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Deputy President William Ruto’s victorious presidential campaign in Kenya’s 2022 elections saw him champion the plight of the ‘hustlers’, young informal economy workers on low, piecemeal incomes. Reconfiguring political identities around notions of economic hardship and struggle, Ruto’s campaign appeared emblematic of what scholars have recently identified as a turn towards ‘populism’ in Africa, transmuting ethno-nationalist identities into class-based ones. However, whilst Ruto’s campaign capitalized on rising prices to devastating political effect, he also channelled discontent with the Jubilee government and its unmet promises of shared prosperity. Drawing on ethnographic data collected in central Kenya’s Kiambu region since 2017, this article understands Ruto’s victory not through the lens of ‘hustler populism’ but rather as an anti-Jubilee ‘backlash’. Ruto’s campaign took advantage of Uhuru Kenyatta’s personal unpopularity as voters increasingly questioned the nature of ‘dynastic’ authority and ‘state capture’, seeking to punish Uhuru personally for his failures to create prosperity in the region whilst enriching himself at their expense. Elaborating on these tensions, the article points towards broken ‘moral economies’ between voters and politicians as a vital field of research.

Tafamidis, a non‐nonsteroidal anti‐inflammatory benzoxazole derivative, acts as a transthyretin (TTR) stabilizer to slow progression of TTR amyloidosis (ATTR). Tafamidis meglumine, available as 20‐mg capsules, is approved in more than 40 countries worldwide for the treatment of adults with early‐stage symptomatic ATTR polyneuropathy. This agent, administered as an 80‐mg, once‐daily dose (4 × 20‐mg capsules), is approved in the United States, Japan, Canada, and Brazil for the treatment of hereditary and wild‐type ATTR cardiomyopathy in adults. An alternative single solid oral dosage formulation (tafamidis 61‐mg free acid capsules) was developed and introduced for patient convenience (approved in the United States, United Arab Emirates, and European Union). In this single‐center, open‐label, randomized, 2‐period, 2‐sequence, crossover, multiple‐dose phase 1 study, the rate and extent of absorption were compared between tafamidis 61‐mg free acid capsules (test) and tafamidis meglumine 80‐mg (4 × 20‐mg) capsules (reference) after 7 days of repeated oral dosing under fasted conditions in 30 healthy volunteers. Ratios of adjusted geometric means (90%CI) for the test/reference formulations were 102.3 (98.0‐106.8) for area under the concentration‐time profile over the dosing interval and 94.1 (89.1‐99.4) for the maximum observed concentration, satisfying prespecified bioequivalence acceptance criteria (90%CI, 80‐125). Both tafamidis regimens had an acceptable safety/tolerability profile in this population.

Contemporary anthropological accounts of economic uncertainty often use the concept of hope as a means of recovering human agency in relation to broader socio-economic structures. At times, however, the emphasis anthropologists place on hope can appear too generically existential. This article argues for a more specific emphasis on the object of hope—an appreciation of more concrete desires held by marginal persons, orienting their economic activity. In the case I unfold from peri-urban central Kenya, low-status male youth are shown to lack the money they require to unlock pleasurable experiences of drinking, a sign of having wealth and the living of a good life. Rendered hopeless, young men turn to crime as an alternative means of realizing their desires for consumption in the short term.

In the 2017 race for Kiambu County's governor seat, debates concerning the morality of incumbent governor William Kabogo played a distinctive role in his defeat at the hands of populist cha...

Anthropology has a long and complicated history in Africa, and its study of economic life is no exception. In the early days of the discipline, in the 1930s and 1940s, anthropologists like Audrey Richards, Meyer Fortes, and E. E. Evans-Pritchard all departed for Africa to conduct fieldwork. In general, early British social anthropology was committed to holistic studies of small-scale societies, and thus what counted as “economic anthropology” was subsumed within broader studies of kinship and sociopolitical organization. Though later criticized by Manchester School anthropologists for their “bounding” of specific peoples, and by Marxist anthropologists for their neglect of “modes of production,” from a contemporary vantage point these early studies made the same point that anthropologists working in the substantivist tradition of Karl Polanyi also would: that the economy is embedded in social relations and practices. The growing influence of Marxist approaches from the 1960s, as well as growing sympathies between social anthropology and the historical study of Africa, introduced an appreciation of historical processes in the formation of local and regional economies. Feminist approaches expanded the frame of inquiry by demonstrating the gendered character of African economic life, and of the crucial role of women and households to markets and production. New analytical tools borrowed from political economy paved the way for studies of colonial economies—for instance, how the emergence of cash crop production shaped labor migration and land ownership, as well as the shift toward cash itself. The contemporary anthropological study of economic life in Africa has been transformed by pressing events in the latter part of the century—structural adjustment and economic liberalization, not to mention scholars’ identification of the “informal economy”—as key terrain for anthropological research. New attentiveness has been given to how Africans imagine and conceive of economic change, as well as the new types of wealth, credit, and debt brought about via access to foreign capital. The era of economic liberalization has transformed cities and African expectations of the future, sometimes in terms of improved living standards and “middle class” lifestyles, but also a growing disparity between rich and poor. Moving away from the narrative of crisis, newer work seeks to explore African attempts to pursue “the good life” amid ongoing economic turbulence. While anthropologists remain attuned to the effects of economic change, what continues to characterize their approach is an understanding of economies embedded in regional contexts, including their values and established practices.

This paper provides an ethnographic perspective on the street-level deliberations of Kenya's opposition supporters between the 2013 and 2017 elections, arguing that rather than appeals to ethnicity what defines its discourse are broader, inclusive notions of political membership. A civic nationalism is enunciated by opposition supporters that congeals support between multiple ethnic groups through its emphasis on universal values – democracy, due process, equality, adherence to the constitution. However, when such civic ideas are used in political campaigning and mobilising rhetoric, describing a resurgent Kenyan ‘people’ that has been systematically disenfranchised, they take on an exclusionary character. As ‘good constitutionalists’, opposition supporters contrast themselves with ‘bad nationalists’ associated with the government, portrayed as mobilising particularistic ethnic loyalties at the expense of a majority of Kenyans. In practice, their civic ideas remain only potentially inclusive.

