Halogenated indole-3-acetic acids as oxidatively activated prodrugs with potential for targeted cancer therapy

Peer reviewe

Resilience in the face of uncertainty: early lessons from the COVID- 19 pandemic

The transboundary dynamics of COVID-19 present an unprecedented test of organisational resilience. In the UK, the National Health Service (NHS), a talisman of collective fortitude against disease and illness, has struggled to cope with inadequate provision of virus tests, ventilators, and personal protective equipment needed to fight the pandemic. In this paper, we reflect on the historic dynamics and strategic priorities that have undermined the NHS’s attempts to navigate these troubled times. We invoke the organisational resilience literature to address ‘the good, the bad and the ugly’ of preparedness in readiness and response to the current pandemic. In particular, we draw on Meyer’s (1982) seminal work on ‘adaptation to jolts’, excavating current preparedness failings. We argue an overreliance on perceived efficiency benefits of ‘lean production’ and ‘just in time’ continuity planning superseded strategic redundancy and slack in the system. This strategic focus was not simply the result of a failure in foresight, but rather a failure to act adaptively on knowledge of the known threats and weaknesses spotlighted by earlier projections of an inevitable pandemic threat. In conclusion, we consider how the UK Government and NHS must now undergo a phase of ‘readjustment’ in Meyer’s terms, in light of these failings. We suggest that independent responsibility for national future preparedness should be handed to the NHS free from political interference. This would operate under the umbrella of a national emergency preparedness, resilience and response public body, enshrined in law, and similar in governance to the current Bank of England. This will help ensure that foresight is accompanied by durability and fortitude in safeguarding the UK against future pandemic threats

Validity of self-reported smoking status: comparison of patients admitted to hospital with acute coronary syndrome and the general population

Many studies rely on self-reported smoking status. We hypothesized that patients with acute coronary syndrome (ACS), a smoking-related condition, would be more prone to misclassify themselves as ex-smokers, because of pressure to quit. We compared patients admitted with ACS with a general population survey conducted in the same country at a similar time. We determined whether ACS patients who classified themselves as ex-smokers (n = 635) were more likely to have cotinine levels suggestive of smoking deception than self-reported ex-smokers in the general population (n = 289). On univariate analysis, the percentage of smoking deceivers was similar among ACS patients and the general population (11% vs. 12%, p = .530). Following adjustment for age, sex and exposure to environmental tobacco smoke, ACS patients were significantly more likely to misclassify themselves (adjusted OR = 14.06, 95% CI 2.13-93.01, p = .006). There was an interaction with age whereby the probability of misclassification fell significantly with increasing age in the ACS group (adjusted OR = 0.95, 95% CI 0.93-0.97, p<.001), but not in the general population. Overall, smoking deception was more common among ACS patients than the general population. Studies comparing patients with cardiovascular disease and healthy individuals risk introducing bias if they rely solely on self-reported smoking status. Biochemical confirmation should be undertaken in such studies

Ceftazidime-avibactam or best available therapy in patients with ceftazidime-resistant Enterobacteriaceae and Pseudomonas aeruginosa complicated urinary tract infections or complicated intra-abdominal infections (REPRISE): a randomised, pathogen-directed, phase 3 study

Background Carbapenems are frequently the last line of defence in serious infections due to multidrug-resistant Gram-negative bacteria, but their use is threatened by the growing prevalence of carbapenemase-producing pathogens. Ceftazidime-avibactam is a potential new agent for use in such infections. We aimed to assess the efficacy, safety, and tolerability of ceftazidime-avibactam compared with best available therapy in patients with complicated urinary tract infection or complicated intra-abdominal infection due to ceftazidime-resistant Gram-negative pathogens. Methods REPRISE was a pathogen-directed, international, randomised, open-label, phase 3 trial that recruited patients from hospitals across 16 countries worldwide. Eligible patients were aged 18–90 years with complicated urinary tract infection or complicated intra-abdominal infection caused by ceftazidime-resistant Enterobacteriaceae or Pseudomonas aeruginosa. Patients were randomised (1:1) to 5–21 days of treatment with either ceftazidime-avibactam (a combination of 2000 mg ceftazidime plus 500 mg avibactam, administered via a 2-h intravenous infusion every 8 h) or best available therapy. The primary endpoint was clinical response at the test-of-cure visit, 7–10 days after last infusion of study therapy, analysed in all patients who had at least one ceftazidime-resistant Gram-negative pathogen, as confirmed by the central laboratory, and who received at least one dose of study drug. Safety endpoints were assessed in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01644643. Findings Between Jan 7, 2013, and Aug 29, 2014, 333 patients were randomly assigned, 165 to ceftazidime-avibactam and 168 to best available therapy. Of these, 154 assigned to ceftazidime-avibactam (144 with complicated urinary tract infection and ten with complicated intra-abdominal infection) and 148 assigned to best available therapy (137 with complicated urinary tract infection and 11 with complicated intra-abdominal infection) were analysed for the primary outcome. 163 (97%) of 168 patients in the best available therapy group received a carbapenem, 161 (96%) as monotherapy. The overall proportions of patients with a clinical cure at the test-of-cure visit were similar with ceftazidime-avibactam (140 [91%; 95% CI 85·6–94·7] of 154 patients) and best available therapy (135 [91%; 85·9–95·0] of 148 patients). 51 (31%) of 164 patients in the ceftazidime-avibactam group and 66 (39%) of 168 in the best available therapy group had an adverse event, most of which were mild or moderate in intensity. Gastrointestinal disorders were the most frequently reported treatment-emergent adverse events with both ceftazidime-avibactam (21 [13%] of 164 patients) and best available therapy (30 [18%] of 168 patients). No new safety concerns were identified for ceftazidime-avibactam. Interpretation These results provide evidence of the efficacy of ceftazidime-avibactam as a potential alternative to carbapenems in patients with ceftazidime-resistant Enterobacteriaceae and P aeruginosa. Funding AstraZeneca

