR1A1 responds only to nitromusks. Structural models of OR5AN1 and OR1A1 based on quantum mechanics/molecular mechanics (QM/MM) hybrid methods were validated through direct comparisons with activation profiles from site-directed mutagenesis experiments and analysis of binding energies for 35 musk-related odorants. The experimentally found chiral selectivity of OR5AN1 to ( R )- over ( S )-muscone was also computationally confirmed for muscone and fluorinated ( R )-muscone analogs. Structural models show that OR5AN1, highly responsive to nitromusks over macrocyclic musks, stabilizes odorants by hydrogen bonding to Tyr260 of transmembrane α-helix 6 and hydrophobic interactions with surrounding aromatic residues Phe105, Phe194, and Phe207. The binding of OR1A1 to nitromusks is stabilized by hydrogen bonding to Tyr258 along with hydrophobic interactions with surrounding aromatic residues Tyr251 and Phe206. Hydrophobic/nonpolar and hydrogen bonding interactions contribute, respectively, 77% and 13% to the odorant binding affinities, as shown by an atom-based quantitative structure-activity relationship model., Competing Interests: The authors declare no conflict of interest.

We present here the use of QM/MM LIE (linear interaction energy) based binding free energy calculations that greatly improve the precision and accuracy of predicting experimental binding affinities, in comparison to most current binding free energy methodologies, while maintaining reasonable computational times. Calculations are done for four sets of ligand-protein complexes, chosen on the basis of diversity of protein types and availability of experimental data, totaling 140 ligands binding to therapeutic protein targets BACE1, TYK2, HSP90, and PERK. This method allows calculations for a diverse set of ligands and multiple protein targets without the need for parametrization or extra calculations. The accuracy achieved with this method can be used to guide small molecule computational drug design programs.

We recently reported a very unusual temperature dependence of the rate of thermal reaction of wild type bovine rhodopsin: the Arrhenius plot exhibits a sharp "elbow" at 47 °C and, in the upper temperature range, an unexpectedly large activation energy (114 ± 8 kcal/mol) and an enormous prefactor (10 72±5 s -1 ). In this report, we present new measurements and a theoretical model that establish convincingly that this behavior results from a collective, entropy-driven breakup of the rigid hydrogen bonding networks (HBNs) that hinder the reaction at lower temperatures. For E181Q and S186A, two rhodopsin mutants that disrupt the HBNs near the binding pocket of the 11-cis retinyl chromophore, we observe significant decreases in the activation energy (∼90 kcal/mol) and prefactor (∼10 60 s -1 ), consistent with the conclusion that the reaction rate is enhanced by breakup of the HBN. The results provide insights into the molecular mechanism of dim-light vision and eye diseases caused by inherited mutations in the rhodopsin gene that perturb the HBNs.

It is important to determine the contaminant retention characteristics of materials when assessing their suitability for use as liners in landfill sites. Sand-bentonite mixtures are commonly used as liners in the construction of landfill sites for industrial and hazardous wastes. Sand is considered to be a passive material with a negligible chemical retention capacity; fly ash, however, offers the additional advantage of adsorbing the heavy metals present in landfill leachates. There have been few studies of the contaminant retention characteristics of fly ash-bentonite mixes. The study reported here determined the contaminant retention characteristics of different fly ashes, bentonite and selected fly ash-bentonite mixes for Pb 2+ using 24 h batch tests. The tests were conducted by varying the initial concentrations of metal ions under uncontrolled pH conditions. The efficiency of the removal of Pb 2+ by the different types of fly ash and fly ash-bentonite mixes was studied. The influence of multiple sources of fly ash on the retention characteristics of fly ash-bentonite mixes was investigated.

