Antimicrobial resistance: a biopsychosocial problem requiring innovative interdisciplinary and imaginative interventions

To date, antimicrobials have been understood through largely biomedical perspectives. There has been a tendency to focus upon the effectiveness of pharmaceuticals within individual bodies. However, the growing threat of antimicrobial resistance demands we reconsider how we think about antimicrobials and their effects. Rather than understanding them primarily within bodies, it is increasingly important to consider their effects between bodies, between species and across environments. We need to reduce the drivers of antimicrobial resistance (AMR) at a global level, focusing on the connections between prescribing in one country and resistance mechanisms in another. We need to engage with the ways antimicrobials within the food chain will impact upon human healthcare. Moreover, we need to realise what happens within the ward will impact upon the environment (through waste water). In the future, imaginative interventions will be required that must make the most of biomedicine but draw equally across a wider range of disciplines (e.g. engineering, ecologists) and include an ever-increasing set of professionals (e.g. nurses, veterinarians and farmers). Such collective action demands a shift to working in new interdisciplinary, inter-professional ways. Mutual respect and understanding is required to enable each perspective to be combined to yield synergistic effects

Low cost, low tech SNP genotyping tools for resource-limited areas: Plague in Madagascar as a model

Genetic analysis of pathogenic organisms is a useful tool for linking human cases together and/or to potential environmental sources. The resulting data can also provide information on evolutionary patterns within a targeted species and phenotypic traits. However, the instruments often used to generate genotyping data, such as single nucleotide polymorphisms (SNPs), can be expensive and sometimes require advanced technologies to implement. This places many genotyping tools out of reach for laboratories that do not specialize in genetic studies and/or lack the requisite financial and technological resources. To address this issue, we developed a low cost and low tech genotyping system, termed agarose-MAMA, which combines traditional PCR and agarose gel electrophoresis to target phylogenetically informative SNPs

Generalized Ricci Curvature Bounds for Three Dimensional Contact Subriemannian manifolds

Measure contraction property is one of the possible generalizations of Ricci curvature bound to more general metric measure spaces. In this paper, we discover sufficient conditions for a three dimensional contact subriemannian manifold to satisfy this property.Comment: 49 page

Subprocess Size in Hard Exclusive Scattering

The interaction region of hard exclusive hadron scattering can have a large transverse size due to endpoint contributions, where one parton carries most of the hadron momentum. The endpoint region is enhanced and can dominate in processes involving multiple scattering and quark helicity flip. The endpoint Fock states have perturbatively short lifetimes and scatter softly in the target. We give plausible arguments that endpoint contributions can explain the apparent absence of color transparency in fixed angle exclusive scattering and the dimensional scaling of transverse rho photoproduction at high momentum transfer, which requires quark helicity flip. We also present a quantitative estimate of Sudakov effects.Comment: 16 pages, 4 figures, JHEP style; v2: quantitative estimate of Sudakov effects and more detailed discussion of endpoint behaviour of meson distribution amplitude added, few other clarifications, version to appear in Phys. Rev.

Corneal ulcerative disease in dogs under primary veterinary care in England: epidemiology and clinical management

Abstract Background Corneal ulcerative disease (CUD) has the potential to adversely affect animal welfare by interfering with vision and causing pain. The study aimed to investigate for the first time the prevalence, breed-based risk factors and clinical management of CUD in the general population of dogs under primary veterinary care in England. Results Of 104,233 dogs attending 110 clinics participating within the VetCompass Programme from January 1st to December 31st 2013, there were 834 confirmed CUD cases (prevalence: 0.80%, 95% confidence interval (CI) 0.75–0.86). Breeds with the highest prevalence included Pug (5.42% of the breed affected), Boxer (4.98%), Shih Tzu (3.45%), Cavalier King Charles Spaniel (2.49%) and Bulldog (2.41%). Purebred dogs had 2.23 times the odds (95% CI 1.84–2.87, P < 0.001) of CUD compared with crossbreds. Brachycephalic types had 11.18 (95% CI 8.72–14.32, P < 0.001) and spaniel types had 3.13 (95% CI 2.38–4.12, P < 0.001) times the odds for CUD compared with crossbreds. Pain was recorded in 385 (46.2%) cases and analgesia was used in 455 (54.6%) of dogs. Overall, 62 (7.4%) cases were referred for advanced management and CUD contributed to the euthanasia decision for 10 dogs. Conclusions Breeds such as the Pug and Boxer, and conformational types such as brachycephalic and spaniels, demonstrated predisposition to CUD in the general canine population. These results suggest that breeding focus on periocular conformation in predisposed breeds should be considered in order to reduce corneal disease

