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The COVID-19 pandemic has had a profound effect on livelihoods everywhere, but especially in the informal economy where crucial forms of protection and security are often absent. A detailed understanding of the impacts for informal workers, the public policy approaches that could most effectively respond to their needs, and the barriers to such policy, is urgently needed. This paper discusses the results of a 2021 street vendor survey in Cali, Colombia, focusing on (1) vendors’ socioeconomic circumstances and (2) their political engagement and attitudes on key policy and governance issues. It argues that while the pandemic and the government responses to it negatively impacted street vendors, there are steps that government could have taken, and can still take, to address vendors’ needs and priorities. To ensure a just, equitable, sustainable recovery, and to protect economically marginalized groups from future crises, informal workers must be more meaningfully included in decision-making processes.

Linerixibat, an oral small molecule ileal bile acid transporter inhibitor under development for cholestatic pruritus in primary biliary cholangitis, was designed for minimal intestinal absorption (site of pharmacological action). This study characterized the pharmacokinetics, absorption, distribution, metabolism, and excretion of [14C]-linerixibat in humans following an intravenous microtracer, concomitant with unlabeled oral tablets, and [14C]-linerixibat oral solution. Linerixibat exhibited absorption-limited flip-flop kinetics: longer oral versus intravenous half-life (6-7 h vs 0.8 h). The short intravenous half-life was consistent with high systemic clearance (61.9 L/h) and low volume of distribution (16.3 L). In vitro studies predicted rapid hepatic clearance via cytochrome P450 (CYP) 3A4 metabolism, which deceptively predicted human hepatic clearance within 1.5-fold. However, linerixibat was minimally metabolized in humans after intravenous administration: ~80% elimination via biliary/fecal excretion (>90-97% as unchanged parent) and ~20% renal elimination by glomerular filtration (>97% as unchanged parent). Absolute oral bioavailability of linerixibat was exceedingly low (0.05%), primarily due to a very low fraction absorbed (0.167%; fgut~100%), with high hepatic extraction ratio (77.0%) acting as a secondary barrier to systemic exposure. Oral linerixibat was almost entirely excreted (>99% recovered radioactivity) in feces as unchanged and unabsorbed linerixibat. Consistent with the low oral fraction absorbed and ~20% renal recovery of intravenous [14C]-linerixibat, urinary elimination of orally administered radioactivity was negligible (

This article explores the recent history of Owino Market in Kampala, Uganda, to analyse the constraints to agency that exist in the informal economy. Detailing conflicts over market management and ...

Phase 0 approaches — which include microdosing — evaluate subtherapeutic exposures of new drugs in first-in-human studies known as exploratory clinical trials. Recent progress extends phase 0 benefits beyond assessment of pharmacokinetics to include understanding of mechanism of action and pharmacodynamics. Phase 0 approaches have the potential to improve preclinical candidate selection and enable safer, cheaper, quicker and more informed developmental decisions. Here, we discuss phase 0 methods and applications, highlight their advantages over traditional strategies and address concerns related to extrapolation and developmental timelines. Although challenges remain, we propose that phase 0 approaches be at least considered for application in most drug development scenarios. Phase 0 approaches, including microdosing, evaluate subtherapeutic exposures to novel drugs, potentially enabling safer, cheaper and quicker first-in-human studies. Here, Burt et al. discuss the fundamentals and applications of phase 0 approaches, highlight the potential advantages of their application in drug development and address the associated limitations.

There has been an explosion in the volume of data that is being accessed from the Internet. As a result, the risk of a Web server being inundated with requests is ever-present. One approach to reducing the performance degradation that potentially comes from Web server overloading is to employ Web caching where data content is replicated in multiple locations. In this paper, we investigate the use of evolutionary algorithms to dynamically alter partition size in Web caches. We use established modeling techniques to compare the performance of our evolutionary algorithm to that found in statically-partitioned systems. Our results indicate that utilizing an evolutionary algorithm to dynamically alter partition sizes can lead to performance improvements especially in environments where the relative size of large to small pages is high.