Olfactory receptors (ORs) comprise the largest G protein-coupled receptor gene superfamily. Recent studies indicate that ORs are also expressed in non-olfactory organs, including metabolically active tissues, although their biological functions in these tissues are largely unknown. In this study, OR1A1 expression was detected in HepG2 liver cells. OR1A1 activation by (-)-carvone, a known OR1A1 ligand, increased the cyclic adenosine monophosphate (cAMP), but not intracellular Ca(2+) concentration, thereby inducing protein kinase A (PKA) activity with subsequent phosphorylation of cAMP response element-binding protein (CREB) and upregulation of the CREB-responsive gene hairy and enhancer of split (HES)-1, a corepressor of peroxisome proliferator-activated receptor-γ (PPAR-γ) in hepatocytes. In (-)-carvone-stimulated cells, the repression of PPAR-γ reduced the expression of the target gene, mitochondrial glycerol-3-phosphate acyltransferase, which encodes a key enzyme involved in triglyceride synthesis. Intracellular triglyceride level and lipid accumulation were reduced in cells stimulated with (-)-carvone, effects that were diminished following the loss of OR1A1 function. These results indicate that OR1A1 may function as a non-redundant receptor in hepatocytes that regulates the PKA-CREB-HES-1 signaling axis and thereby modulates hepatic triglyceride metabolism., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

The vibrational theory of olfaction assumes that electron transfer occurs across odorants at the active sites of odorant receptors (ORs), serving as a sensitive measure of odorant vibrational frequencies, ultimately leading to olfactory perception. A previous study reported that human subjects differentiated hydrogen/deuterium isotopomers (isomers with isotopic atoms) of the musk compound cyclopentadecanone as evidence supporting the theory. Here, we find no evidence for such differentiation at the molecular level. In fact, we find that the human musk-recognizing receptor, OR5AN1, identified using a heterologous OR expression system and robustly responding to cyclopentadecanone and muscone, fails to distinguish isotopomers of these compounds in vitro. Furthermore, the mouse (methylthio)methanethiol-recognizing receptor, MOR244-3, as well as other selected human and mouse ORs, responded similarly to normal, deuterated, and (13)C isotopomers of their respective ligands, paralleling our results with the musk receptor OR5AN1. These findings suggest that the proposed vibration theory does not apply to the human musk receptor OR5AN1, mouse thiol receptor MOR244-3, or other ORs examined. Also, contrary to the vibration theory predictions, muscone-d30 lacks the 1,380- to 1,550-cm(-1) IR bands claimed to be essential for musk odor. Furthermore, our theoretical analysis shows that the proposed electron transfer mechanism of the vibrational frequencies of odorants could be easily suppressed by quantum effects of nonodorant molecular vibrational modes. These and other concerns about electron transfer at ORs, together with our extensive experimental data, argue against the plausibility of the vibration theory.

Visual pigments can be thermally activated via isomerization of the retinyl chromophore and hydrolysis of the Schiff base (SB) through which the retinyl chromophore is bound to the opsin protein. Here, we present the first combined experimental and theoretical study of the thermal activation of a Siberian hamster ultraviolet (SHUV) pigment. We measured the rates of thermal isomerization and hydrolysis in the SHUV pigment and bovine rhodopsin. We found that these rates were significantly faster in the UV pigment than in rhodopsin due to the difference in the structural and electrostatic effects surrounding the unprotonated Schiff base (USB) retinyl chromophore in the UV pigment. Theoretical (DFT-QM/MM) calculations of the cis-trans thermal isomerization revealed a barrier of ∼23 kcal/mol for the USB retinyl chromophore in SHUV compared to ∼40 kcal/mol for protonated Schiff base (PSB) chromophore in rhodopsin. The lower barrier for thermal isomerization in the SHUV pigment is attributed to the (i) lessening of the steric restraints near the β-ionone ring and SB ends of the chromophore, (ii) displacement of the transmembrane helix 6 (TM6) away from the binding pocket toward TM5 due to absence of the salt bridge between the USB and the protonated E113 residue, and (iii) change in orientation of the hydrogen-bonding networks (HBNs) in the extracellular loop 2 (EII). The results in comparing thermal stability of UV cone pigment and rhodopsin provide insight into molecular evolution of vertebrate visual pigments in achieving low discrete dark noise and high photosensitivity in rod pigments for dim-light vision.

