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This article argues that it is relevant to apply the complex adaptive system approach to urbanized deltas. On the basis of this, it discusses some important planning issues related to these areas: adapting them to changing circumstances, synchronizing the various sectors in the areas, and organizing collective action to realize this. The paper also suggests how planners can better deal with these issues: by systematically exploring uncertainties related to future trends and disruptive events, by thinking through the impacts of each sector on other sectors and the area as a whole, and by making joint visions and identifying strategic projects not only among public actors but also with private and civic actors. The approach presented, integrating social, ecological and physical aspects of systems, is relevant for planners as well as scientists. [ABSTRACT FROM AUTHOR]

The aims of this investigation were to calculate the pharmacokinetic parameters and to identify parameters, based on individual plasma concentration–time curves of amoxicillin and clavulanic acid in dogs, that may govern the observed differences in absorption of both drugs. The evaluation was based on the data from plasma concentration–time curves obtained following a single dose in an open, randomized, two-way crossover study involving 24 male Beagle dogs treated with two Amoxi–Clav formulations (A Clavubactin® and B Synulox® , each with 200/50 mg). Plasma amoxicillin and clavulanic acid concentrations were determined using validated bioassay methods. The half-life of elimination of amoxicillin was 1.5 h (t 1/2 = 1.52 ± 0.19 h, C max = 11.4 ± 2.74 μg/mL), and that of clavulanic acid 0.76 h (t 1/2 = 0.71 ± 0.23 h, C max = 2.06 ± 1.05 μg/mL). There was a fivefold variation in the AUC t of clavulanic acid for both formulations, while the AUC t of amoxicillin varied by a factor of 2. The mean ratio of the AUC t amoxicillin : clavulanic acid was 12.7 ± 3.65 for formulation A and 11.8 ± 5.22 for formulation B (P = 0.51). [ABSTRACT FROM AUTHOR]

Objective: To identify the differences in esterase hydrolysis of lovastatin between male and female volunteers. Study design and participants: Data for plasma concentration and area under the concentration-time curve until the last measured concentration (AUC) of lovastatin and its active metabolite lovastatin-β-hydroxy acid (mevinolinic acid) were obtained from a randomised, crossover bioequivalence study in 36 subjects (18 females and 18 males). Methods: Participants received a single 80mg oral dose of two different formulations of lovastatin (formulations I and II). Plasma lovastatin and lovastatin-β-hydroxy acid concentrations were determined according to validated methods involving gas chromatography-mass spectrometry. Results: The group of female volunteers showed a higher yield of the active metabolite lovastatin-β-hydroxy acid than the group of males (p < 0.002). This difference was not related to the bodyweight of the two groups. In both male and female groups, a subject-dependent yield of lovastatin-β-hydroxy acid was demonstrated, which was independent of the formulation. The variation in plasma/liver hydrolysis resulted in a fan-shaped distribution of datapoints when the AUC of lovastatin was plotted against that of the hydroxy acid metabolite. In the fan of datapoints, subgroups could be distinguished, each showing a different regression line and with a different y-intercept (AUCof lovastatin-β-hydroxy acid). It was possible to discriminate between hydrolysis of lovastatin by plasma/liver or tissue esterase activity. The three subgroups of subjects (males/females) showing a different but high yield of lovastatin-β-hydroxy acid can be explained by variable hydrolysis by plasma and hepatic microsomal and cytosolic carboxyesterase activity. Conclusion: This study showed clearly that in addition to subject-dependent hydrolysis of lovastatin to the active metabolite, males tend to hydrolyse less than females. Therefore, the dosage of lovastatin should be individualised with reference to plasma concentration or clinical effect. [ABSTRACT FROM AUTHOR]