SAM-760 [(2-methyl-1-(phenylsulfonyl)-4-(piperazin-1-yl)-1H-benzo[d]imidazole)], a 5HT6 antagonist, was investigated in humans for the treatment of Alzheimer's disease. In liver microsomes and recombinant cytochrome P450 (P450) isozymes, SAM-760 was predominantly metabolized by CYP3A (∼85%). Based on these observations and an expectation of a 5-fold magnitude of interaction with moderate to strong CYP3A inhibitors, a clinical DDI study was performed. In the presence of ketoconazole, the mean Cmax and area under the plasma concentration-time curve from time zero extrapolated to infinite time values of SAM-760 showed only a modest increase by 30% and 38%, respectively. In vitro investigation of this unexpectedly low interaction was undertaken using [14C]SAM-760. Radiometric profiling in human hepatocytes confirmed all oxidative metabolites previously observed with unlabeled SAM-760; however, the predominant radiometric peak was an unexpected polar metabolite that was insensitive to the pan-P450 inhibitor 1-aminobenzotriazole. In human hepatocytes, radiometric integration attributed 43% of the total metabolism of SAM-760 to this non-P450 pathway. Using an authentic standard, this predominant metabolite was confirmed as benzenesulfinic acid. Additional investigation revealed that the benzenesulfinic acid metabolite may be a novel, nonenzymatic, thiol-mediated reductive cleavage of an aryl sulfonamide group of SAM-760. We also determined the relative contribution of P450 to the metabolism of SAM-760 in human hepatocytes by following the rate of formation of oxidative metabolites in the presence and absence of P450 isoform-specific inhibitors. The P450-mediated oxidative metabolism of SAM-760 was still primarily attributed to CYP3A (33%), with minor contributions from P450 isoforms CYP2C19 and CYP2D6. Thus, the disposition of [14C]SAM-760 in human hepatocytes via novel sulfonamide metabolism and CYP3A verified the lower than expected clinical DDI when SAM-760 was coadministered with ketoconazole.

Background/Aims: Few studies have modeled individual Neuropsychiatric Inventory (NPI) symptom scores for Alzheimer disease (AD) patients and assessed the value of therapeutic interventions that can potentially impact them. The main objective of this study was to evaluate the impact of new AD symptomatic treatments on relevant health economic outcomes via their potential effects on cognition and neuropsychiatric symptoms such as depression, irritability, anxiety, and sleep disorder. Methods: We enhanced the previously published AHEAD model (Assessment of Health Economics in Alzheimer’s Disease) by including new variables and functional relations to capture the NPI’s individual neuropsychiatric symptoms in addition to the total NPI score. This update allowed us to study the longitudinal effect of improvements in specific NPI subscale scores and the downstream impact on outcomes such as psychiatric medication use, survival, and institutional placement. Results: The model base-case results showed that a hypothetical treatment with symptomatic effects on anxiety, depression, and irritability NPI subscales was not cost-effective; however, the treatment’s cost-effectiveness was improved once a direct link between NPI subscales and mortality was explored or under relatively stronger treatment effects. Conclusion: Treatments that influence specific symptoms within the overall NPI have the potential to improve patient outcomes in a cost-effective way. This model is a useful tool for evaluating target product profiles of drugs with effect on NPI symptoms in early stages of development.

Contemporary accounts of masculinity in Britain have tended to focus on the politics of body image: how and why young men aspire to appear a certain way through forms of body modification. Drawing on ethnography carried out amongst young British males in Essex, this paper homes in on the technical processes of body modification itself, arguing that what is at stake in practices such as working out at the gym is not only the transformation of appearance. Rather than seeing practices such as weight-lifting as failed acts of resistance, where men attempt to craft themselves as physically powerful individuals while ultimately conforming to gender stereotypes and norms, what follows is an argument that posits the body as a locus of sensory self-enunciation. Drawing upon the praxeological method of Jean-Pierre Warnier, I advance a sensorylogical analysis of weight-lifting practices to show how young men quite literally embody themselves as capable and agentive persons. I further explore these questions of embodied self-enunciation at the Billericay Boxing Hut where I analyse forms and logics of sensory experience that allow men to render themselves persons defined by the capacity to overcome pain from within. I argue that boxing training and weight-lifting in the gym instantiate a local principle of male personhood, autology: the sense young men have of being individual, self-determining and agentive persons. Gym-work and boxing are thus re-interpreted as acts of bodily autology: practical acts that elicit a singular and capable self.