Treatment of myopic children with a dual-focus soft contact lens (DFCL; MiSight 1 day) produced sustained slowing of myopia progression over a 6-year period. Significant slowing was also observed in children switched from a single vision control to treatment lenses (3 years in each lens).This study aimed to evaluate the effectiveness of DFCLs in sustaining slowed progression of juvenile-onset myopia over a 6-year treatment period and assess myopia progression in children who were switched to a DFCL at the end of year 3.Part 1 was a 3-year clinical trial comparing DFCLs with a control contact lens (Proclear 1 day) at four investigational sites. In part 2, subjects completing part 1 were invited to continue for 3 additional years during which all children were treated with MiSight 1 day DFCLs (52 and 56 from the initially treated [T6] and control [T3] groups, respectively). Eighty-five subjects (45 [T3] and 40 [T6]) completed part 2. Cyclopleged spherical equivalent refractive errors (SEREs) and axial lengths (ALs) were monitored, and a linear mixed model was used to compare their adjusted change annually.Average ages at part 2 baseline were 13.2 ± 1.3 and 13.0 ± 1.5 years for the T6 and T3 groups, respectively. Slowed myopia progression in the T6 group observed during part 1 was sustained throughout part 2 (mean ± standard error of the mean: change from baseline SERE [in diopters], -0.52 ± 0.076 vs. -0.51 ± 0.076; change in AL [in millimeters], 0.28 ± 0.033 vs. 0.23 ± 0.033; both P.05). Comparing progression rates in part 2 for the T6 and T3 groups, respectively, indicates that prior treatment does not influence efficacy (SERE, -0.51 ± 0.076 vs. -0.34 ± 0.077; AL, 0.23 ± 0.03 vs. 0.18 ± 0.03; both P.05). Within-eye comparisons of AL growth revealed a 71% slowing for the T3 group (3 years older than part 1) and further revealed a small subset of eyes (10%) that did not respond to treatment.Dual-focus soft contact lenses continue to slow the progression of myopia in children over a 6-year period revealing an accumulation of treatment effect. Eye growth of the initial control cohort with DFCL was slowed by 71% over the subsequent 3-year treatment period.

Archaeological trial trench evaluation following geophysical surveyin advance of a domestic housing development Nothing significant found

BackgroundMutations in the L/M cone opsin gene array cause abnormally high perceived retinal contrast and the development of myopia. Environmental factors may also lead to high visual contrast and cause myopia. Diffusion optics technology (DOT) lenses are designed to reduce contrast signalling in the retina and slow myopia progression.MethodsTheControl of Myopia UsingPeripheral Diffusion LensesEfficacy andSafetyStudy (CYPRESS,NCT03623074) is a 36-month, multicentre, randomised, controlled, double-masked trial evaluating two investigational spectacle lenses versus control lenses in myopic children aged 6–10, with a planned interim analysis at 12 months. The primary endpoints are change from baseline in axial length (AL) and spherical equivalent refraction (SER).Results256 children (58% female; mean age at screening, 8.1 years) were dispensed spectacles. Across all groups, baseline averages were AL 24.02 mm (SD±0.77 mm), SER −2.01 D (SD±0.9 D) using manifest refraction, and SER −1.94 D (SD±1.0 D) using cycloplegic autorefraction. At 12 months, mean difference in SER progression for test 1 versus control was −0.40 D (pConclusion12-month results from this ongoing trial demonstrate the safety and effectiveness of DOT spectacles for reducing myopic progression.