Uncertainty in ammonia (NH 3 ) emissions causes the inaccuracy of fine particulate matter simulations, which is associated with human health. To address this uncertainty, in this work, we employ the iterative finite difference mass balance (iFDMB) technique to revise NH 3 emissions over East Asia using the Cross-track Infrared Sounder (CRIS) satellite for July, August, and September 2019. Compared to the emissions, the revised NH 3 emissions show an increase in China, particularly in the North China Plain (NCP) region, corresponding to agricultural land use in July, August, and September and a decrease in South Korea in September. The enhancement in NH 3 emissions resulted in a remarkable increase in concentrations of NH 3 by 5 ppb. in July and September, there is an increase in ammonium (NH 4 + ) and nitrate (NO 3 - ) concentrations by 5 μg/m3, particularly in the NCP region, while in August, both NH 4 + and NO 3 - concentrations exhibit a decrease. For sulfate (SO 4 2- ), in August and September, the concentrations decreased over most regions of China and Taiwan, as a result of the production of ammonium sulfate; increased concentrations of SO 4 2- , however, were simulated over South Korea, Japan, and the southern region of Chengdu, caused by higher relative humidity (RH). In contrast, during the month of July, our simulations showed an increase in SO 4 2- concentrations over most regions of China. To gain a more comprehensive understanding, we defined a sulfur conversion ratio ( [Formula: see text] ), which explains how changes in sulfur in the gas phase affect changes in sulfate concentrations. A subsequent sensitivity analysis performed in this study indicated the same relationship between changes in ammonia and its effect on inorganic fine particulate matter (PM 2.5 ). This study highlights the challenge of controlling and managing inorganic PM 2.5 and indicates that reducing the emissions of air pollutants do not necessarily lead to a reduction in their concentrations., 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 Author(s). Published by Elsevier Ltd.. All rights reserved.)

India experiences some of the highest levels of ambient PM 2.5 aerosol pollution in the world. However, due to the historical dearth of in situ measurements, chemical transport models that are often used to estimate PM 2.5 exposure over the region are rarely evaluated. Here, we conduct a novel model comparison with speciated airborne measurements of fine aerosol, revealing large biases in the ammonium and nitrate simulations. To address this, we incorporate process-level changes to the model and use satellite observations from the Cross-track Infrared Sounder (CrIS) and the TROPOspheric Monitoring Instrument (TROPOMI) to constrain ammonia and nitrogen oxide emissions. The resulting simulation demonstrates significantly lower bias (NMB Modified : 0.19; NMB Base : 0.61) when validated against the airborne aerosol measurements, particularly for the nitrate (NMB Modified : 0.08; NMB Base : 1.64) and ammonium simulation (NMB Modified : 0.49; NMB Base : 0.90). We use this validated simulation to estimate a population-weighted annual PM 2.5 exposure of 61.4 μg m -3 , with the RCO (residential, commercial, and other) and energy sectors contributing 21% and 19%, respectively, resulting in an estimated 961,000 annual PM 2.5 -attributable deaths. Regional exposure and sectoral source contributions differ meaningfully in the improved simulation (compared to the baseline simulation). Our work highlights the critical role of speciated observational constraints in developing accurate model-based PM 2.5 aerosol source attribution for health assessments and air quality management in India., Competing Interests: The authors declare no competing financial interest., (© 2022 The Authors. Published by American Chemical Society.)

We conduct the first 4D-Var inversion of NH 3 accounting for NH 3 bi-directional flux, using CrIS satellite NH 3 observations over Europe in 2016. We find posterior NH 3 emissions peak more in springtime than prior emissions at continental to national scales, and annually they are generally smaller than the prior emissions over central Europe, but larger over most of the rest of Europe. Annual posterior anthropogenic NH 3 emissions for 25 European Union members (EU25) are 25% higher than the prior emissions and very close (<2% difference) to other inventories. Our posterior annual anthropogenic emissions for EU25, the UK, the Netherlands, and Switzerland are generally 10%-20% smaller than when treating NH 3 fluxes as uni-directional emissions, while the monthly regional difference can be up to 34% (Switzerland in July). Compared to monthly mean in-situ observations, our posterior NH 3 emissions from both schemes generally improve the magnitude and seasonality of simulated surface NH 3 and bulk NH x wet deposition throughout most of Europe, whereas evaluation against hourly measurements at a background site shows the bi-directional scheme better captures observed diurnal variability of surface NH 3 . This contrast highlights the need for accurately simulating diurnal variability of NH 3 in assimilation of sun-synchronous observations and also the potential value of future geostationary satellite observations. Overall, our top-down ammonia emissions can help to examine the effectiveness of air pollution control policies to facilitate future air pollution management, as well as helping us understand the uncertainty in top-down NH 3 emissions estimates associated with treatment of NH 3 surface exchange., (© 2022. The Authors.)

