Finding Nano-\"Otzi: Semi-Supervised Volume Visualization for Cryo-Electron Tomography

Cryo-Electron Tomography (cryo-ET) is a new 3D imaging technique with unprecedented potential for resolving submicron structural detail. Existing volume visualization methods, however, cannot cope with its very low signal-to-noise ratio. In order to design more powerful transfer functions, we propose to leverage soft segmentation as an explicit component of visualization for noisy volumes. Our technical realization is based on semi-supervised learning where we combine the advantages of two segmentation algorithms. A first weak segmentation algorithm provides good results for propagating sparse user provided labels to other voxels in the same volume. This weak segmentation algorithm is used to generate dense pseudo labels. A second powerful deep-learning based segmentation algorithm can learn from these pseudo labels to generalize the segmentation to other unseen volumes, a task that the weak segmentation algorithm fails at completely. The proposed volume visualization uses the deep-learning based segmentation as a component for segmentation-aware transfer function design. Appropriate ramp parameters can be suggested automatically through histogram analysis. Finally, our visualization uses gradient-free ambient occlusion shading to further suppress visual presence of noise, and to give structural detail desired prominence. The cryo-ET data studied throughout our technical experiments is based on the highest-quality tilted series of intact SARS-CoV-2 virions. Our technique shows the high impact in target sciences for visual data analysis of very noisy volumes that cannot be visualized with existing techniques

Examination of the Structural Response of the Orion European Service Module to Reverberant and Direct Field Acoustic Testing

The NASA Orion Multi-Purpose Crew Vehicle (MPCV), comprised of the Service Module, the Crew Module, and the Launch Abort System, is the next generation human spacecraft designed and built for deep space exploration. Orion will launch on NASAs new heavy-lift rocket, the Space Launch System. The European Space Agency (ESA) is responsible for providing the propulsion sub-assembly of the Service Module to NASA, called the European Service Module (ESM). The ESM is being designed and built by Airbus Safran Launchers for ESA. Traditionally, NASA has utilized reverberant acoustic testing for qualification of spaceflight hardware. The ESM Structural Test Article (E-STA) was tested at the NASA Plum Brook Stations (PBS) Reverberant Acoustic Test Facility in April-May 2016. However, Orion is evaluating an alternative acoustic test method, using direct field acoustic excitation, for the MPCVs Service Module and Crew Module. Lockheed Martin is responsible for the Orion proof-of-concept direct field acoustic test program. The E-STA was exposed to direct field acoustic testing at NASA PBS in February 2017. This paper compares the dynamic response of the E-STA structure and its components to both the reverberant and direct field acoustic test excitations. Advantages and disadvantages of direct field acoustic test excitation method are discussed

The NCATS BioPlanet – An Integrated Platform for Exploring the Universe of Cellular Signaling Pathways for Toxicology, Systems Biology, and Chemical Genomics

Chemical genomics aims to comprehensively define, and ultimately predict, the effects of small molecule compounds on biological systems. Chemical activity profiling approaches must consider chemical effects on all pathways operative in mammalian cells. To enable a strategic and maximally efficient chemical profiling of pathway space, we have created the NCATS BioPlanet, a comprehensive integrated pathway resource that incorporates the universe of 1,658 human pathways sourced from publicly available, manually curated sources, which have been subjected to thorough redundancy and consistency cross-evaluation. BioPlanet supports interactive browsing, retrieval, and analysis of pathways, exploration of pathway connections, and pathway search by gene targets, category, and availability of corresponding bioactivity assay, as well as visualization of pathways on a 3-dimensional globe, in which the distance between any two pathways is proportional to their degree of gene component overlap. Using this resource, we propose a strategy to identify a minimal set of 362 biological assays that can interrogate the universe of human pathways. The NCATS BioPlanet is a public resource, which will be continually expanded and updated, for systems biology, toxicology, and chemical genomics, available at http://tripod.nih.gov/bioplanet/

Overview of the Acoustic Testing of the European Service Module Structural Test Article (E-STA)