The income elasticity of the value of travel time savings: A meta-analysis

The value of travel time savings (VTTS) is an important concept used in cost-benefit analyses for project appraisals and demand modelling in the transport sector. The relationship between the VTTS and income is particularly important since it underpins how official VTTS recommendations are uplifted over time as incomes grow. The income elasticity of VTTS has been investigated in many empirical studies, exhibiting considerable variation across them. Notably, repeat studies tend to find the lowest implied income effects and meta-analyses the largest income elasticities, with those obtained from cross-sectional inter-personal comparisons somewhere between. This paper aims to explain the VTTS variation in terms of an individual's or household's income level by using the meta-analysis technique. The analysis covers 268 income elasticities of the VTTS extracted from 49 studies conducted from 1968 to 2019 in countries across the globe. The meta-analysis method determines the factors that influence these income elasticity variations. The results of the meta-model highlight that the variation of the income elasticity is explained by several factors, including income levels, the transport mode, personal or household income, inter-temporal or cross-sectional elasticity, journey purpose and year of the survey, shedding light on how the VTTS income elasticity varies across different sources

Introducing willingness-to-pay for noise changes into transport appraisal: an application of benefit transfer.

Numerous research studies have elicited willingness-to-pay values for transport-related noise, however, in many industrialised countries including the UK, noise costs and benefits are still not incorporated into appraisals for most transport projects and policy changes (Odgaard et al, 2005; Grant-Muller et al, 2001). This paper describes the actions recently taken in the UK to address this issue, comprising: primary research based on the city of Birmingham; an international review of willingness-to-pay evidence; development of values using benefit transfers over time and locations; and integration with appraisal methods. Amongst the main findings are: that the willingness-to-pay estimates derived for the UK are broadly comparable with those used in appraisal elsewhere in Europe; that there is a case for a lower threshold at 1 45dB(A)Leq,18hr1 rather than the more conventional 55dB(A); and that values per dB(A) increase with the noise level above this threshold. There are significant issues over the valuation of rail versus road noise, the neglect of non-residential noise and the valuation of high noise levels in different countries. Conclusions are drawn regarding the feasibility of noise valuation based on benefit transfers in the UK and elsewhere, and future research needs in this field are discussed

Extension of Yeast Chronological Lifespan by Methylamine

Background: Chronological aging of yeast cells is commonly used as a model for aging of human post-mitotic cells. The yeast Saccharomyces cerevisiae grown on glucose in the presence of ammonium sulphate is mainly used in yeast aging research. We have analyzed chronological aging of the yeast Hansenula polymorpha grown at conditions that require primary peroxisome metabolism for growth. Methodology/Principal Findings: The chronological lifespan of H. polymorpha is strongly enhanced when cells are grown on methanol or ethanol, metabolized by peroxisome enzymes, relative to growth on glucose that does not require peroxisomes. The short lifespan of H. polymorpha on glucose is mainly due to medium acidification, whereas most likely ROS do not play an important role. Growth of cells on methanol/methylamine instead of methanol/ammonium sulphate resulted in further lifespan enhancement. This was unrelated to medium acidification. We show that oxidation of methylamine by peroxisomal amine oxidase at carbon starvation conditions is responsible for lifespan extension. The methylamine oxidation product formaldehyde is further oxidized resulting in NADH generation, which contributes to increased ATP generation and reduction of ROS levels in the stationary phase. Conclusion/Significance: We conclude that primary peroxisome metabolism enhanced chronological lifespan of H. polymorpha. Moreover, the possibility to generate NADH at carbon starvation conditions by an organic nitrogen source supports further extension of the lifespan of the cell. Consequently, the interpretation of CLS analyses in yeast should include possible effects on the energy status of the cell.

The transformation of transport policy in Great Britain? 'New Realism' and New Labour's decade of displacement activity

In a 1999 paper, Goodwin announced ‘the transformation of transport policy in Great Britain’. His central point was that consensus was emerging among policy makers and academics based on earlier work including Transport: The New Realism, which rejected previous orthodoxy that the supply of road space could and should be continually expanded to match demand. Instead a combination of investment in public transport, walking and cycling opportunities and – crucially – demand management should form the basis of transport policy to address rising vehicle use and associated increases in congestion and pollution / carbon emissions. This thinking formed the basis of the 1997 Labour government’s ‘sustainable transport’ policy, but after 13 years in power ministers neither transformed policy nor tackled longstanding transport trends. Our main aim in this paper is to revisit the concept of New Realism and re-examine its potential utility as an agent of change in British transport policy. Notwithstanding the outcome of Labour’s approach to transport policy, we find that the central tenets of the New Realism remain robust and that the main barriers to change are related to broader political and governance issues which suppress radical policy innovation