PD-L1 testing for lung cancer in the UK: recognizing the challenges for implementation.

A new approach to the management of non-small-cell lung cancer (NSCLC) has recently emerged that works by manipulating the immune checkpoint controlled by programmed death receptor 1 (PD-1) and its ligand programmed death ligand 1 (PD-L1). Several drugs targeting PD-1 (pembrolizumab and nivolumab) or PD-L1 (atezolizumab, durvalumab, and avelumab) have been approved or are in the late stages of development. Inevitably, the introduction of these drugs will put pressure on healthcare systems, and there is a need to stratify patients to identify those who are most likely to benefit from such treatment. There is evidence that responsiveness to PD-1 inhibitors may be predicted by expression of PD-L1 on neoplastic cells. Hence, there is considerable interest in using PD-L1 immunohistochemical staining to guide the use of PD-1-targeted treatments in patients with NSCLC. This article reviews the current knowledge about PD-L1 testing, and identifies current research requirements. Key factors to consider include the source and timing of sample collection, pre-analytical steps (sample tracking, fixation, tissue processing, sectioning, and tissue prioritization), analytical decisions (choice of biomarker assay/kit and automated staining platform, with verification of standardized assays or validation of laboratory-devised techniques, internal and external quality assurance, and audit), and reporting and interpretation of the results. This review addresses the need for integration of PD-L1 immunohistochemistry with other tests as part of locally agreed pathways and protocols. There remain areas of uncertainty, and guidance should be updated regularly as new information becomes available

Role of Flares and Shocks in Determining Solar Energetic Particle Abundances

We examine solar energetic particle (SEP) event-averaged abundances of Fe relative to O and intensity versus time profiles at energies above 25 MeV/nucleon using the SIS instrument on ACE. These data are compared with solar wind conditions during each event and with estimates of the strength of the associated shock based on average travel times to 1 AU. We find that the majority of events with an Fe to O abundance ratio greater than two times the average 5–12 MeV/nuc value for large SEP events (0.134) occur in the western hemisphere. Furthermore, in most of these Fe-rich events the profiles peak within 12 hours of the associated flare, suggesting that some of the observed interplanetary particles are accelerated in these flares. The vast majority of events with Fe/O below 0.134 are influenced by interplanetary shock acceleration. We suggest that variations in elemental composition in SEP events mainly arise from the combination of flare particles and shock acceleration of these particles and/or the ambient medium

The Roles of Flares and Shocks in determining SEP Abundances

We examine solar energetic particle (SEP) event-averaged abundances of Fe relative to O and intensity versus time profiles at energies above 25 MeV/nucleon using the SIS instrument on ACE. These data are compared with solar wind conditions during each event and with estimates of the strength of the associated shock based on average travel times to 1 AU. We find that the majority of events with an Fe to 0 abundance ratio greater than two times the average 5-12 MeV/nuc value for large SEP events (0.134) occur in the western hemisphere. Furthermore, in most of these Fe-rich events the profiles peak within 12 hours of the associated flare, suggesting that some of the observed interplanetary particles are accelerated in these flares. The vast majority of events with Fe/O below 0.134 are influenced by interplanetary shock acceleration. We suggest that variations in elemental composition in SEP events mainly arise from the combination of flare particles and shock acceleration of these particles and/or the ambient medium

Vaccine induced herd immunity for control of respiratory syncytial virus disease in a low-income country setting

Background: Respiratory syncytial virus (RSV) is globally ubiquitous, and infection during the first six months of life is a major risk for severe disease and hospital admission; consequently RSV is the most important viral cause of respiratory morbidity and mortality in young children. Development of vaccines for young infants is complicated by the presence of maternal antibodies and immunological immaturity, but vaccines targeted at older children avoid these problems. Vaccine development for young infants has been unsuccessful, but this is not the case for older children (> 6m). Would vaccinating older children have a significant public health impact? We developed a mathematical model to explore the benefits of a vaccine against RSV. Methods and Findings: We have used a deterministic age structured model capturing the key epidemiological characteristics of RSV and performed a statistical maximum-likelihood fit to age-specific hospitalization data from a developing country setting. To explore the effects of vaccination under different mixing assumptions, we included two versions of contact matrices: one from a social contact diary study, and the second a synthesised construction based on demographic data. Vaccination is assumed to elicit an immune response equivalent to primary infection. Our results show that immunisation of young children (5–10m) is likely to be a highly effective method of protection of infants (<6m) against hospitalisation. The majority benefit is derived from indirect protection (herd immunity). A full sensitivity and uncertainty analysis using Latin Hypercube Sampling of the parameter space shows that our results are robust to model structure and model parameters. Conclusions: This result suggests that vaccinating older infants and children against RSV can have a major public health benefit