Ultraviolet (UV) cone pigments can provide insights into the molecular evolution of vertebrate vision since they are nearer to ancestral pigments than the dim-light rod photoreceptor rhodopsin. While visible-absorbing pigments contain an 11-cis retinyl chromophore with a protonated Schiff-base (PSB11), UV pigments uniquely contain an unprotonated Schiff-base (USB11). Upon F86Y mutation in model UV pigments, both the USB11 and PSB11 forms of the chromophore are found to coexist at physiological pH. The origin of this intriguing equilibrium remains to be understood at the molecular level. Here, we address this phenomenon and the role of the USB11 environment in spectral tuning by combining mutagenesis studies with spectroscopic (UV-vis) and theoretical [DFT-QM/MM (SORCI+Q//B3LYP/6-31G(d): Amber96)] analysis. We compare structural models of the wild-type (WT), F86Y, S90A and S90C mutants of Siberian hamster ultraviolet (SHUV) cone pigment to explore structural rearrangements that stabilize USB11 over PSB11. We find that the PSB11 forms upon F86Y mutation and is stabilized by an "inter-helical lock" (IHL) established by hydrogen-bonding networks between transmembrane (TM) helices TM6, TM2, and TM3 (including water w2c and amino acid residues Y265, F86Y, G117, S118, A114, and E113). The findings implicate the involvement of the IHL in constraining the displacement of TM6, an essential component of the activation of rhodopsin, in the spectral tuning of UV pigments.

The spectral tuning of halorhodopsin from Halobacterium salinarum (shR) during anion transport was analyzed at the molecular level using DFT-QM/MM [SORCI+Q//B3LYP/6-31G(d):Amber96] hybrid methods. Insights into the influence of Cl(-) depletion, Cl(-) substitution by N3(-) or NO3(-), and mutation of key amino acid residues along the ion translocation pathway (H95A, H95R, Q105E, R108H, R108I, R108K, R108Q, T111V, R200A, R200H, R200K, R200Q, and T203V) were analyzed for the first time in a fully atomistic model of the shR photoreceptor. We found evidence that structural rearrangements mediated by specific hydrogen bonds of internal water molecules and counterions (D238 and Cl(-)) in the active site induce changes in the bond-length alternation of the all-trans retinyl chromophore and affect the wavelength of maximal absorption in shR.

Background: Studying drug use pattern among medical practitioners is of vital importance in the present scenario where irrational drug use and development of drug resistance is becoming rampant., Objective: To assess, the pattern of prescribing practices among the general practitioners in a defined rural and urban area of Tamil Nadu., Materials and Methods: A community based descriptive study was conducted to collect 600 prescriptions from the catchment areas of rural and urban health training centers of a medical college using prescribing indicators as per the WHO "How to investigate drug use in health facilities" tool., Results: This prescription study revealed that multivitamins (19.5%), antibiotics (19.3%), drugs for gastro-intestinal tract (GIT) (18%), analgesic non-steroidal anti-inflammatory drugs/ (NSAID's) (15.1%), and antihistaminic (12.5%) were prescribed frequently. Among the antibiotics, amoxicillin (49.2%) was the most commonly prescribed followed by gentamicin (31.7%). Percentage of prescriptions with an antibiotic was 55% and nearly 62% of the practitioners prescribed drugs by their generic names. As a practice of poly-pharmacy, it was observed that the average number of drugs prescribed in urban and rural area was nearly 5 and 4, respectively. Nearly 80% of the urban and rural practitioners were prescribing at least one injection. Study of the quality of prescriptions revealed that there was poor legibility, high usage of abbreviations, inadequate details of the drugs, and absence of signature by practitioners in the prescriptions., Conclusion: This study clearly highlights the practice of poly-pharmacy, low usage of generic drugs, injudicious usage of antibiotics and injections and low usage of drugs prescribed from essential drugs list.