Background: Limited data exist on the presence of pregabalin in human breast milk of nursing mothers. Objectives: This study aimed to determine pregabalin concentrations in breast milk, estimate the infant daily pregabalin dose from nursing mothers, and evaluate pregabalin pharmacokinetic data in lactating women (≥ 12 weeks postpartum). Methods: In this multiple-dose, open-label, pharmacokinetic study, 4 doses of pregabalin 150 mg were administered orally at 12-hour intervals. Urine, blood, and breast milk samples were collected up to 12, 24, and 48 hours, respectively, following the fourth dose. Pharmacokinetic parameters were estimated using noncompartmental methods. Adverse events were monitored throughout. Results: Ten healthy lactating women (age 24-37 years) received pregabalin. Geometric mean pregabalin Cmaxss and AUCτ values in breast milk were approximately 53% and 76%, respectively, of those for plasma. The mean amount of pregabalin in breast milk recovered in a 24-hour period after the last dose was 574 μg (range, 270-1720 μg), which is approximately 0.2% of the administered daily maternal dose of 300 mg. The estimated average daily infant dose of pregabalin from breast milk was 0.31 mg/kg/day, which would be approximately 7% (23% coefficient of variation) of the body weight normalized maternal dose. Approximately 89% of the dose administered was recovered in urine. Renal clearance averaged 68.2 mL/min. Adverse events were of mild or moderate severity. Conclusion: Lactation appears to have had little influence on pregabalin pharmacokinetics. Overall, the estimated dose of pregabalin in breastfed children of women receiving pregabalin is low. Pregabalin was well tolerated in lactating women. Declaration of Conflicting Interests The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Peter A. Lockwood, Lynne Pauer, Joseph M. Scavone, Maud Allard, Laure Mendes da Costa, Tanja Alebic-Kolbah, Anna Plotka, Christine W. Alvey, and Marci L. Chew were all full-time employees of Pfizer at the time the study was completed and hold stock and/or stock options in Pfizer. Funding The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was sponsored by Pfizer, which was involved in the study design, the collection, analysis, and interpretation of the data, the writing of the report, and the decision to submit the paper for publication. Medical writing support was provided by Penny Gorringe, MSc, of Engage Scientific Solutions and funded by Pfizer.

SAM-760 [(2-methyl-1-(phenylsulfonyl)-4-(piperazin-1-yl)-1H-benzo[d]imidazole)], a 5HT

The conventional model of aggregate formation suggests a hierarchy where micro-aggregates with lower porosity and therefore reduced soil organic carbon (SOC) mineralization form inside macro-aggregates. This model has however been questioned for highly weathered Oxisols where inconclusive results regarding the presence of aggregate hierarchy have been obtained to date. We hypothesized that in Oxisols (i) an aggregate hierarchy would be present (ii) the porosity of micro-aggregates would be lower than that of macro-aggregates and (iii) pore geometry of aggregates would influence SOC mineralization. We collected topsoils from Oxisols in northern New South Wales, Australia from which macro-aggregates (>250 μm), micro-aggregates (53–250 μm) and

Background Symptomatic benefits have been reported for 5-HT6 receptor antagonists in Alzheimer’s disease (AD) trials. SAM-760 is a potent and selective 5-HT6 receptor antagonist that has demonstrated central 5-HT6 receptor saturation in humans at a dose of 30 mg. Methods This was a randomized, double-blind, placebo-controlled, parallel-group, multicenter trial evaluating the efficacy and safety of SAM-760 30 mg once daily (QD) for 12 weeks in subjects with AD on a stable regimen of donepezil 5 to 10 mg QD. The study included an interim analysis with stopping rules for futility or efficacy after 180 subjects completed the week 12 visit. Up to 342 subjects with AD (Mini-Mental State Examination (MMSE) score 10–24) and neuropsychiatric symptoms (Neuropsychiatric Inventory (NPI) total score ≥ 10) were to be enrolled if the study continued after the interim analysis. After a 4-week, single-blind, placebo run-in period, subjects entered the 12-week double-blind period and were randomized to either SAM-760 or placebo. The primary and key secondary efficacy endpoints were the change from baseline in Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog13) and NPI total scores. Mixed models for repeated measures were used to analyze the data. Results At the interim analysis, when 186 subjects had been randomized and 163 had completed the week 12 visit, the study met futility criteria and was stopped. The mean week 12 treatment difference was 0.70 points (P = 0.43) for ADAS-cog13 and 2.19 points (P = 0.20) for NPI score, both of which were numerically in favor of placebo. Other secondary endpoints did not demonstrate any significant benefit for SAM-760. In total, 46.2% of SAM-760 subjects reported adverse events (AE) versus 44.7% for placebo, and there were 5 (5.5%) serious AEs in the SAM-760 group versus 3 (3.2%) for placebo. There were two deaths, one prior to randomization and one in the SAM-760 group (due to a traffic accident during washout of active treatment). Conclusions SAM-760 was safe and well tolerated, but there was no benefit of SAM-760 on measures of cognition, neuropsychiatric symptoms, or daily function. Differences in trial design, study population, region, or pharmacological profile may explain differences in outcome compared with other 5-HT6 receptor antagonists. Trial registration Clinicaltrials.gov, NCT01712074. Registered 19 October 2012. Electronic supplementary material The online version of this article (10.1186/s13195-018-0368-9) contains supplementary material, which is available to authorized users.

A B S T R A C T The performance of the Rothamsted Carbon Model (RothC) in simulating soil carbon (SOC) storage in cotton based cropping systems under different tillage management practices on an irrigated Vertisol in semi-arid, subtropics was evaluated using data from a long-term (1994–2012) cotton cropping systems experiment near Narrabri in north-western New South Wales, Australia. The experimental treatments were continuous cotton/conventional tillage (CC/CT), continuous cotton/minimum tillage (CC/MT), and cotton-wheat (Triticum aestivum L.) rotation/minimum tillage (CW/MT). Soil carbon (C) input was calculated by published functions that relate crop yield to soil C input. Measured values showed a loss in SOC of 34%, 24% and 31% of the initial SOC storages within 19 years (1994–2012) under CC/CT, CC/MT, and CW/MT, respectively. RothC satisfactorily simulated the dynamics of SOC in cotton based cropping systems under minimum tillage (CC/MT and CW/MT), whereas the model performance was poor under intensive conventional tillage (CC/CT). The model RothC overestimated SOC storage in cotton cropping under conventional intensive tillage management system. This over estimation could not be attributed to the overestimation of soil C inputs, or errors in initial quantification of SOC pools for model initialization, or the ratio of incoming decomposable plant materials to resistant plant materials. Among other different factors affecting SOC dynamics and its modelling under intensive tillage in tropics and sub-tropics, we conclude that factors for tillage and soil erosion might be needed when modelling SOC dynamics using RothC under intensive tillage management system in the tropics and the sub-tropics.