TROPOMI, on-board the Sentinel-5 Precursor satellite is a nadir-viewing spectrometer measuring reflected sunlight in the ultraviolet, visible, near-infrared, and shortwave infrared spectral range. From these spectra several important air quality and climate-related atmospheric constituents are retrieved at an unprecedented high spatial resolution, including nitrogen dioxide (NO 2 ). We present the first retrievals of TROPOMI NO 2 over the Canadian Oil Sands, contrasting them with observations from the OMI satellite instrument, and demonstrate its ability to resolve individual plumes and highlight its potential for deriving emissions from individual mining facilities. Further, the first TROPOMI NO 2 validation is presented, consisting of aircraft and surface in-situ NO 2 observations, as well as ground-based remote-sensing measurements between March and May 2018. Our comparisons show that the TROPOMI NO 2 vertical column densities are highly correlated with the aircraft and surface in-situ NO 2 observations, and the ground-based remote-sensing measurements with a low bias (15-30 %) over the Canadian Oil Sands., Plain Language Summary: Nitrogen dioxide (NO 2 ) is a pollutant that is linked to respiratory health issues and has negative environmental impacts such as soil and water acidification. Near the surface the most significant sources of NO 2 are fossil fuel combustion and biomass burning. With a recently launched satellite instrument (TROPOspheric Monitoring Instrument; TROPOMI) NO 2 can be measured with an unprecedented combination of accuracy, spatial coverage, and resolution. This work presents the first TROPOMI NO 2 measurements near the Canadian Oil Sands and shows that these measurements have an outstanding ability to detect NO 2 on a very high horizontal resolution that is unprecedented for satellite NO 2 observations. Further, these satellite measurements are in excellent agreement with aircraft and ground-based measurements.