An innovative open-label, crossover clinical study was used to investigate the excretion balance, pharmacokinetics, and metabolism of nemiralisib-an inhaled phosphoinositide 3-kinase delta inhibitor being developed for respiratory diseases. Six healthy men received a single intravenous microtracer of 10 µg [14C]nemiralisib with a concomitant inhaled nonradiolabeled 1000 µg dose followed by an oral 800 µg dose of [14C]nemiralisib 14 days later. Complementary methods including accelerator mass spectrometry allowed characterization of a range of parameters including oral absorption (Fabs), proportion of nemiralisib escaping gut wall metabolism (Fg), hepatic extraction (Eh), fraction of dose absorbed from inhaled dose (Flung), and renal clearance. Intravenous pharmacokinetics of nemiralisib were characterized by low blood clearance (10.0 l/h), long terminal half-life (55 hours), and high volume of distribution at steady state (728 l). Nemiralisib exhibited moderate inhaled and oral bioavailability (38% and 35%) while Flung was 29%. Absorption and first-pass parameters were corrected for blood renal clearance and compared with values without correction. Any swallowed nemiralisib was relatively well absorbed (Fabs, 0.48) with a high fraction escaping gut wall metabolism and low extraction by the liver (Fg and Eh being 0.83 and 0.10, respectively). There were no major human plasma metabolites requiring further qualification in animal studies. Both unchanged nemiralisib and its oxidative/conjugative metabolites were secreted in bile, with nemiralisib likely subject to further metabolism through enterohepatic recirculation. Direct renal clearance and metabolism followed by renal clearance were lesser routes of elimination. SIGNIFICANCE STATEMENT: A number of innovative features have been combined into one small clinical study enabling a comprehensive description of the human pharmacokinetics and metabolism of an inhaled molecule. Design elements included an intravenous 14C tracer administration concomitant with an inhalation dose that enabled derivation of parameters such as fraction absorbed (Fabs), the proportion of drug escaping first-pass extraction through the gut wall and liver (Fg and Fh) and hepatic extraction (Eh). Entero-test bile sampling enabled characterization of biliary elimination pathways.

The complex dynamics of the informal food sector in urban Africa are poorly understood. Urban informal food systems are beginning to receive attention from scholars and policymakers, but the notable absence of detailed empirical information and necessary theoretical engagement with their emergence, structure, and operation has thus far limited efforts to understand the central role that they play in urban development processes. This Special Issue brings together a diverse collection of case studies from seven countries across the Global South—China, Jamaica, Mozambique, Namibia, Nigeria, South Africa, and Uganda—to explore these dynamics by placing Africa’s urban informal food sector in comparative international context. This introduction provides an overview of how this Special Issue contributes to debates about the origins of informal food economies in cities in the Global South, the potential of the informal food sector to contribute to inclusive urban development, the relationship between informal food vendors and the state, and interactions between formal and informal food systems, all of which have important implications for theorizing urban governance and development in Africa and beyond.

Understanding the root causes of informal economic activity is crucial for the effective governance of the informal sphere. Precisely what these root causes are, however, is subject to significant debate. This article contributes to these debates by arguing that the state is central to the origin and evolution of informality. Stressing the importance of understanding informality through a historically rooted political economy approach, it analyzes the modern history of informal vending in Kampala, Uganda, and identifies six ways in which the state has fundamentally shaped informal economic activity in the city: colonial planning, a history of poor governance and instability, economic liberalization, geographic development trends, an ineffective taxation regime, and the self-interest of state officials. An appropriate understanding of the centrality of the state in the informal economy highlights the necessity of designing effective institutions, policies, and interventions that prioritize the needs of the urban poor.

Phase 0 approaches, including microdosing, involve the use of sub-therapeutic exposures to the tested drugs, thus enabling safer, more-relevant, quicker and cheaper first-in-human (FIH) testing. These approaches also have considerable potential to limit the use of animals in human drug development. Recent years have witnessed progress in applications, methodology, operations, and drug development culture. Advances in applications saw an expansion in therapeutic areas, developmental scenarios and scientific objectives, in, for example, protein drug development and paediatric drug development. In the operational area, the increased sensitivity of Liquid Chromatography Tandem Mass Spectrometry (LC-MS/MS), expansion of the utility of Positron Emission Tomography (PET) imaging, and the introduction of Cavity Ring-Down Spectroscopy (CRDS), have led to the increased accessibility and utility of Phase 0 approaches, while reducing costs and exposure to radioactivity. PET has extended the application of microdosing, from its use as a predominant tool to record pharmacokinetics, to a method for recording target expression and target engagement, as well as cellular and tissue responses. Advances in methodology include adaptive Phase 0/Phase 1 designs, cassette and cocktail microdosing, and Intra-Target Microdosing (ITM), as well as novel modelling opportunities and simulations. Importantly, these methodologies increase the predictive power of extrapolation from microdose to therapeutic level exposures. However, possibly the most challenging domain in which progress has been made, is the culture of drug development. One of the main potential values of Phase 0 approaches is the opportunity to terminate development early, thus not only applying the principle of ‘kill-early-kill-cheap’ to enhance the efficiency of drug development, but also obviating the need for the full package of animal testing required for therapeutic level Phase 1 studies. Finally, we list developmental scenarios that utilised Phase 0 approaches in novel drug development.