Understanding the interactions between the initial biochemical composition and subsequent decomposition of plant litter will improve our understanding of its influence on microbial substrate use to explain the flow of organic matter between soil carbon pools. We determined the effects of land use (cultivation/native woodland/native pasture), litter type (above and below ground) and their interaction on the initial biochemical composition (carbon, nitrogen, water soluble carbon, lignin, tannin and cellulose) and decomposition of litter. Litter decomposition was studied as the mineralization of C from litter by microbial respiration and was measured as CO2–C production during 105 d of laboratory incubation with soil. A two-pool model was used to quantify C mineralization kinetics. For all litter types, the active C pool decay rate constants ranged from 0.072 d−1 to 0.805 d−1 which represented relatively short half-lives of between 1 and 10 days, implying that this pool contained compounds that were rapidly mineralized by microbes during the initial stages of incubation. Conversely, the decay rate constants for the slow C pool varied widely between litter types within and among land uses ranging from 0.002 d−1 and 0.019 d−1 representing half-lives of between 37 and 446 days. In all litter types, the initial lignin:N ratio strongly and negatively influenced the decay rate of the slow C pool which implied that the interaction between these two litter quality variables had important controls over the decomposition of the litter slow C pool. We interpret our results to suggest that where the flow of C from the active pool to the slow pool is largely driven by microbial activity in soil, the rate of transfer of C will be largely controlled by the quality of litter under different land-use systems and particularly the initial lignin:N ratio of the litter. Compared with native pastures and cultivation, above and below ground litter from native woodland was characterized by higher lignin:N ratio and more slowly decomposing slow C pools which implies that litter is likely to persist in soils, however based on the sandy nature of the soils in this study, it is likely to lack protection from microbial degradation in the long term.

Understanding the changes in soil organic matter (SOM) composition during aggregate formation is crucial to explain the stabilization of SOM in aggregates. The objectives of this study were to investigate (i) the composition of SOM associated with different aggregates and size-density fractions and (ii) the role of selective preservation in determining the composition of organic matter in aggregate and size-density fractions. Surface soil samples were collected from an Alfisol on the Northern Tablelands of NSW, Australia with contrasting land uses native pasture, crop-pasture rotation and woodland. Solid state 13C cross-polarization and magic angle spinning (CPMAS) Nuclear Magnetic Resonance (NMR) spectroscopy was used to determine the SOM composition in macroaggregates (250-2000 µm), microaggregates (53-250 µm), and

The effects of nutrient and lime additions on antimony (Sb) and arsenic (As) accumulation by native Australian and naturalised plants growing in two contaminated mine site soils (2,735 mg kg(-1) and 4,517 mg kg(-1) Sb; 826 mg kg(-1) and 1606 As mgkg(-1)) was investigated using a glasshouse pot experiment. The results indicated an increase in soil solution concentrations with nutrient addition in both soils and also with nutrient+lime addition for Sb in one soil. Metalloid concentrations in plant roots were significantly greater than concentrations in above ground plant parts. The metalloid transfer to above ground plant parts from the roots and from the soil was, however, low (ratio of leaf concentration/soil concentration≪1) for all species studied. Eucalyptus michaeliana was the most successful at colonisation with lowest metalloid transfer to above ground plant parts. Addition of nutrients and nutrients+lime to soils, in general, increased plant metalloid accumulation. Relative As accumulation was greater than that of Sb. All the plant species studied were suitable for consideration in the mine soil phytostabilisation strategies but lime additions should be limited and longer term trials also recommended.

Summary Model initialization in soil organic carbon (SOC) turnover models has often been described as a crucial step in making future projections. Model initialization by the spin-up of pools of SOC (model equilibrium run) has been questioned, because equilibrium has to be assumed. Measured SOC pools are independent of model assumptions and are thought to reflect better real site conditions. It has been suggested that model initialization with measured SOC fractions could provide an advantage over model spin-up of SOC pools. In this study we tested this suggestion in relatively undisturbed native grasslands in Australia. We tested the Rothamsted SOC turnover model (RothC) under climate change at 12 sites with three different initialization methods, viz. model initialization with (i) spin-up of model pools with inert organic matter (IOM) pool size calculated from a regression equation, (ii) spin-up of model pools with measured IOM and (iii) all pools estimated from measured fractions. Averaged over the sites and initialization methods, maximum absolute variations (absolute differences in projected SOC stocks expressed as a percentage of initial 2008 SOC stocks) as well as averaged absolute variations throughout the projection period were very small (2.2 and 1.6%, respectively). Averaged across the sites, there were no significant differences in projected grassland SOC stocks under climate change after 93 years of simulation with model initialization by different methods and averaged absolute variation was only 1.6% across initialization methods. These findings suggest that in a relatively undisturbed land-use system such as native grassland, projections of SOC under climate change are relatively insensitive to the model initialization method.