Background: We did a phase 3 study in previous non-responders with chronic hepatitis C virus (HCV) genotype 1 infection and compensated liver disease that related to the standard of care for these patients at the time this study was initiated. We investigated whether simeprevir is non-inferior in terms of efficacy to telaprevir, each in combination with peginterferon alfa-2a and ribavirin., Methods: We did this randomised, double-blind, phase 3 trial at 169 investigational sites in 24 countries. We enrolled adults (≥18 years) with chronic HCV genotype 1 infection, compensated liver disease, and plasma HCV RNA higher than 10 000 IU/mL who were null or partial responders during at least one previous course of peginterferon alfa-2a and ribavirin treatment. We randomly assigned (1:1) patients (stratified by HCV genotype 1 subtype [1a plus other/1b] and previous treatment response [partial or null]) to receive simeprevir (150 mg once a day) plus telaprevir placebo (three times a day 7-9 h apart) or telaprevir (750 mg three times a day) plus simeprevir placebo (once a day) in combination with peginterferon alfa-2a and ribavirin for 12 weeks followed by 36 weeks of peginterferon alfa-2a and ribavirin alone. The primary efficacy endpoint was sustained virological response 12 weeks after end of treatment (SVR12) in the intention-to-treat and the per-protocol population. We compared groups with the Cochran-Mantel-Haenszel test. We established a non-inferiority margin of 12%. Adverse events were reported descriptively. This trial is registered with ClinicalTrials.gov, number NCT01485991., Findings: Patient screening began on Jan 19, 2012, and the last visit was on April 7, 2014. We included 763 patients (472 previous null responders [62%]). Simeprevir and peginterferon alfa-2a and ribavirin was non-inferior to telaprevir and peginterferon alfa-2a and ribavirin for SVR12 (54% [203/379] vs 55% [210/384]; difference -1·1%, 95% CI -7·8 to 5·5; p=0·0007). SVR12 was achieved in 70% (101/145) versus 68% (100/146) of previous partial responders and 44% (102/234) versus 46% (110/238) of previous null responders with simeprevir and peginterferon alfa-2a and ribavirin and telaprevir and peginterferon alfa-2a and ribavirin treatment, respectively. We recorded differences between treatment groups in simeprevir or telaprevir-related adverse events (69% [261/379] in the simeprevir group vs 86% [330/384] in the telaprevir group), serious adverse events (2% [8/379] vs 9% [33/384]), and adverse events leading to simeprevir or telaprevir discontinuation (2% [7/379] vs 8% [32/384])., Interpretation: Simeprevir once a day with peginterferon alfa-2a and ribavirin was well tolerated in HCV genotype 1-infected previous non-responders and was non-inferior to telaprevir, thus providing an alternative treatment in areas of the world where all-oral HCV regimens are not available or accessible., Funding: Janssen., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Objective: To identify differences in the disposition of isosorbide-5-mononitrate between male and female volunteers., Method: Plasma concentration and area under the concentration-time curve (AUC(SS)) data of isosorbide-5-mononitrate were obtained in a randomized, crossover, multiple-dose bioequivalence study in 24 subjects (12 females and 12 males). Participants received a single oral dose of 60 mg isosorbide-5-mononitrate prolonged-release tablet formulation (formulations I and II) on each of 6 consecutive days. Plasma isosorbide-5-mononitrate concentrations were determined according to validated methods involving liquid chromatography mass spectrometry., Results: A total of 2 x 24 plasma concentration-time curves of the parent drug could be analyzed. The intersubject variation in plasma concentrations ranged from 25-50% (coefficient of variation). With both formulations, the mean plasma concentration-time curves for males and females ran parallel. The parameters Cmax, Cmin, AUC(SS), and AUC(SS)/kg in females were significantly higher than in males (p < 0.0001). This difference was solely attributed to the difference in body weight (p = 0.0024) and body mass index between males and females (p = 0.0113). Seven females showed a t = 0 = 24 h (Cmin) plasma concentration that was twice as high as the other 5 females and all the males; 125 +/- 12.2 ng/ml versus 59.3 +/- 9.2 ng/ml, respectively, in females (p < 0.0001) and 56.3 +/- 6.9 ng/ml in males (p < 0.0001). With both formulations, females in the n = 7 group had a longer t(1/2) and MRT than females in the n = 5 group, 5.06 +/- 0.76 h, 11.2 +/- 0.55 h versus 4.19 +/- 0.56, 9.40 +/- 0.62 h (p = 0.0057). The male group did not show this phenomenon, their disposition was similar to that of the female group of n = 5., Conclusion: The difference found in the Cmax and AUC(SS)/kg of isosorbide-5-mononitrate between male and female subjects must be due to the difference in dose/kg, following a standard dose of 60 mg. Fixed dose administration is common practice due to the available pharmaceutical formulations, while in the ideal situation the dose should be based on dose/kg or titrated to the required clinical effect.

The objective of this study was to identify differences in disposition and esterase hydrolysis of ramipril between male and female volunteers. Plasma concentration and area under the concentration-time curve until the last measured concentration (AUCt) data of ramipril and its active metabolite ramiprilat (-diacid) were obtained from a randomised, cross-over bioequivalence study in 36 subjects (18 females and 18 males). Participants received a single 5-mg oral dose of two different formulations of ramipril (Formulation I and II). Plasma ramipril and ramiprilat concentrations were determined according to validated methods involving liquid chromatography-mass spectrometry. A total number of 2 x 34 available plasma concentration-time curves of both the parent drug and the metabolite could be analysed, and variations (50-100% coefficient of variation [CV]) in plasma concentrations of both parent drug and metabolite were found. With both the formulations, the mean plasma concentrations-time curves of males and females were identical. The groups of female and male volunteers showed similar yields (AUCt = microg x h/L) of the metabolite ramiprilat (p = 0.37); however, females showed a higher AUCt/kg than males (p = 0.046). This difference was solely attributed to the difference in body weight between males and females (p = 0.00049). In both male and female groups, a subject-dependent yield of active metabolite ramiprilat was demonstrated, which was independent of the formulation. There is a large variation in the ramiprilat t1/2beta (50-60% CV). There is a group of subjects who showed a t1/2beta of approximately 80 h (15% CV), and two apparent groups with a longer t1/2beta for each formulation (124 h, 22.5% CV; 166 h, 21.6% CV, respectively, p = 0.0013). This variation in the terminal half-life of ramiprilat is not sex related. In all three groups of half-lives, the corresponding Cmax values (mean +/- SD) of ramiprilat in males and females were identical. Thus, with identical Cmax and half-lives, the difference found in the AUCt/kg of ramiprilat must be due to the difference in dose, as the consequence of the difference in body weight, following a standard dose of 5 mg in both males and females. This study showed clearly that despite subject-dependent hydrolysis of ramipril to the active metabolite ramiprilat, the variability in the rate of hydrolysis between males and females is similar. With a fixed dose (5 mg), females received a higher dose/kg than males and consequently showed a higher AUCt/kg of the active metabolite ramiprilat.

