Consensus-based antimicrobial resistance and stewardship competencies for UK undergraduate medical students.

BACKGROUND: In the UK there is limited coverage of antimicrobial stewardship across postgraduate curricula and evidence that final year medical students have insufficient and inconsistent antimicrobial stewardship teaching. A national undergraduate curriculum for antimicrobial resistance and stewardship is required to standardize an adequate level of understanding for all future doctors. OBJECTIVES: To provide a UK national consensus on competencies for antimicrobial resistance and stewardship for undergraduate medical education. METHODS: Using the modified Delphi method over two online survey rounds, an expert panel comprising leads for infection teaching from 25 UK medical schools reviewed competency descriptors for antimicrobial resistance and stewardship education. RESULTS: There was a response rate of 100% with all 28 experts who agreed to take part completing both survey rounds. Following the first-round survey, of the initial 55 descriptors, 43 reached consensus (78%). The second-round survey included the 12 descriptors from the first round in which agreement had not been reached, four amended descriptors and 12 new descriptors following qualitative feedback from the panel members. Following the second-round survey, a total of 58 consensus-based competency descriptors within six overarching domains were identified. CONCLUSIONS: The consensus-based competency descriptors defined here can be used to inform standards, design curricula, develop assessment tools and direct UK undergraduate medical education

Frequency of extreme Sahelian storms tripled since 1982 in satellite observations

The hydrological cycle is expected to intensify under global warming, with studies reporting more frequent extreme rain events in many regions of the world, and predicting increases in future flood frequency. Such early, predominantly mid-latitude observations are essential because of shortcomings within climate models in their depiction of convective rainfall. A globally important group of intense storms—mesoscale convective systems (MCSs)—poses a particular challenge, because they organize dynamically on spatial scales that cannot be resolved by conventional climate models. Here, we use 35 years of satellite observations from the West African Sahel to reveal a persistent increase in the frequency of the most intense MCSs. Sahelian storms are some of the most powerful on the planet, and rain gauges in this region have recorded a rise in ‘extreme’ daily rainfall totals. We find that intense MCS frequency is only weakly related to the multidecadal recovery of Sahel annual rainfall, but is highly correlated with global land temperatures. Analysis of trends across Africa reveals that MCS intensification is limited to a narrow band south of the Sahara desert. During this period, wet-season Sahelian temperatures have not risen, ruling out the possibility that rainfall has intensified in response to locally warmer conditions. On the other hand, the meridional temperature gradient spanning the Sahel has increased in recent decades, consistent with anthropogenic forcing driving enhanced Saharan warming. We argue that Saharan warming intensifies convection within Sahelian MCSs through increased wind shear and changes to the Saharan air layer. The meridional gradient is projected to strengthen throughout the twenty-first century, suggesting that the Sahel will experience particularly marked increases in extreme rain. The remarkably rapid intensification of Sahelian MCSs since the 1980s sheds new light on the response of organized tropical convection to global warming, and challenges conventional projections made by general circulation models

Response of the North Atlantic storm track to climate change shaped by ocean–atmosphere coupling

A poleward shift of the mid-latitude storm tracks in response to anthropogenic greenhouse-gas forcing has been diagnosed in climate model simulations1, 2. Explanations of this effect have focused on atmospheric dynamics3, 4, 5, 6, 7. However, in contrast to storm tracks in other regions, the North Atlantic storm track responds by strengthening and extending farther east, in particular on its southern flank8. These adjustments are associated with an intensification and extension of the eddy-driven jet towards western Europe9 and are expected to have considerable societal impacts related to a rise in storminess in Europe10, 11, 12. Here, we apply a regression analysis to an ensemble of coupled climate model simulations to show that the coupling between ocean and atmosphere shapes the distinct storm-track response to greenhouse-gas forcing in the North Atlantic region. In the ensemble of simulations we analyse, at least half of the differences between the storm-track responses of different models are associated with uncertainties in ocean circulation changes. We compare the fully coupled simulations with both the associated slab model simulations and an ocean-forced experiment with one climate model to establish causality. We conclude that uncertainties in the response of the North Atlantic storm track to anthropogenic emissions could be reduced through tighter constraints on the future ocean circulation

Short interspersed nuclear element (SINE) sequences in the genome of the human pathogenic fungus Aspergillus fumigatus Af293.

Copyright: © 2016 The Authors. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Citation: Kanhayuwa L, Coutts RHA (2016) Short Interspersed Nuclear Element (SINE) Sequences in the Genome of the Human Pathogenic Fungus Aspergillus fumigatus Af293. PLoS ONE 11(10): e0163215. https://doi.org/10.1371/journal.pone.0163215.Novel families of short interspersed nuclear element (SINE) sequences in the human pathogenic fungus Aspergillus fumigatus, clinical isolate Af293, were identified and categorised into tRNA-related and 5S rRNA-related SINEs. Eight predicted tRNA-related SINE families originating from different tRNAs, and nominated as AfuSINE2 sequences, contained target site duplications of short direct repeat sequences (4-14 bp) flanking the elements, an extended tRNA-unrelated region and typical features of RNA polymerase III promoter sequences. The elements ranged in size from 140-493 bp and were present in low copy number in the genome and five out of eight were actively transcribed. One putative tRNAArg-derived sequence, AfuSINE2-1a possessed a unique feature of repeated trinucleotide ACT residues at its 3'-terminus. This element was similar in sequence to the I-4_AO element found in A. oryzae and an I-1_AF long nuclear interspersed element-like sequence identified in A. fumigatus Af293. Families of 5S rRNA-related SINE sequences, nominated as AfuSINE3, were also identified and their 5'-5S rRNA-related regions show 50-65% and 60-75% similarity to respectively A. fumigatus 5S rRNAs and SINE3-1_AO found in A. oryzae. A. fumigatus Af293 contains five copies of AfuSINE3 sequences ranging in size from 259-343 bp and two out of five AfuSINE3 sequences were actively transcribed. Investigations on AfuSINE distribution in the fungal genome revealed that the elements are enriched in pericentromeric and subtelomeric regions and inserted within gene-rich regions. We also demonstrated that some, but not all, AfuSINE sequences are targeted by host RNA silencing mechanisms. Finally, we demonstrated that infection of the fungus with mycoviruses had no apparent effects on SINE activity.Peer reviewedFinal Published versio