This chapter presents the findings of the work of the Centre for Sustainable, Healthy and Learning Cities and Neighbourhoods (SHLC) that is funded via UK Research and Innovation as part of the UK Government’s Global Challenges Research Fund (GCRF). The chapter is based on case study research conducted in two cities in each of the seven countries in the Global South. The cities are Cape Town and Johannesburg (South Africa), Dar es Salaam and Dodoma (Tanzania), Kigali and Huye (Rwanda), Delhi and Madurai (India), Dhaka and Khulna (Bangladesh), Chongqing and Datong (China) and Manila and Batangas (Philippines). Based on an analysis of data drawn from planning and urban development policy documents in the respective countries over the last two decades, the case studies identify key ideas and policies that have shaped the delivery of public services, especially education and health care. The chapter focusses on four themes: urban inequalities, urban planning policies, understanding health and well-being and learning cities.

The role of the informal food sector in the urban food system cannot be appreciated or understood without the compilation and analysis of systematic and representative data on the activities of informal enterprises across a city and along food supply chains outside it. At present, there are significant gaps in the knowledge base about the character, operation, and roles of the informal food sector, a pre-requisite for sound and supportive governance. This paper presents evidence on the relative importance of the informal food sector and discusses various methodologies for improving the knowledge base. The paper identifies the challenges and opportunities facing individuals and enterprises operating in the sector as well as the challenges posed by informality more generally. The paper also examines the issue of informal sector governance including policy prescriptions that have followed from different understandings of informality and discusses various existing policies and possible interventions. We argue that maximizing the potential benefits of the informal food sector requires well designed institutional and policy frameworks, an appropriate enabling environment, and effective policies and interventions. The final section identifies priority areas for future research.

Phase 0 approaches - which include microdosing - evaluate subtherapeutic exposures of new drugs in first-in-human studies known as exploratory clinical trials. Recent progress extends phase 0 benefits beyond assessment of pharmacokinetics to include understanding of mechanism of action and pharmacodynamics. Phase 0 approaches have the potential to improve preclinical candidate selection and enable safer, cheaper, quicker and more informed developmental decisions. Here, we discuss phase 0 methods and applications, highlight their advantages over traditional strategies and address concerns related to extrapolation and developmental timelines. Although challenges remain, we propose that phase 0 approaches be at least considered for application in most drug development scenarios.

Boiling flows are an extremely efficient mechanism for the transfer of ultrahigh heat fluxes and used in numerous industrial applications. In this paper, the accuracy of computational fluid dynamics in predicting the temperature distributions and heat transfer performance is examined within a nuclear fusion reactor divertor. The aim is to establish the role of computational fluid dynamics (CFD) within the design of complicated high heat flux components using a semi-mechanistic approach to flow boiling that is independent of geometry and flow conditions. An Eulerian–Eulerian two-fluid method is developed and a conjugate heat transfer model is validated against the existing experimental data where available. Overall, a satisfactory accuracy is achieved in the prediction of several important quantities. Temperature distribution throughout the divertor is found to be highly accurate and aligns with the physical testing across two expected operating regimes. Additionally, the system heat transfer coefficients and coolant temperatures are close to the assumptions already established within the literature. Heat transfer enhancement is a critical component of the divertor design, and a twisted-tape insert appears to be necessary for the system to withstand ultrahigh heat fluxes encountered within the fusion reactor. The results show that the inclusion of a twisted tape improved the heat transfer coefficient of the system by almost 45% allowing the divertor to withstand the required heat fluxes of 10 MW/m2 and 20 MW/m2.