Multiwavelength Monitoring of the Dwarf Seyfert 1 Galaxy NGC 4395. II. X-ray and Ultraviolet Continuum Variability

We report on two Chandra observations, and a simultaneous Hubble Space Telescope ultraviolet observation, of the dwarf Seyfert 1 galaxy NGC 4395. Each Chandra observation had a duration of ~30 ks, with a separation of ~50 ks. The spectrum was observed to harden between these observations via a scaling down of the soft-band flux. The inter-observation variability is in a different sense to the observed variability within each observation and is most likely the result of increased absorption. Spectral variations were seen during the first observation suggesting that the X-ray emission is produced in more than one disconnected region. We have also re-analyzed a ~17 ks Chandra observation conducted in 2000. During the three Chandra observations the 2-10 keV flux is about a factor of 2 lower than seen during an XMM-Newton observation conducted in 2003. Moreover, the fractional variability amplitude exhibited during the XMM-Newton observation is significantly softer than seen during the Chandra observations. A power-spectral analysis of the first of the two new Chandra observations revealed a peak at 341s with a formal detection significance of 99%. A similar peak was seen previously in the 2000 Chandra data. However, the detection of this feature is tentative given that it was found in neither the second of our two new Chandra observations nor the XMM-Newton data, and it is much narrower than expected. The Hubble Space Telescope observation was conducted during part of the second Chandra visit. A zero-lag correlation between the ultraviolet and X-ray fluxes was detected with a significance of about 99.5%, consistent with the predictions of the two-phase model for the X-ray emission from active galactic nuclei.Comment: 31 pages, 10 figures, accepted for publication in Ap

Cognitive dysfunction in naturally occurring canine idiopathic epilepsy

Globally, epilepsy is a common serious brain disorder. In addition to seizure activity, epilepsy is associated with cognitive impairments including static cognitive impairments present at onset, progressive seizure-induced impairments and co-morbid dementia. Epilepsy occurs naturally in domestic dogs but its impact on canine cognition has yet to be studied, despite canine cognitive dysfunction (CCD) recognised as a spontaneous model of dementia. Here we use data from a psychometrically validated tool, the canine cognitive dysfunction rating (CCDR) scale, to compare cognitive dysfunction in dogs diagnosed with idiopathic epilepsy (IE) with controls while accounting for age. An online cross-sectional study resulted in a sample of 4051 dogs, of which n = 286 had been diagnosed with IE. Four factors were significantly associated with a diagnosis of CCD (above the diagnostic cut-off of CCDR ≥50): (i) epilepsy diagnosis: dogs with epilepsy were at higher risk; (ii) age: older dogs were at higher risk; (iii) weight: lighter dogs (kg) were at higher risk; (iv) training history: dogs with more exposure to training activities were at lower risk. Impairments in memory were most common in dogs with IE, but progression of impairments was not observed compared to controls. A significant interaction between epilepsy and age was identified, with IE dogs exhibiting a higher risk of CCD at a young age, while control dogs followed the expected pattern of low-risk throughout middle age, with risk increasing exponentially in geriatric years. Within the IE sub-population, dogs with a history of cluster seizures and high seizure frequency had higher CCDR scores. The age of onset, nature and progression of cognitive impairment in the current IE dogs appear divergent from those classically seen in CCD. Longitudinal monitoring of cognitive function from seizure onset is required to further characterise these impairments

Examination of the Cytotoxic and Embryotoxic Potential and Underlying Mechanisms of Next-Generation Synthetic Trioxolane and Tetraoxane Antimalarials