The aim of this pharmacokinetic evaluation was to show the effect of the extra methyl group in simvastatin on esterase hydrolysis between lovastatin and simvastatin in male and female volunteers. This study was based on the plasma concentration-time curves and the pharmacokinetics of lovastatin and simvastatin with its respective active metabolite statin-beta-hydroxy acid obtained from two different bioequivalence studies, each with 18 females and 18 males. Results were: The group of female volunteers showed a higher yield of the active metabolite beta-hydroxy acid than the group of males (p < 0.002) for both lovastatin and simvastatin. This difference was not related to the body weight of both groups. In the male/female groups, subject-dependent yield of active metabolite beta-hydroxy acid was demonstrated, which was independent of the formulation. The variation in plasma/liver hydrolysis resulted in a fan-shaped distribution of data points when the AUCt lovastatin was plotted vs. that of the beta-hydroxy acid metabolite. In the fan of data points, subgroups could be distinguished, each showing a different regression line and with a different Y-intercept (AUCtbeta-hydroxy acid). Lovastatin hydrolysis was higher than simvastatin hydrolysis. It was possible to discriminate between hydrolysis of both lovastatin and simvastatin by plasma/liver or tissue esterase activity. The three subgroups of subjects (males/females) showing different but high yield of statin beta-hydroxy acid can be explained by variable hydrolysis of plasma and hepatic microsomal and cytosolic carboxyesterase activity. This study showed clearly that despite the subject-dependent hydrolysis of lovastatin/simvastatin to the active metabolite, males tend to hydrolyse less than females. The extra methyl group in simvastatin results in less hydrolysis due to steric hindrance.

The aims of this investigation were to calculate the pharmacokinetic parameters and to identify parameters, based on individual plasma concentration-time curves of amoxicillin and clavulanic acid in dogs, that may govern the observed differences in absorption of both drugs. The evaluation was based on the data from plasma concentration-time curves obtained following a single dose in an open, randomized, two-way crossover study involving 24 male Beagle dogs treated with two Amoxi-Clav formulations (A Clavubactin and B Synulox, each with 200/50 mg). Plasma amoxicillin and clavulanic acid concentrations were determined using validated bioassay methods. The half-life of elimination of amoxicillin was 1.5 h (t1/2 = 1.52 +/- 0.19 h, Cmax = 11.4 +/- 2.74 microg/mL), and that of clavulanic acid 0.76 h (t1/2 = 0.71 +/- 0.23 h, Cmax = 2.06 +/- 1.05 microg/mL). There was a fivefold variation in the AUCt of clavulanic acid for both formulations, while the AUCt of amoxicillin varied by a factor of 2. The mean ratio of the AUCt amoxicillin : clavulanic acid was 12.7 +/- 3.65 for formulation A and 11.8 +/- 5.22 for formulation B (P = 0.51).