The European Space Agency (ESA) and their prime contractor Airbus Defense Space (ADS) are developing the European Service Module (ESM) for integration and utilization with other modules of NASAs Orion Multi-Purpose Crew Vehicle. As part of this development, ESA, ADS, NASA and the Lockheed Martin Company performed a series of reverberant acoustic tests in April-May 2016 on the ESM Structural Test Article (E-STA), the mechanical mock-up of the ESM designated for mechanical tests. Testing the E-STA under acoustic qualification loads verifies whether it can successfully withstand the medium and high frequency mechanical environment occurring during the vehicles lift-off and atmospheric phases of flight. The testing occurred at the Reverberant Acoustic Test Facility (RATF) at the NASA Glenn Research Centers Plum Brook Station site in Sandusky, OH, USA. This highly successful acoustic test campaign excited the E-STA to acoustic test levels as high as 149.4 dB Overall Sound Pressure Level. This acoustic testing met all the ESA and ADSs test objectives, including establishingverifying the random vibration qualification test levels for numerous hardware components of the ESM, and qualifying the ESMs Solar Array Wing electrical power system. This paper will address the test objectives, the test articles configuration, the test instrumentation and excitation levels, the RATF site and capabilities, the series of acoustic tests performed, and the technical issues faced and overcome to result in a successful acoustic test campaign for the ESM. A discussion of several test results is also included

Peri-operative red blood cell transfusion in neonates and infants: NEonate and Children audiT of Anaesthesia pRactice IN Europe: A prospective European multicentre observational study

BACKGROUND: Little is known about current clinical practice concerning peri-operative red blood cell transfusion in neonates and small infants. Guidelines suggest transfusions based on haemoglobin thresholds ranging from 8.5 to 12 g dl-1, distinguishing between children from birth to day 7 (week 1), from day 8 to day 14 (week 2) or from day 15 (≥week 3) onwards. OBJECTIVE: To observe peri-operative red blood cell transfusion practice according to guidelines in relation to patient outcome. DESIGN: A multicentre observational study. SETTING: The NEonate-Children sTudy of Anaesthesia pRactice IN Europe (NECTARINE) trial recruited patients up to 60 weeks' postmenstrual age undergoing anaesthesia for surgical or diagnostic procedures from 165 centres in 31 European countries between March 2016 and January 2017. PATIENTS: The data included 5609 patients undergoing 6542 procedures. Inclusion criteria was a peri-operative red blood cell transfusion. MAIN OUTCOME MEASURES: The primary endpoint was the haemoglobin level triggering a transfusion for neonates in week 1, week 2 and week 3. Secondary endpoints were transfusion volumes, 'delta haemoglobin' (preprocedure - transfusion-triggering) and 30-day and 90-day morbidity and mortality. RESULTS: Peri-operative red blood cell transfusions were recorded during 447 procedures (6.9%). The median haemoglobin levels triggering a transfusion were 9.6 [IQR 8.7 to 10.9] g dl-1 for neonates in week 1, 9.6 [7.7 to 10.4] g dl-1 in week 2 and 8.0 [7.3 to 9.0] g dl-1 in week 3. The median transfusion volume was 17.1 [11.1 to 26.4] ml kg-1 with a median delta haemoglobin of 1.8 [0.0 to 3.6] g dl-1. Thirty-day morbidity was 47.8% with an overall mortality of 11.3%. CONCLUSIONS: Results indicate lower transfusion-triggering haemoglobin thresholds in clinical practice than suggested by current guidelines. The high morbidity and mortality of this NECTARINE sub-cohort calls for investigative action and evidence-based guidelines addressing peri-operative red blood cell transfusions strategies. TRIAL REGISTRATION: ClinicalTrials.gov, identifier: NCT02350348

Exploring UK medical school differences: the MedDifs study of selection, teaching, student and F1 perceptions, postgraduate outcomes and fitness to practise.