Radiocarbon is a useful tool for studying carbon dynamics in soil aggregates. The objective of the current study was to determine the mean residence time (MRT) of soil organic carbon (SOC) in macroaggregates and microaggregates under contrasting land uses. Contrasting land uses investigated at Alfisol (equivalent to Dermosol in Australian Soil Classification) sites were native pasture (NP), crop-pasture rotation (CP), and Eucalypt woodland (WL), whereas in Oxisol (Ferrosol in Australian Soil Classification) sites, land uses comprised improved pasture (IP), cropping (CR), and forest (FR). Soil aggregates were separated into macroaggregates (250–2000 μm) and microaggregates (53–250 μm) by wet-sieving, and their 14C signatures were determined by accelerator mass spectrometry (AMS). The 14C activity in both macro- and microaggregates was >100 pMC, indicating the presence of post-bomb carbon in the soil. The mean residence time (MRT) of SOC in macro- and microaggregates (MRTagg) was on average 68 yr longer in the Oxisol compared with that in the Alfisol. The MRTagg in microaggregates was 10 yr longer than that of macroaggregates in the Alfisol. However, the MRTagg in microaggregates was 50 yr shorter compared to macroaggregates in the Oxisol.The MRT of macro- and microaggregates can be separated into active, slow, and stable SOC pools. Among the 3 SOC pools, the MRT of the stable pool is of higher significance in terms of SOC stabilization in soil aggregates because of its longer MRT. However, isolation and direct MRT estimation of the stable SOC pool is difficult. The MRT of active and slow SOC pools associated with macro- and microaggregates was measured using a SOC mineralization experiment to estimate the MRT of the stable SOC pool under contrasting land uses by applying a mass balance criterion. The MRT of active (MRTA) and slow (MRTS) SOC pools in macro- and microaggregates varied between 1–50 days and 13–38 yr, respectively. The estimated MRT of the stable pool carbon (MRTP) in microaggregates was 897 yr longer compared to that of macroaggregates in the Alfisol. However, in the Oxisol, MRTP in microaggregates was 568 yr shorter than that of macroaggregates. Among the land uses, WL in Alfisol and CR in Oxisol had longer MRTagg and MRTP compared to other land uses.

Aggregates play a key role in protecting soil organic carbon (SOC) from microbial decomposition. The objectives of this study were to investigate the influence of pore geometry on the organic carbon decomposition rate and bacterial diversity in both macro- (250–2000 μm) and micro-aggregates (53–250 μm) using field samples. Four sites of contrasting land use on Alfisols (i.e. native pasture, crop/pasture rotation, woodland) were investigated. 3D Pore geometry of the micro-aggregates and macro-aggregates were examined by X-ray computed tomography (μCT). The occluded particulate organic carbon (oPOC) of aggregates was measured by size and density fractionation methods. Micro-aggregates had 54% less μCT observed porosity but 64% more oPOC compared with macro-aggregates. In addition, the pore connectivity in micro-aggregates was lower than macro-aggregates. Despite both lower μCT observed porosity and pore connectivity in micro-aggregates, the organic carbon decomposition rate constant (Ksoc) was similar in both aggregate size ranges. Structural equation modelling showed a strong positive relationship of the concentration of oPOC with bacterial diversity in aggregates. We use these findings to propose a conceptual model that illustrates the dynamic links between substrate, bacterial diversity, and pore geometry that suggests a structural explanation for differences in bacterial diversity across aggregate sizes.

Symptomatic benefits have been reported for 5-HT6 receptor antagonists in Alzheimer’s disease (AD) trials. SAM-760 is a potent and selective 5-HT6 receptor antagonist that has demonstrated central 5-HT6 receptor saturation in humans at a dose of 30 mg. This was a randomized, double-blind, placebo-controlled, parallel-group, multicenter trial evaluating the efficacy and safety of SAM-760 30 mg once daily (QD) for 12 weeks in subjects with AD on a stable regimen of donepezil 5 to 10 mg QD. The study included an interim analysis with stopping rules for futility or efficacy after 180 subjects completed the week 12 visit. Up to 342 subjects with AD (Mini-Mental State Examination (MMSE) score 10–24) and neuropsychiatric symptoms (Neuropsychiatric Inventory (NPI) total score ≥ 10) were to be enrolled if the study continued after the interim analysis. After a 4-week, single-blind, placebo run-in period, subjects entered the 12-week double-blind period and were randomized to either SAM-760 or placebo. The primary and key secondary efficacy endpoints were the change from baseline in Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog13) and NPI total scores. Mixed models for repeated measures were used to analyze the data. At the interim analysis, when 186 subjects had been randomized and 163 had completed the week 12 visit, the study met futility criteria and was stopped. The mean week 12 treatment difference was 0.70 points (P = 0.43) for ADAS-cog13 and 2.19 points (P = 0.20) for NPI score, both of which were numerically in favor of placebo. Other secondary endpoints did not demonstrate any significant benefit for SAM-760. In total, 46.2% of SAM-760 subjects reported adverse events (AE) versus 44.7% for placebo, and there were 5 (5.5%) serious AEs in the SAM-760 group versus 3 (3.2%) for placebo. There were two deaths, one prior to randomization and one in the SAM-760 group (due to a traffic accident during washout of active treatment). SAM-760 was safe and well tolerated, but there was no benefit of SAM-760 on measures of cognition, neuropsychiatric symptoms, or daily function. Differences in trial design, study population, region, or pharmacological profile may explain differences in outcome compared with other 5-HT6 receptor antagonists. Clinicaltrials.gov, NCT01712074 . Registered 19 October 2012.

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The soil nutrient status (0–10 cm) of two farming systems (organic (OF) and conventional or integrated (CF) vegetable farms) at three locations (Gatton, Stanthorpe and Dorrigo) was examined for the suite of fertility indicators. A wide range chemical parameters and microbial biomass carbon were similar between farming systems, in contrast to some broad-acre organic systems. Examination of farm management records revealed substantial overlap between nutrient inputs at all localities with CF systems also receiving organic inputs, e.g. green manure and composts. Labile soil phosphorus levels were high (>100 mg kg −1 ) in both farming systems, at all sites. The nutrient levels of these intensive vegetable production systems revealed potential environmental risks especially in sandy well drained soils and should be monitored accordingly. Future research could be focused on crop management measures to mitigate runoff and deep drainage loss of nutrients from these farms.