The aims of this investigation were to calculate the pharmacokinetic parameters of amoxicillin and clavulanic acid, and to identify parameters that may affect their observed differences in absorption. Data were obtained from plasma concentration-time curves from four different open, randomized, two-treatment, two-period, two-sequence, crossover Phase I bioequivalence studies, with the following co-amoxiclav formulations: tablets 250/125, 500/125 and 875/125 mg, or 10 mL of an oral suspension 250/62.5 mg per 5 mL. Data from 144 subjects and 288 drug administrations were available for evaluation. After a 125 mg clavulanic acid dose (administered as potassium clavulanate) for all four different formulations, the clavulanic acid AUC(t) data ranged from 1.5 to 8 mg.h/L, varying by a factor of 5. The absorption of clavulanic acid was not related to the absorption of amoxicillin, or demographic factors, and we were unable to identify the reasons for the large variability in the absorption of clavulanic acid. We conclude that the absorption of clavulanic acid, after oral administration, is highly variable and may vary over a five-fold range between patients.

The aims of this investigation were to calculate the pharmacokinetic parameters and to identify parameters, based on individual plasma concentration-time curves of amoxicillin and clavulanic acid in cats, that may govern the observed differences in absorption of both drugs. The evaluation was based on the data from plasma concentration-time curves obtained following a single-dose, open, randomised, two-way crossover phase-I study, each involving 24 female cats treated with two Amoxi-Clav formulations (formulation A was Clavubactin and formulation was B Synulox; 80/20 mg, 24 animals, 48 drug administrations). Plasma amoxicillin and clavulanic acid concentrations were determined using validated bioassay methods. The half-life of elimination of amoxicillin is 1.2 h (t1/2 = 1.24 +/- 0.28 h, Cmax = 12.8 +/- 2.12 microg/ml), and that of clavulanic acid 0.6 h (t1/2 = 0.63 +/- 0.16 h, Cmax = 4.60 +/- 1.68 microg/ml). There is a ninefold variation in the AUCt of clavulanic acid for both formulations, while the AUCt of amoxicillin varies by a factor of two. The highest clavulanic acid AUCt values indicate the best absorption; all other data indicate less absorption. Taking into account that the amoxicillin-to-clavulanic acid dose ratio in the two products tested was 4:1, the blood concentration ratios may actually vary much more, apparently without compromising the products" high efficacy against susceptible microorganisms.

This study was based on data from a bioequivalence study (n=24) of two different formulations of suppositories containing 500 mg mesalazine (formulation I and II), with a similar dissolution profile in phosphate buffer pH 6.8. There was a large intra- and intersubject variability in the plasma concentration-time curves of mesalazine from both suppositories. The aim of the investigation was to identify the parameters that caused the observed large variations in release and absorption of mesalazine in the rectum. Plasma mesalazine and acetylmesalazine, and urine acetylmesalazine concentrations were determined according to validated methods involving HPLC analysis with coulometric detection. Lower limit of quantitation values were respectively 10.4 and 19.4 ng mL(-1) in plasma and 0.96 microg mL(-1) in urine. The time of defecation before and after insertion was recorded. There was a clear distinction between subjects who showed monophasic mesalazine release/absorption and those who showed biphasic and more extended release/absorption. With formulation I there was a correlation between time of defecation before dosing and the type of absorption, monophasic and biphasic absorbers showed a significant difference in the time of defecation, e.g. 9.7+/-5.6 h vs 18.8+/-11.9 h (P = 0.0218). The impact of time of defecation before dosing was non-significant with formulation II, 16.7+/-7.2 h vs 15.1+/-4.2 h (P = 0.67). The impact of the time elapsed between administration and time of defecation after the insertion of the suppository was not significant for the type of release/absorption. The plasma concentration-time curves of the metabolite ran parallel to that of the parent drug, the more parent drug was released/absorbed, the more was acetylated (P = 0.0013) and excreted into the urine (P = 0.0004). After absorption the compound was metabolized into acetylmesalazine, and renally excreted (12-13% of the dose). Monophasic release/ absorption resulted in 7.1% metabolite with I and 10.3% with II (P = 0.0004), while biphasic release/absorption gave 16.8% metabolite with I and 15.5% with II. The renal clearance of the metabolite acetylmesalazine was independent of the observed defecation patterns (300 mL min(-1), P > 0.8), stool composition, and type of absorption.