Chronic obstructive pulmonary disease (COPD) is an inflammatory lung condition, causing progressive decline in lung function leading to premature death. Acute exacerbations in COPD patients are predominantly associated with respiratory viruses. Ribavirin is a generic broad-spectrum antiviral agent that could be used for treatment of viral respiratory infections in COPD. Using the Particle Replication In Nonwetting Templates (PRINT) technology, which produces dry-powder particles of uniform shape and size, two new inhaled formulations of ribavirin (ribavirin-PRINT-CFI and ribavirin-PRINT-IP) were developed for efficient delivery to the lung and to minimize bystander exposure., Chronic obstructive pulmonary disease (COPD) is an inflammatory lung condition, causing progressive decline in lung function leading to premature death. Acute exacerbations in COPD patients are predominantly associated with respiratory viruses. Ribavirin is a generic broad-spectrum antiviral agent that could be used for treatment of viral respiratory infections in COPD. Using the Particle Replication In Nonwetting Templates (PRINT) technology, which produces dry-powder particles of uniform shape and size, two new inhaled formulations of ribavirin (ribavirin-PRINT-CFI and ribavirin-PRINT-IP) were developed for efficient delivery to the lung and to minimize bystander exposure. Ribavirin-PRINT-CFI was well tolerated in healthy participants after single dosing and ribavirin-PRINT-IP was well tolerated in healthy and COPD participants after single and repeat dosing. Ribavirin-PRINT-CFI was replaced with ribavirin-PRINT-IP since the latter formulation was found to have improved physicochemical properties and it had a higher ratio of active drug to excipient per unit dose. Ribavirin concentrations were measured in lung epithelial lining fluid in both healthy and COPD participants and achieved target concentrations. Both formulations were rapidly absorbed with approximately dose proportional pharmacokinetics in plasma. Exposure to bystanders was negligible based on both the plasma and airborne ribavirin concentrations with the ribavirin-PRINT-IP formulation. Thus, ribavirin-PRINT-IP allowed for an efficient and convenient delivery of ribavirin to the lungs while minimizing systemic exposure. Further clinical investigations would be required to demonstrate ribavirin-PRINT-IP antiviral characteristics and impact on COPD viral-induced exacerbations. (The clinical trials discussed in this study have been registered at ClinicalTrials.gov under identifiers NCT03243760 and NCT03235726.)

Daprodustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, is being investigated for treatment of anemia in chronic kidney disease. This phase 1, nonrandomized, 2-period, crossover study in 6 healthy men characterized the absorption, distribution, and excretion of daprodustat when administered as oral and intravenous (IV) doses of unlabeled and radiolabeled daprodustat ([14 C]-GSK1278863). Tolerability and pharmacokinetic properties of daprodustat, and its 6 metabolites in the systemic circulation, were also evaluated. The mean recovery of radiolabeled daprodustat was ≈95% by day 5, with the majority in feces and minor renal elimination, indicating that daprodustat and metabolites are primarily eliminated via hepatobiliary and fecal routes. Approximately 40% of total circulating radioactivity in plasma following both IV and oral administration was daprodustat; thus, 60% was attributed to metabolites. It was estimated that ≈80% of daprodustat was absorbed across the gastrointestinal tract, and ≈18% cleared by hepatic extraction. Pharmacokinetics were essentially dose proportional, with moderate (≈66%) oral tablet bioavailability. Following IV administration, daprodustat plasma clearance (19.3 L/h) and volume of distribution (14.6 L) were low, suggesting low tissue distribution outside systemic circulation with likely low penetration into tissues. Daprodustat was generally well tolerated, with no deaths or serious or significant adverse events reported.