Many Australian cotton farmers are interested in using organic waste products such as composted cotton gin trash as soil amendments because of perceived benefits to soil health and the environment. However, detailed information on the relative benefits and costs involved is not readily available to cotton growers who farm on clayey Vertisols. The objective of this study was to quantify soil changes in a farmer-established trial to evaluate the potential benefits of applying composted cotton gin trash and/or lime to a Vertisol. Selected soil properties were measured in an experiment located on a commercial cotton farm near Goondiwindi in southern Queensland, Australia. Cotton gin trash compost improved potassium availability and soil microbial biomass in soil, whereas lime improved only the latter.

Electromagnetic induction sensors, such as EM38, are used widely for monitoring and mapping soil attributes via the apparent electrical conductivity (EC"a) of the soil. The sensor response is the depth-integrated combination of the depth-response function of the EM38 and 'local' electrical conductivity (EC"a"z) at depth. In deep, Vertosol soils, assuming the instrument depth-response function is not perturbed by the soil and where volumetric moisture content at depth (@q"v(z)) dominates EC"a"z, EM38 should be capable of predicting average moisture content without recourse to mathematically complicated, and unstable profile inversion processes. Firstly a multi-height EM38 experiment was conducted over deep Vertosol soils to confirm the veracity of the EM38 depth-response function and test the concomitant hypothesis of the EM38 response being an integrated (i.e. additive) combination of depth-response function and @q"v(z). Secondly, depth profiles of moisture content were used to calibrate the EM38 to infer average @q"v(z) within the 'root-zone' of crop plants-here taken to be surface-0.8m and surface-1.2m. EM38 calibration was performed using soil samples acquired from both extracted cores and excavated pits. Mathematical summation of measured @q"v(z) from sectioned cores and the known depth-response function of the EM38 was found to explain 99% and 97% of the variance in measured EC"a for horizontal and vertical dipole configurations at multiple sensor heights above the ground. Average @q"v from surface to 0.8m (@[email protected]?"0"."8) and surface to 1.2m (@[email protected]?"1"."2) explained only 37% and 46% of the variance in on-ground EC"a for vertical dipole configuration measurements compared to 55% and 56% of the variance for horizontal dipole configuration. In a separate validation experiment, the shape of the vertical moisture profile proved highly influential in determining the ability of the calibration equations to infer underlying average moisture content, especially where the depth profile shapes differed between sensor calibration and subsequent field validation (for example following rainfall or irrigation).

The adverse effects of sodicity on plant growth are difficult to quantify using naturally occurring soils because of the confounding variation in other soil properties, particularly salinity, pH, organic matter, soil nutrients, mineralogy, and texture. We applied a method involving the equilibration of large soil volumes with solutions varying in sodium adsorption ratio (SAR), followed by excess salt removal with solutions of similar SAR but lower ionic strength. Application of this method to a calcareous nonsodic, nonsaline Vertosol from Narrabri, New South Wales, resulted in soils with exchangeable sodium percentage (ESP) values between 2% and 25% but with similar magnesium and potassium concentrations and constant electrical conductivity (∼2.7 dS/m). Soil pH and solution phosphorus concentrations automatically increased as the ESP of the soil rose, which is important to consider when addressing plant growth results. This method can successfully minimize the confounding of sodicity with other soil prope...

We examined uptake of the model therapeutic agent, minoxidil, into appendages, stratum corneum (SC), and through human skin, under the influence of different vehicles. Quantitative estimation of therapeutic drug deposition into all three areas has not previously been reported. Finite doses of minoxidil (2%, w/v) in formulations containing varying amounts of ethanol, propylene glycol (PG), and water (60:20:20, 80:20:0, and 0:80:20 by volume, respectively) were used. Minoxidil in SC (by tape stripping), appendages (by cyanoacrylate casting), and receptor fluid was determined by liquid scintillation counting. At early times (30 min, 2 h), ethanol-containing formulations (60:20:20 and 80:20:0) caused significantly greater minoxidil retention in SC and appendages, compared to the formulation lacking ethanol (0:80:20). A significant increase in minoxidil receptor penetration occurred with the PG-rich 0:80:20 formulation after 12 h. We showed that deposition of minoxidil into appendages, SC, and skin penetration into receptor fluid were similar in magnitude. Transport by the appendageal route is likely to be a key determinant of hair growth promotion by minoxidil. Refereed/Peer-reviewed

In Australia, the surface and subsurface soils of the majority of cotton (Gossypium hirsutum L.)-growing regions are sodic. Application of organic amendments can be an option to stabilize the structure of sodic Vertisols due to their potential positive effect on soil physical properties. An incubation experiment was conducted for 4 wk in a temperature-controlled (30°C) growth chamber to study the effect of organic amendments on the properties of two Vertisols with different sodicity levels. The exchangeable Na percentages (ESPs) in these Vertisol soils collected from the Australian Cotton Research Institute (ACRI) near Narrabri, New South Wales, and a commercial cotton farm near Dalby, Queensland, were modified such that three different sodicity levels resulted, i.e., nonsodic (ESP 15). The organic amendments used were cotton gin trash (60 Mg ha -1 ), cattle manure (60 Mg ha -1 ), and composted chicken manure (18 Mg ha -1 ), as well as an unamended control. The organic amendments improved the physical properties of both Vertisols by decreasing clay dispersion. In the Dalby soil, cotton gin trash produced the largest decrease (29%) in the dispersion index over the control at the moderate sodicity level, whereas in the strongly sodic soil, the lowest dispersion index resulted from the application of chicken manure. Nutrient availability (N, P, and K) was also increased significantly at higher sodicity levels for both the ACRI and Dalby soils by using organic amendments. These results indicate that using organic amendments can be beneficial for the amelioration of sodic Vertisols and also to sustain soil quality.