Semisynthetic artemisinin-based therapies are the first-line treatment for P. falciparum malaria, but next-generation synthetic drug candidates are urgently required to improve availability and respond to the emergence of artemisinin-resistant parasites. Artemisinins are embryotoxic in animal models and induce apoptosis in sensitive mammalian cells. Understanding the cytotoxic propensities of antimalarial drug candidates is crucial to their successful development and utilization. Here, we demonstrate that, similarly to the model artemisinin artesunate (ARS), a synthetic tetraoxane drug candidate (RKA182) and a trioxolane equivalent (FBEG100) induce embryotoxicity and depletion of primitive erythroblasts in a rodent model. We also show that RKA182, FBEG100 and ARS are cytotoxic toward a panel of established and primary human cell lines, with caspase-dependent apoptosis and caspase-independent necrosis underlying the induction of cell death. Although the toxic effects of RKA182 and FBEG100 proceed more rapidly and are relatively less cell-selective than that of ARS, all three compounds are shown to be dependent upon heme, iron and oxidative stress for their ability to induce cell death. However, in contrast to previously studied artemisinins, the toxicity of RKA182 and FBEG100 is shown to be independent of general chemical decomposition. Although tetraoxanes and trioxolanes have shown promise as next-generation antimalarials, the data described here indicate that adverse effects associated with artemisinins, including embryotoxicity, cannot be ruled out with these novel compounds, and a full understanding of their toxicological actions will be central to the continuing design and development of safe and effective drug candidates which could prove important in the fight against malaria

Assessing the ecological impacts of invasive species based on their functional responses and abundances

Invasive species management requires allocation of limited resources towards the proactive mitigation of those species that could elicit the highest ecological impacts. However, we lack predictive capacity with respect to the identities and degree of ecological impacts of invasive species. Here, we combine the relative per capita effects and relative field abundances of invader as compared to native species into a new metric, “Relative Impact Potential” (RIP), and test whether this metric can reliably predict high impact invaders. This metric tests the impact of invaders relative to the baseline impacts of natives on the broader ecological community. We first derived the functional responses (i.e. per capita effects) of two ecologically damaging invasive fish species in Europe, the Ponto-Caspian round goby (Neogobius melanostomus) and Asian topmouth gudgeon (Pseudorasbora parva), and their native trophic analogues, the bullhead (Cottus gobio; also C. bairdi) and bitterling (Rhodeus amarus), towards several prey species. This establishes the existence and relative strengths of the predator-prey relationships. Then, we derived ecologically comparable field abundance estimates of the invader and native fish from surveys and literature. This establishes the multipliers for the above per capita effects. Despite both predators having known severe detrimental field impacts, their functional responses alone were of modest predictive power in this regard; however, incorporation of their abundances relative to natives into the RIP metric gave high predictive power. We present invader/native RIP biplots that provide an intuitive visualisation of comparisons among the invasive and native species, reflecting the known broad ecological impacts of the invaders. Thus, we provide a mechanistic understanding of invasive species impacts and a predictive tool for use by practitioners, for example, in risk assessments

Differential modes of DNA binding by mismatch uracil DNA glycosylase from Escherichia coli: implications for abasic lesion processing and enzyme communication in the base excision repair pathway

Mismatch uracil DNA glycosylase (Mug) from Escherichia coli is an initiating enzyme in the base-excision repair pathway. As with other DNA glycosylases, the abasic product is potentially more harmful than the initial lesion. Since Mug is known to bind its product tightly, inhibiting enzyme turnover, understanding how Mug binds DNA is of significance when considering how Mug interacts with downstream enzymes in the base-excision repair pathway. We have demonstrated differential binding modes of Mug between its substrate and abasic DNA product using both band shift and fluorescence anisotropy assays. Mug binds its product cooperatively, and a stoichiometric analysis of DNA binding, catalytic activity and salt-dependence indicates that dimer formation is of functional significance in both catalytic activity and product binding. This is the first report of cooperativity in the uracil DNA glycosylase superfamily of enzymes, and forms the basis of product inhibition in Mug. It therefore provides a new perspective on abasic site protection and the findings are discussed in the context of downstream lesion processing and enzyme communication in the base excision repair pathway