Near-earth cosmic ray decreases associated with remote coronal mass ejections

Galactic cosmic ray (GCR) flux is modulated by both particle drift patterns and solar wind structures on a range of timescales. Over solar cycles, GCR flux varies as a function of the total open solar magnetic flux and the latitudinal extent of the heliospheric current sheet. Over hours, drops of a few percent in near-Earth GCR flux (Forbush decreases, FDs) are well known to be associated with the near-Earth passage of solar wind structures resulting from corotating interaction regions (CIRs) and transient coronal mass ejections (CMEs). We report on four FDs seen at ground-based neutron monitors which cannot be immediately associated with significant structures in the local solar wind. Similarly, there are significant near-Earth structures which do not produce any corresponding GCR variation. Three of the FDs are during the STEREO era, enabling in situ and remote observations from three well-separated heliospheric locations. Extremely large CMEs passed the STEREO-A spacecraft, which was behind the West limb of the Sun, approximately 2–3 days before each near- Earth FD. Solar wind simulations suggest that the CMEs combined with pre-existing CIRs, enhancing the pre-existing barriers to GCR propagation. Thus these observations provide strong evidence for the modulation of GCR flux by remote solar wind structures

Exploring the behavioural drivers of veterinary surgeon antibiotic prescribing: a qualitative study of companion animal veterinary surgeons in the UK

Background: Multi-drug resistant bacteria are an increasing concern in both human and veterinary medicine. Inappropriate prescribing and use of antibiotics within veterinary medicine may be a contributory factor to antimicrobial resistance (AMR). The ‘One Health’ Initiative aims to work across species and environments to reduce AMR, however; little is currently known about the factors which influence antibiotic prescribing among veterinary surgeons in companion animal practice. This paper reports on qualitative data analysis of interviews with veterinary surgeons whose practice partially or wholly focuses on companion animals (N = 16). The objective of the research was to explore the drivers of companion animal veterinary surgeons’ antibiotic prescribing behaviours. The veterinary surgeons interviewed were all practising within the UK (England (n = 4), Scotland (n = 11), Northern Ireland (n = 1)). A behavioural thematic analysis of the data was undertaken, which identified barriers and facilitators to specific prescribing-related behaviours. Results: Five components of prescribing behaviours were identified: 1) confirming clinical need for antibiotics; 2) responding to clients; 3) confirming diagnosis; 4) determining dose, duration and type of antibiotic; and 5) preventing infection around surgery (with attendant appropriate and inappropriate antibiotic prescribing behaviours). Barriers to appropriate prescribing identified include: business, diagnostic, fear, habitual practice and pharmaceutical factors. Facilitators include: AMR awareness, infection prevention, professional learning and regulation and government factors. Conclusion: This paper uses a behavioural lens to examine drivers which are an influence on veterinary surgeons’ prescribing behaviours. The paper contributes new understandings about factors which influence antibiotic prescribing behaviours among companion animal veterinary surgeons. This analysis provides evidence to inform future interventions, which are focused on changing prescribing behaviours, in order to address the pressing public health concern of AMR

The Longitudinal Distribution of Solar Energetic Particles

Using observations from the High Energy Telescopes (HETs) on STEREO A and B and similar observations from SoHO, near-Earth, we have identified ~250 individual solar energetic particle events that include >14 MeV protons since the beginning of the STEREO mission [1]. Between the end of December 2009, when the STEREO A and B spacecraft were, respectively, ahead and behind Earth by ~ 65° in ecliptic longitude, and the end of December 2013, 43 different events were clearly detected at all three locations. The observed intensities of such an event are usually assumed to be Gaussian distributed as a function of the longitudes of the Parker Spiral footpoints at the Sun for each observer. This neglects the fact that the interplanetary magnetic field may have large deviations from Parker Spirals, e.g. due to coronal mass ejections from prior events. Nonetheless, we have fit Gaussians to the peak intensities observed simultaneously at three spacecraft for all 43 events. The Gaussian peak intensity is poorly correlated with the corresponding CME speed and the FWHM is uncorrelated with the CME speed. Surprisingly, however, there appear to be distinctly non-random variations of the FWHM values from event to event

Does body size predict the buzz-pollination frequencies used by bees?

Body size is an important trait linking pollinators and plants. Morphological matching between pollinators and plants is thought to reinforce pollinator fidelity, as the correct fit ensures that both parties benefit from the interaction. We investigated the influence of body size in a specialized pollination system (buzz‐pollination) where bees vibrate flowers to release pollen concealed within poricidal stamens. Specifically, we explored how body size influences the frequency of buzz‐pollination vibrations. Body size is expected to affect frequency as a result of the physical constraints it places on the indirect flight muscles that control the production of floral vibrations. Larger insects beat their wings less rapidly than smaller‐bodied insects when flying, but whether similar scaling relationships exist with floral vibrations has not been widely explored. This is important because the amount of pollen ejected is determined by the frequency of the vibration and the displacement of a bee's thorax. We conducted a field study in three ecogeographic regions (alpine, desert, grassland) and recorded flight and floral vibrations from freely foraging bees from 27 species across four families. We found that floral vibration frequencies were significantly higher than flight frequencies, but never exceeded 400 Hz. Also, only flight frequencies were negatively correlated with body size. As a bee's size increased, its buzz ratio (floral frequency/flight frequency) increased such that only the largest bees were capable of generating floral vibration frequencies that exceeded double that of their flight vibrations. These results indicate size affects the capacity of bees to raise floral vibration frequencies substantially above flight frequencies. This may put smaller bees at a competitive disadvantage because even at the maximum floral vibration frequency of 400 Hz, their inability to achieve comparable thoracic displacements as larger bees would result in generating vibrations with lower amplitudes, and thus less total pollen ejected for the same foraging effort