Informal economic activity is often a defining feature of the political economy of conflict and post-conflict cities. Despite its prevalence, however, its implications for peacebuilding remain largely under-theorised. This article draws on the extensive literature on informal economic activity more generally, with a focus on cities, to outline three contrasting perspectives on its significance for peacebuilding: first, that informal economies can support peacebuilding efforts by providing crucial livelihood support and access to essential goods and services in the absence of functioning formal markets; second, that they are a manifestation of resistance to unpopular top-down peacebuilding processes that fail to cohere with local understandings of economic justice; and third, that they can reproduce the conditions that led to conflict by re-establishing socio-economic hierarchies and systems of marginalisation. It argues that each of these perspectives has important implications for the theory and praxis of peacebuilding and raises conceptual challenges that remain unresolved. It then claims that any effort to incorporate urban informal economies into peacebuilding processes must prioritise democratic inclusion, grassroots organisation and formal employment creation if they are to have a meaningful impact on the lives of the urban poor.

Presented here is a background to the technology of Accelerator Mass Spectrometry (AMS) and its application as a supremely sensitive detector for analysis of radiocarbon (14C) label in drugs of interest. We highlight the wide variety of clinical study designs supported by AMS that deliver information on human absorption, distribution, metabolism, excretion, and pharmacokinetics (ADME-PK), including absolute bioavailability. The challenges and future opportunities for the application of AMS, including new generation instrumentation and alternative approaches in drug discovery and development are discussed.

Inhaled batefenterol is an investigational bifunctional molecule for the treatment of chronic obstructive pulmonary disease. The excretion balance and pharmacokinetics of batefenterol using [14C]‐radiolabeled drug administered orally and as intravenous (IV) infusion were assessed. In this 2‐period, open‐label study, 6 healthy male subjects received a single IV microtracer 1‐hour infusion of 4 μg [14C]‐batefenterol concomitant with inhaled nonradiolabeled batefenterol (1200 μg) followed by oral [14C]‐batefenterol (200 μg) in period 2 after a 14‐day washout. The primary end points included: the area under the concentration‐time curve from time zero to last time of quantifiable concentration (AUC0‐t); maximum observed concentration (Cmax); and time of occurrence of maximum observed concentration. Following IV administration, the geometric mean AUC0‐t of [14C]‐batefenterol was 121.9 pgEq • h/mL; maximum observed concentration and time of occurrence of maximum observed concentration were 92.7 pgEq/mL and 0.8 hours, respectively; absolute oral bioavailability was 0.012%. The mean AUC0‐t ratio indicated that [14C]‐batefenterol accounted for 85% of total circulating radioactivity in the plasma initially and declined rapidly following IV administration, but only ∼0.2% of total circulating radioactivity following oral administration. Cumulative mean recovery of total radioactive [14C]‐batefenterol in urine and feces was 6.31% and 77.6%, respectively. Overall, batefenterol exhibited low systemic bioavailability after inhaled and oral administration, and high fecal excretion and low urinary excretion following IV and oral administration.

The political evolution of Kampala under the National Resistance Movement (NRM) has profoundly affected the fortunes of the city’s street vendors. This article examines the effects of institutional changes brought about by the NRM’s efforts to monopolize power in the city, arguing that the twin forces of democratization and decentralization allowed street vending to flourish while the reversal of these processes precipitated its dramatic decline. Democratization and decentralization initiated a period of intense political competition in which vendors could trade political support for protection from politicians who were more interested in political survival than the implementation of policy. This ability was lost when the central government introduced a new city government that shifted the balance of power from elected politicians to appointed technocrats. The new city government has since sought legitimacy through development and urban management initiatives that aim to transform Kampala into a supposedly modern, well-organized city. In doing so, it has sought to eradicate street vending, a practice it sees as the antithesis of and an obstacle to its ambitions. Lacking the channels for political influence that they previously enjoyed, street vendors have been forced to face the full brunt of government repression.