NFV, an HIV-1 protease inhibitor, induces growth arrest, reduced Akt signalling, apoptosis and docetaxel sensitisation in NSCLC cell lines

HIV-1 protease inhibitor (PI), nelfinavir (NFV) induced growth arrest and apoptosis of NCI-H460 and -H520, A549, EBC-1 and ABC-1 non-small-cell lung cancer (NSCLC) cells in association with upregulation of p21waf1, p27 kip1 and p53, and downregulation of Bcl-2 and matrix metalloproteinase (MMP)-2 proteins. We found that NFV blocked Akt signalling in these cells as measured by Akt kinase assay with glycogen synthase kinase-3α/β (GSK-3α/β) as a substrate. To explore the role of Akt signalling in NFV-mediated growth inhibition of NSCLC cells, we blocked this signal pathway by transfection of Akt small interfering RNA (siRNA) in these cells; transient transfection of Akt siRNA in NCI-H460 cells decreased the level of Bcl-2 protein and slowed their proliferation compared to the nonspecific siRNA-transfected cells. Conversely, forced-expression of Akt partially reversed NFV-mediated growth inhibition of these cells, suggesting that Akt may be a molecular target of NFV in NSCLC cells. Also, we found that inhibition of Akt signalling by NFV enhanced the ability of docetaxel to inhibit the growth of NCI-H460 and -H520 cells, as measured by MTT assay. Importantly, NFV slowed the proliferation and induced apoptosis of NCI-H460 cells present as tumour xenografts in nude mice without adverse systemic effects. Taken together, this family of compounds might be useful for the treatment of individuals with NSCLC

Frontal GABA Levels Change during Working Memory

Functional neuroimaging metrics are thought to reflect changes in neurotransmitter flux, but changes in neurotransmitter levels have not been demonstrated in humans during a cognitive task, and the relationship between neurotransmitter dynamics and hemodynamic activity during cognition has not yet been established. We evaluate the concentration of the major inhibitory (GABA) and excitatory (glutamate + glutamine: Glx) neurotransmitters and the cerebral perfusion at rest and during a prolonged delayed match-to-sample working memory task. Resting GABA levels in the dorsolateral prefrontal cortex correlated positively with the resting perfusion and inversely with the change in perfusion during the task. Further, only GABA increased significantly during the first working memory run and then decreased continuously across subsequent task runs. The decrease of GABA over time was paralleled by a trend towards decreased reaction times and higher task accuracy. These results demonstrate a link between neurotransmitter dynamics and hemodynamic activity during working memory, indicating that functional neuroimaging metrics depend on the balance of excitation and inhibition required for cognitive processing

Simulating the midlatitude atmospheric circulation: what might we gain from high-resolution modeling of air-sea interactions?

Purpose of Review. To provide a snapshot of the current research on the oceanic forcing of the atmospheric circulation in midlatitudes and a concise update on previous review papers. Recent findings. Atmospheric models used for seasonal and longer timescales predictions are starting to resolve motions so far only studied in conjunction with weather forecasts. These phenomena have horizontal scales of ~ 10–100 km which coincide with energetic scales in the ocean circulation. Evidence has been presented that, as a result of this matching of scale, oceanic forcing of the atmosphere was enhanced in models with 10–100 km grid size, especially at upper tropospheric levels. The robustness of these results and their underlying mechanisms are however unclear. Summary. Despite indications that higher resolution atmospheric models respond more strongly to sea surface temperature anomalies, their responses are still generally weaker than those estimated empirically from observations. Coarse atmospheric models (grid size greater than 100 km) will miss important signals arising from future changes in ocean circulation unless new parameterizations are developed

The importance of the cellular stress response in the pathogenesis and treatment of type 2 diabetes

Organisms have evolved to survive rigorous environments and are not prepared to thrive in a world of caloric excess and sedentary behavior. A realization that physical exercise (or lack of it) plays a pivotal role in both the pathogenesis and therapy of type 2 diabetes mellitus (t2DM) has led to the provocative concept of therapeutic exercise mimetics. A decade ago, we attempted to simulate the beneficial effects of exercise by treating t2DM patients with 3 weeks of daily hyperthermia, induced by hot tub immersion. The short-term intervention had remarkable success, with a 1 % drop in HbA1, a trend toward weight loss, and improvement in diabetic neuropathic symptoms. An explanation for the beneficial effects of exercise and hyperthermia centers upon their ability to induce the cellular stress response (the heat shock response) and restore cellular homeostasis. Impaired stress response precedes major metabolic defects associated with t2DM and may be a near seminal event in the pathogenesis of the disease, tipping the balance from health into disease. Heat shock protein inducers share metabolic pathways associated with exercise with activation of AMPK, PGC1-a, and sirtuins. Diabetic therapies that induce the stress response, whether via heat, bioactive compounds, or genetic manipulation, improve or prevent all of the morbidities and comorbidities associated with the disease. The agents reduce insulin resistance, inflammatory cytokines, visceral adiposity, and body weight while increasing mitochondrial activity, normalizing membrane structure and lipid composition, and preserving organ function. Therapies restoring the stress response can re-tip the balance from disease into health and address the multifaceted defects associated with the disease