Solution culture was used to investigate whether the high solution Na concentrations and Na:Ca ratios found in sodic soils could directly affect the early growth and nutrient uptake of cotton (Gossypium hirsutum L.). Cotton was grown in nutrient solutions with three Na:Ca ratios (46:1, 4:1 and 0.2:1 mM) and three electrical conductivities (EC) (2.5, 4.25 and 6 dS m−1) combined in a factorial design with four replicates. Most cotton growth parameters (including shoot and root dry weight, fruit number and weight) were unaffected by increasing solution EC or Na:Ca ratio, but at the highest Na concentration (56.6 mM), plant height was reduced. It was concluded that young cotton has the ability to tolerate solution Na concentrations up to those found in moderately sodic soils. Increasing solution Na:Ca increased plant root and shoot concentrations and plant accumulation for Na, and decreased them for Ca. Increasing EC also increased plant Na concentration and accumulation. Shoot K and P concentrations decreased with EC, but actually increased as the sodicity (Na:Ca ratio) of the nutrient solution increased. The results suggest that the low K and P concentrations commonly found in cotton grown in sodic soils are not a direct result of Na:Ca ratio in the soil solution.

In low input (e.g. organic) farming systems where soil phosphorus (P) fertilisers such as superphosphate are not used, maintaining sufficient available soil P for plant growth can be a major challenge. The use of P accumulating cover crops may increase P availability for subsequent crops. We hypothesised that P release from organic residues of legumes (faba bean (Vicia faba) and field peas (Pisum sativum)) could supply adequate P to meet the needs of a subsequent crop in a low P soil. A pot experiment was conducted to determine the contribution of P by legume green manure to subsequent corn using 33P labelled legume residues and 32P labelled inorganic fertiliser (KH2PO4). The treatments included two rates of P application, (a) 10 kg P ha−1 as legume root and shoot residues or as inorganic fertiliser with and without a C source, and (b) 38 kg P ha−1as a combination of legume shoot and root residues or a combination of root and inorganic fertiliser and inorganic fertiliser alone. An absolute control (zero P) was also used. Shoot dry matter, P uptake and P source (residues or fertilisers) of total P in corn were measured at harvest. Faba bean and field pea residues alone or in combination with fertilisers contributed up to 10% and 5% of the total P uptake by corn respectively, compared with up to 54% by inorganic fertilisers. Incorporation of field pea and faba bean residues with P concentrations higher than those observed under field conditions, may not always lead to adequate net P release to supply the early growth phase of subsequent crops.

The low productivity and escalating costs of drug development have been well documented over the past several years. Less than 10% of new compounds that enter clinical trials ultimately make it to the market, and many more fail in the preclinical stages of development. These challenges in the "critical path" of drug development are discussed in a 2004 publication by the US Food and Drug Administration. The document emphasizes new tools and various opportunities to improve drug development. One of the opportunities recommended is the application of "model-based drug development (MBDD)." This paper discusses what constitutes the key elements of MBDD and how these elements should fit together to inform drug development strategy and decision-making.

Sequential extraction techniques have been used to make inferences about speciation of phosphorus (P) and to a lesser extent arsenic (As) in soils. However, sequential extraction studies on the less‐abundant group V element, antimony (Sb), are limited. In this work, a widely used P sequential extraction scheme was modified and used to extract P, As, and Sb from two acidic soils from the Macleay River floodplain, NSW, that were enriched with Sb (26.9 and 23.0 mg kg−1). An ammonium oxalate–oxalic acid step was included in the extraction sequence to dissolve the noncrystalline iron (Fe) and aluminium (Al) hydroxide phase. It extracted 30 to 47% of Sb, indicating the importance of this fraction, which may be mobilized in the floodplain by acid sulfate soil processes and periodic waterlogging. The original method overestimated P, As, and Sb in the residual fraction (30–71%). Relative efficiency values of extracts for P, As, and Sb were compared, and inferences about phase distributions were made. The ...

Clinical trial simulation (CTS) was used to select a robust design to test the hypothesis that a new treatment was effective for Alzheimer's disease (AD). Typically, a parallel group, placebo controlled, 12-week trial in 200-400 AD patients would be used to establish drug effect relative to placebo (i.e., Ho: Drug Effect = 0). We evaluated if a crossover design would allow smaller and shorter duration trials.A family of plausible drug and disease models describing the time course of the AD assessment scale (ADAS-Cog) was developed based on Phase I data and literature reports of other treatments for AD. The models included pharmacokinetic, pharmacodynamic, disease progression, and placebo components. Eight alternative trial designs were explored via simulation. One hundred replicates of each combination of drug and disease model and trial design were simulated. A 'positive trial' reflecting drug activity was declared considering both a dose trend test (p0.05) and pair-wise comparisons to placebo (p0.025).A 4 x 4 Latin Square design was predicted to have at least 80% power to detect activity across a range of drug and disease models. The trial design was subsequently implemented and the trial was completed. Based on the results of the actual trial, a conclusive decision about further development was taken. The crossover design provided enhanced power over a parallel group design due to the lower residual variability.CTS aided the decision to use a more efficient proof of concept trial design, leading to savings of up to US 4 M dollars in direct costs and a firm decision 8-12 months earlier than a 12-week parallel group trial.

Commercial forestry plantations as a postmining land use in the Upper Hunter Valley of New South Wales, Australia are restricted by both the poor nutrient availability of mining substrates and low regional rainfall. An experiment was conducted to investigate whether municipal waste products and saline groundwater from coal mining operations could improve early tree growth without impacting on the environment through salt accumulation and/or nutrient enrichment and changes in groundwater quality. Potential impacts were investigated by quantifying the nutrient cycling dynamics within the plantation using an input-output mass balance approach for exchangeable calcium (Ca(2+)), exchangeable magnesium (Mg(2+)), exchangeable potassium (K(+)), exchangeable sodium (Na(+)), nitrogen (N), and phosphorus (P). Measured inputs to and outputs from the available nutrient pool in the 0-30 cm of the overburden subsystem were used to estimate the net effect of unmeasured inputs and outputs (termed "residuals"). Residual values in the mass balance of the irrigated treatments demonstrated large leaching losses of exchangeable Ca, Mg, K, and Na. Between 96% and 103% of Na applied in saline mine-water irrigation was leached below the 0-30-cm soil profile zone. The fate of these salts beyond 30 cm is unknown, but results suggest that irrigation with saline mine water had minimal impact on the substrate to 30 cm over the first 2 years since plantation establishment. Accumulations of N and P were detected for the substrate amendments, suggesting that organic amendments (particularly compost) retained the applied nutrients with very little associated losses, particularly through leaching.