This article explores the reasons behind Canada’s declining participation in United Nations peacekeeping operations. It proposes a decision-making model that explains how politicians assess opportunities to commit personnel to peacekeeping missions by balancing their policy objectives with the pressures of electoral politics. Emphasizing the importance of voters in political decision-making processes, it argues that participation in peacekeeping is dependent on three key factors: a belief in the value of peacekeeping in principle; a belief in the value of a given peacekeeping operation; and risk aversion in response to the potential costs of peacekeeping. Tracing Canada’s declining participation in peacekeeping operations since the 1990s, it particularly focuses on how this calculus has, in different ways, limited Canada’s involvement in peacekeeping under Stephen Harper’s Conservative government and Justin Trudeau’s Liberal government, arguing that the former undervalued peacekeeping as a means of obtaining its foreign policy objectives and as a feature of national identity, minimizing the perceived benefits of participation, while the latter has focused on the inherent risks of peacekeeping despite a professed commitment to peacekeeping in principle, maximizing the perceived costs of further personnel commitments. The decisions of successive Canadian governments have led to a free-rider problem in which Canada is willing to enjoy the benefits of peacekeeping but unwilling to bear the costs.

The article documents the results of a series of investigations undertaken by the Bamburgh Research Project (BRP) within the Inner Ward of Bamburgh Castle, Northumberland between 1997 and 2010, using resistivity, ground penetrating radar survey, and limited excavation. Throughout the course of the investigation around the ruins of the medieval chapel, material evidence was found of Romano-British activity. Furthermore, stone structures of pre-twelfth-century date were revealed. Two phases of a possible early medieval defensive wall were identified beneath the north wall of the current chapel structure, and a stone building was found beneath the main body of the church which may represent part of the church of St Peter, mentioned by Bede.

Metabolite quantification and profiling continues to grow in importance in today's drug development. The guidance provided by the 2008 FDA Metabolites in Safety Testing Guidance and the subsequent ICH M3(R2) Guidance (2009) has led to a more streamlined process to assess metabolite exposures in preclinical and clinical studies in industry. In addition, the European Bioanalysis Forum (EBF) identified an opportunity to refine the strategies on metabolite quantification considering the experience to date with their recommendation paper on the subject dating from 2010 and integrating the recent discussions on the tiered approach to bioanalytical method validation with focus on metabolite quantification. The current manuscript summarizes the discussion and recommendations from a recent EBF Focus Workshop into an updated recommendation for metabolite quantification in drug development.

The study aim was to investigate the pharmacokinetics of single high doses and repeated therapeutic doses of fluticasone furoate (FF) and batefenterol (BAT; a bifunctional muscarinic antagonist and β2‐agonist) administered in combination (BAT/FF) or as monotherapy. In this open‐label, 6‐period, crossover study of 48 subjects, the treatment sequences were (1) single high‐dose BAT/FF 900/300 μg followed by repeated therapeutic doses of BAT/FF 300/100 μg (once daily for 7 days); (2) single high‐dose BAT 900 μg administered concurrently with FF 300 μg; (3) single high‐dose BAT 900 μg followed by repeated therapeutic‐dose BAT 300 μg; (4) single high‐dose FF 300 μg followed by repeated therapeutic‐dose FF 100 μg; (5) single high‐dose FF 300 μg (magnesium stearate); and (6) single high‐dose FF/vilanterol 300/75 μg. Plasma FF area under the plasma drug concentration‐time curve (AUC) was reduced after single high‐dose BAT/FF versus FF alone (ratio of geometric least squares means: 0.79; 90% confidence interval: 0.75‐0.83). After repeat dosing, FF AUC at the lower therapeutic dosage was similar for BAT/FF and FF (primary endpoint; AUC geometric least squares means: 1.03). Adverse events were minor, the most common being cough. These data support the feasibility of developing BAT/inhaled corticosteroid triple therapy in a single inhaler.

While recent efforts to analyse resistance to post-conflict interventions have led to important insights into the nature of contemporary peacebuilding efforts, their failure to adequately problematize the concept of resistance itself and to adapt it to the specific realities of post-conflict neoliberalism has proven to be problematic. This article explores the internal tensions and inconsistencies that define the concept of resistance in post-conflict environments, focusing specifically on five topics: the interaction of structure and agency; the presence of intent; the role of power; the nature of markets; and the possibility of emancipation. Key problems are highlighted, and, where possible, potential solutions are proposed. The issues raised by this article demand immediate attention if the conceptual viability and analytical value of resistance are to be maintained in post-conflict contexts.