The nonvisual ocular photoreceptor melanopsin, found in the neurons of vertebrate inner retina, absorbs blue light and triggers the "biological clock" of mammals by activating the suprachiasmatic nuclei (a small region of the brain that regulates the circadian rhythms of neuronal and hormonal activities over 24 h cycles). The structure of melanopsin, however, has yet to be established. Here, we propose for the first time a structural model of the active site of mouse melanopsin. The homology model is based on the crystal structure of squid rhodopsin (λ(max) = 490 nm) and shows a maximal absorbance (λ(max) = 447 nm) consistent with the observed absorption of the photoreceptor. The 43 nm spectral shift is due to an increased bond-length alternation of the protonated Schiff base of 11-cis-retinal chromophore, induced by N87Q mutation and water-mediated H-bonding interactions with the Schiff base linkage. These findings, analogous to spectral changes observed in the G89Q bovine rhodopsin mutant, suggest that single site mutations can convert photopigments into visual light sensors or nonvisual sensory photoreceptors.

Eyes gather information, and color forms an extremely important component of the information, more so in the case of animals to forage and navigate within their immediate environment. By using the ONIOM (QM/MM) (ONIOM = our own N-layer integrated molecular orbital plus molecular mechanics) method, we report a comprehensive theoretical analysis of the structure and molecular mechanism of spectral tuning of monkey red- and green-sensitive visual pigments. We show that interaction of retinal with three hydroxyl-bearing amino acids near the β-ionone ring part of the retinal in opsin, A164S, F261Y, and A269T, increases the electron delocalization, decreases the bond length alternation, and leads to variation in the wavelength of maximal absorbance of the retinal in the red- and green-sensitive visual pigments. On the basis of the analysis, we propose the "OH-site" rule for seeing red and green. This rule is also shown to account for the spectral shifts obtained from hydroxyl-bearing amino acids near the Schiff base in different visual pigments: at site 292 (A292S, A292Y, and A292T) in bovine and at site 111 (Y111) in squid opsins. Therefore, the OH-site rule is shown to be site-specific and not pigment-specific and thus can be used for tracking spectral shifts in any visual pigment.

Since Vogt's discovery of A(3)-retinal or 3-hydroxyretinal in insects in 1983 and Matsui's discovery of A(4)-retinal or 4-hydroxyretinal in firefly squid in 1988, hydroxyretinal-protein interactions mediating vision have remained largely unexplored. In the present study, A(3)- and A(4)-retinals are theoretically incorporated into squid and bovine visual pigments by use of the hybrid quantum mechanics/molecular mechanics [SORCI+Q//B3LYP/6-31G(d):Amber96] method, and insights into structure, enantioselectivity, and spectroscopy are gathered and presented for the first time. Contrary to general perception, our findings rule out the formation of a hydrogen bond between the hydroxyl-bearing β-ionone ring portion of retinal and opsin. Compared to A(1)-pigments, A(3)- and A(4)-pigments exhibit slightly blue-shifted absorption maxima due to increase in bond-length alternation of the hydroxyretinal. We suggest that (i) the binding site of firefly squid (Watasenia scintillans) opsin is very similar to that of the Japanese common squid (Todarodes pacificus) opsin; (ii) the molecular mechanism of spectral tuning in small white butterflies involve sites S116 and T185 and breaking of a hydrogen bond between sites E180 and T185; and finally (iii) A(3)-retinal may have occurred during the conversion of A(1)- to A(2)-retinal and insects may have acquired them, in order to absorb light in the blue-green wavelength region and to speed up the G-protein signaling cascade., (© 2011 American Chemical Society)