Moderate levels of enrichment with environmental contaminants, such as arsenic (As) and antimony (Sb), have received less attention than gross contamination related to obvious point sources of pollution. Within the Macleay floodplain of north-eastern NSW it was found that approximately 90% of the floodplain is enriched in As and Sb, and 6-8% of the floodplain contains As and Sb levels greater than current Australian soil environmental investigation levels. Variation in surface and depth distributions indicated flood deposition of As and Sb across major environmental floodplain environments, with highest accumulation in modern swamp depositional environments. The soil enrichment was reflected by pasture uptake (up to 6.4 and 2.2 mg kg(-1) for As and Sb, respectively) and elevated surface water concentrations (up to 10 and 21 times drinking guideline values and 2.9 and 6.9 times freshwater trigger values for protection of 95% of species for As and Sb, respectively) of these metalloids. Significant relationships between pasture and total soil levels imply higher relative availability than is typical at grossly contaminated sites. Implications for metalloid mobility and availability in acid sulfate soil environments in the floodplain are discussed.

The idea of model-based drug development championed by Lewis Sheiner, in which pharmacostatistical models of drug efficacy and safety are developed from preclinical and available clinical data, offers a quantitative approach to improving drug development and development decision-making. Examples are presented that support this paradigm. The first example describes a preclinical model of behavioral activity to predict potency and time-course of response in humans and assess the potential for differentiation between compounds. This example illustrates how modeling procedures expounded by Lewis Sheiner provided the means to differentiate potency and the lag time between drug exposure and response and allow for rapid decision making and dose selection. The second example involves planning a Phase 2a dose-ranging and proof of concept trial in Alzheimer's disease (AD). The issue was how to proceed with the study and what criteria to use for a go/no go decision. The combined knowledge of AD disease progression, and preclinical and clinical information about the drug were used to simulate various clinical trial scenarios to identify an efficient and effective Phase 2 study. A design was selected and carried out resulting in a number of important learning experiences as well as extensive financial savings. The motivation for this case in point was the "Learn-Confirm" paradigm described by Lewis Sheiner. The final example describes the use of Pharmacokinetic and Pharmacodynamic (PK/PD) modeling and simulation to confirm efficacy across doses. In the New Drug Application for gabapentin, data from two adequate and well-controlled clinical trials was submitted to the Food and Drug Administration (FDA) in support of the approval of the indication for the treatment of post-herpetic neuralgia. The clinical trial data was not replicated for each of the sought dose levels in the drug application presenting a regulatory dilemma. Exposure response analysis submitted in the New Drug Application was applied to confirm the evidence of efficacy across these dose levels. Modeling and simulation analyses showed that the two studies corroborate each other with respect to the pain relief profiles. The use of PK/PD information confirmed evidence of efficacy across the three studied doses, eliminating the need for additional clinical trials and thus supporting the approval of the product. It can be speculated that the work by Lewis Sheiner reflected in the FDA document titled "Innovation or Stagnation: Challenge and Opportunity on the Critical Path to New Medical Products" made this scientific approach to the drug approval process possible.

Recommended alternative digestion methods for elemental analysis of soil often omit arsenic (As) and antimony (Sb) as viable analytes. In addition, comparisons of these methods for analysis of a wide range of elements by ICP-OES are few, limiting the viability of recommended methods. Four methods for the digestion of soils (microwave aqua regia, open aqua regia, microwave nitric, and open nitric) were assessed in seven field soil samples analyzed by ICP-OES. Relative extraction strength and analytical precision were compared for 18 elements [aluminum (Al), iron (Fe), manganese (Mn), magnesium (Mg), calcium (Ca), potassium (K), phosphorus (P), sulfur (S), arsenic (As), cadmium (Cd), cobalt (Co), chromium (Cr), copper (Cu), sodium (Na), nickel (Ni), lead (Pb), antimony (Sb), and zinc (Zn)] with the emphasis on obtaining optimal analytical results for the volatiles As and Sb. The microwave aqua regia digestion was found to give better elemental extraction and analytical variability for the widest ra...

Pregabalin is being evaluated for the treatment of neuropathic pain. Two phase 2 studies were simulated to determine how precisely the dose that caused a one-point reduction in the pain score could be estimated. The likelihood of demonstrating at least a one-point change for each available dose strength was also calculated.A pharmacokinetic-pharmacodynamic (PK/PD) model relating pain relief to gabapentin plasma concentrations was derived from a phase 3 study. The PK component of the model was modified to reflect pregabalin PK. The PD component was modified by scaling the gabapentin concentration-effect relationship to reflect pregabalin potency, which was based on preclincal data. Uncertainty about the potency difference and the steepness of the concentration-response slope necessitated simulating a distribution of outcomes for a series of PK/PD models.Analysis of the simulated data suggested that after accounting for the uncertainty, there was an 80% chance that the dose defining the clinical feature was within 45% of the true value. The likelihood of estimating a dose that was within an acceptable predefined precision range relative to a known value approximated 60%. The minimum dose that should be studied to have a reasonable chance of estimating the dose that caused a one-point change was 300 mg.Doses that identify predefined response may be imprecisely estimated, suggesting that replication of a similar outcome may be elusive in a confirmatory study. Quantification of this precision provides a rationale for phase 2 trial design and dose selection for confirmatory studies.