Human radiolabel studies are traditionally conducted to provide a definitive understanding of the human absorption, distribution, metabolism and excretion (ADME) properties of a drug. However, advances in technology over the past decade have allowed alternative methods to be employed to obtain both clinical ADME and pharmacokinetic (PK) information. These include microdose and microtracer approaches using accelerator mass spectrometry, and the identification and quantification of metabolites in samples from classical human PK studies using technologies suitable for non-radiolabelled drug molecules, namely liquid chromatography-mass spectrometry and nuclear magnetic resonance spectroscopy. These recently developed approaches are described here together with relevant examples primarily from experiences gained in support of drug development projects at GlaxoSmithKline. The advantages of these study designs together with their limitations are described. We also discuss special considerations which should be made for a successful outcome to these new approaches and also to the more traditional human radiolabel study in order to maximize knowledge around the human ADME properties of drug molecules.

Aims The aim of this phase 1, single centre, open label study in four patients with solid tumours was to determine the absolute bioavailability of a 2 mg oral dose of trametinib. Trametinib is an orally bioavailable, reversible and selective allosteric inhibitor of MEK1 and MEK2 activation and kinase activity. Methods A microtracer study approach, in which a 5 μg radiolabelled i.v. microdose of trametinib was given concomitantly with an unlabelled 2 mg oral tablet formulation, was used to recover i.v. and oral pharmacokinetic parameters, simultaneously. Results The least-squares mean (90% confidence interval) absolute bioavailability of trametinib (2 mg tablet) was 72.3% (50.0%, 104.6%). Median tmax after oral administration was 1.5 h and the geometric mean terminal half-life was 11 days. The geometric mean clearance and volume of distribution after i.v. administration were 3.21 l h−1 and 976 l, respectively, resulting in a terminal elimination half-life of 11 days. Conclusions Trametinib absolute bioavailability was moderate to high, whereas first pass metabolism was low.

Dabrafenib is an orally bioavailable, potent, and selective inhibitor of human wild-type BRAF and CRAF kinases as well as mutant forms of BRAF kinase. The aim of this phase 1, single-center, open-label study in four patients with BRAF mutation-positive solid tumors was to determine the absolute bioavailability of a 150 mg oral dose of dabrafenib. A microtracer study approach, in which a 50 µg radiolabeled intravenous (IV) microdose of dabrafenib was given concomitantly with a 150 mg oral dose, was used to simultaneously recover IV and oral pharmacokinetic parameters. The least squares mean (90% CI) absolute bioavailability of dabrafenib (HPMC capsules) was 94.5% (81.3%, 109.7%). Median T(max) after oral administration was 2.0 hours and the geometric mean terminal half-life was 4.8 hours. The geometric mean clearance and volume of distribution after IV administration were 12.0 L/h and 45.5 L, respectively. Human clearance and volume of distribution at steady state were in agreement with predictions made using allometric scaling of pharmacokinetic parameters from four preclinical species. In conclusion, dabrafenib absolute bioavailability was high, whereas first-pass metabolism was low. Furthermore, the microtracer approach provided an innovative and efficient method for assessing the absolute bioavailability of dabrafenib in patients with advanced cancer.

National Electrostatics Corporation (NEC), Massachusetts Institute of Technology (MIT), and GlaxoSmithKline (GSK) collectively have been developing an interface to introduce CO2 produced by the laser combustion of liquid chromatograph eluate deposited on a CuO substrate directly into the ion source of an AMS system, thereby bypassing the customary graphitization process. The Automated Laser Gas Interface (ALGI) converts dried liquid samples to CO2 gas quickly and efficiently, allowing 96 samples to be measured in as little as 16 h. 14C:12C ratios stabilize typically within 2 min of analysis time per sample. Presented is the recent progress of NEC’s ALGI, a stand-alone accessory to an NEC gas-enabled multi-cathode source of negative ions by Cs sputtering (MC-SNICS) ion source.