One of the basic and unresolved puzzles in the chemistry of vision concerns the natural selection of 11-cis-retinal as the light-sensing chromophore in visual pigments. A detailed computational examination of the structure, stability, energetics, and spectroscopy of 7-cis-, 9-cis-, 11-cis-, and 13-cis-retinal isomers in vertebrate (bovine, monkey) and invertebrate (squid) visual pigments was carried out using a hybrid quantum mechanics/molecular mechanics (QM/MM) method. The results show that the electrostatic interaction between retinal and opsin dominates the natural selection of 11-cis-retinal over other cis isomers in the dark state. In all of the pigments, 9-cis-retinal was found to be only slightly higher in energy than 11-cis-retinal, which provides strong evidence for the presence of 9-cis-rhodopsin in nature. 7-cis-Retinal is suggested to be an "upside-down" version of the all-trans isomer because the structural rearrangements observed for 7-cis-rhodopsin from squid were found to be very similar to those for squid bathorhodopsin. The progressive red shift in the calculated absorption wavelength (λ(max)) (431, 456, 490, and 508 nm for the 7-cis-, 9-cis-, 11-cis-, and 13-cis-retinal isomers) is due to the decrease in bond length alternation of the retinal.

The synthesis of perylene 3,4:9,10-tetracarboxylic acid bisimides (PBIs) dendronized with first-generation dendrons containing 0 to 4 methylenic units (m) between the imide group and the dendron, (3,4,5)12G1-m-PBI, is reported. Structural analysis of their self-organized arrays by DSC, X-ray diffraction, molecular modeling, and solid-state (1)H NMR was carried out on oriented samples with heating and cooling rates of 20 to 0.2 °C/min. At high temperature, (3,4,5)12G1-m-PBI self-assemble into 2D-hexagonal columnar phases with intracolumnar order. At low temperature, they form orthorhombic (m = 0, 2, 3, 4) and monoclinic (m = 1) columnar arrays with 3D periodicity. The orthorhombic phase has symmetry close to hexagonal. For m = 0, 2, 3, 4 ,they consist of tetramers as basic units. The tetramers contain a pair of two molecules arranged side by side and another pair in the next stratum of the column, turned upside-down and rotated around the column axis at different angles for different m. In contrast, for m = 1, there is only one molecule in each stratum, with a four-strata 2(1) helical repeat. All molecules face up in one column, and down in the second column, of the monoclinic cell. This allows close and extended π-stacking, unlike in the disruptive up-down alteration from the case of m = 0, 2, 3, 4. Most of the 3D structures were observed only by cooling at rates of 1 °C/min or less. This complex helical self-assembly is representative for other classes of dendronized PBIs investigated for organic electronics and solar cells., (© 2011 American Chemical Society)

Study Objective: To evaluate the extent of agreement between plasma gentamicin concentrations determined from samples collected by using implantable subcutaneous central venous catheters (ports) with the push-pull method and those collected by finger lancet punctures in children with febrile neutropenia., Design: Prospective, randomized study., Setting: University-affiliated, tertiary care hospital., Patients: Sixty-two children with cancer who had single- or double-lumen ports and who received gentamicin for treatment of febrile neutropenia between February 2008 and October 2009., Intervention: One blood sample was collected from the port by using the push-pull method at the same time one blood sample was collected by finger lancet puncture for determination of plasma gentamicin concentrations., Measurements and Main Results: Forty-four pairs of samples were available for assessment of agreement, and 43 were available for pharmacokinetic analysis. Agreement between plasma gentamicin concentrations determined from blood samples from ports and finger lancet punctures was assessed by the intraclass correlation coefficient (ICC), Bland-Altman analysis, and comparison of simulated dosage adjustments. Changes in port patency were monitored for 1 week after port sampling. Differences in simulated dosage adjustments calculated by using either the port or finger lancet puncture samples that differed by greater than 20% were considered clinically significant. Agreement between the 44 finger lancet puncture and port sample pairs was excellent (ICC 0.991, 95% confidence interval 0.984-0.995). Port plasma gentamicin concentrations were 4.7% lower than those concentrations determined in blood from finger lancet punctures. The observed limits of agreement ranged from -20.5% to 11%. Differences in dosage adjustments calculated by using port and finger lancet puncture plasma gentamicin concentrations were not clinically significant in 38 (88%) of 43 cases. No changes in port patency were observed in the week after port sampling., Conclusion: The push-pull method of blood sampling is a reliable and safe option for determining plasma gentamicin concentrations in children with ports.