BACKGROUND: Medical schools differ, particularly in their teaching, but it is unclear whether such differences matter, although influential claims are often made. The Medical School Differences (MedDifs) study brings together a wide range of measures of UK medical schools, including postgraduate performance, fitness to practise issues, specialty choice, preparedness, satisfaction, teaching styles, entry criteria and institutional factors. METHOD: Aggregated data were collected for 50 measures across 29 UK medical schools. Data include institutional history (e.g. rate of production of hospital and GP specialists in the past), curricular influences (e.g. PBL schools, spend per student, staff-student ratio), selection measures (e.g. entry grades), teaching and assessment (e.g. traditional vs PBL, specialty teaching, self-regulated learning), student satisfaction, Foundation selection scores, Foundation satisfaction, postgraduate examination performance and fitness to practise (postgraduate progression, GMC sanctions). Six specialties (General Practice, Psychiatry, Anaesthetics, Obstetrics and Gynaecology, Internal Medicine, Surgery) were examined in more detail. RESULTS: Medical school differences are stable across time (median alpha = 0.835). The 50 measures were highly correlated, 395 (32.2%) of 1225 correlations being significant with p < 0.05, and 201 (16.4%) reached a Tukey-adjusted criterion of p < 0.0025. Problem-based learning (PBL) schools differ on many measures, including lower performance on postgraduate assessments. While these are in part explained by lower entry grades, a surprising finding is that schools such as PBL schools which reported greater student satisfaction with feedback also showed lower performance at postgraduate examinations. More medical school teaching of psychiatry, surgery and anaesthetics did not result in more specialist trainees. Schools that taught more general practice did have more graduates entering GP training, but those graduates performed less well in MRCGP examinations, the negative correlation resulting from numbers of GP trainees and exam outcomes being affected both by non-traditional teaching and by greater historical production of GPs. Postgraduate exam outcomes were also higher in schools with more self-regulated learning, but lower in larger medical schools. A path model for 29 measures found a complex causal nexus, most measures causing or being caused by other measures. Postgraduate exam performance was influenced by earlier attainment, at entry to Foundation and entry to medical school (the so-called academic backbone), and by self-regulated learning. Foundation measures of satisfaction, including preparedness, had no subsequent influence on outcomes. Fitness to practise issues were more frequent in schools producing more male graduates and more GPs. CONCLUSIONS: Medical schools differ in large numbers of ways that are causally interconnected. Differences between schools in postgraduate examination performance, training problems and GMC sanctions have important implications for the quality of patient care and patient safety

The Analysis of Teaching of Medical Schools (AToMS) survey: an analysis of 47,258 timetabled teaching events in 25 UK medical schools relating to timing, duration, teaching formats, teaching content, and problem-based learning.

BACKGROUND: What subjects UK medical schools teach, what ways they teach subjects, and how much they teach those subjects is unclear. Whether teaching differences matter is a separate, important question. This study provides a detailed picture of timetabled undergraduate teaching activity at 25 UK medical schools, particularly in relation to problem-based learning (PBL). METHOD: The Analysis of Teaching of Medical Schools (AToMS) survey used detailed timetables provided by 25 schools with standard 5-year courses. Timetabled teaching events were coded in terms of course year, duration, teaching format, and teaching content. Ten schools used PBL. Teaching times from timetables were validated against two other studies that had assessed GP teaching and lecture, seminar, and tutorial times. RESULTS: A total of 47,258 timetabled teaching events in the academic year 2014/2015 were analysed, including SSCs (student-selected components) and elective studies. A typical UK medical student receives 3960 timetabled hours of teaching during their 5-year course. There was a clear difference between the initial 2 years which mostly contained basic medical science content and the later 3 years which mostly consisted of clinical teaching, although some clinical teaching occurs in the first 2 years. Medical schools differed in duration, format, and content of teaching. Two main factors underlay most of the variation between schools, Traditional vs PBL teaching and Structured vs Unstructured teaching. A curriculum map comparing medical schools was constructed using those factors. PBL schools differed on a number of measures, having more PBL teaching time, fewer lectures, more GP teaching, less surgery, less formal teaching of basic science, and more sessions with unspecified content. DISCUSSION: UK medical schools differ in both format and content of teaching. PBL and non-PBL schools clearly differ, albeit with substantial variation within groups, and overlap in the middle. The important question of whether differences in teaching matter in terms of outcomes is analysed in a companion study (MedDifs) which examines how teaching differences relate to university infrastructure, entry requirements, student perceptions, and outcomes in Foundation Programme and postgraduate training

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Differentiable Electron Microscopy Simulation: Methods and Applications for Visualization

We propose a new microscopy simulation system that can depict atomistic models in a micrograph visual style, similar to results of physical electron microscopy imaging. This system is scalable, able to represent simulation of electron microscopy of tens of viral particles and synthesizes the image faster than previous methods. On top of that, the simulator is differentiable, both its deterministic as well as stochastic stages that form signal and noise representations in the micrograph. This notable property has the capability for solving inverse problems by means of optimization and thus allows for generation of microscopy simulations using the parameter settings estimated from real data. We demonstrate this learning capability through two applications: (1) estimating the parameters of the modulation transfer function defining the detector properties of the simulated and real micrographs, and (2) denoising the real data based on parameters trained from the simulated examples. While current simulators do not support any parameter estimation due to their forward design, we show that the results obtained using estimated parameters are very similar to the results of real micrographs. Additionally, we evaluate the denoising capabilities of our approach and show that the results showed an improvement over state-of-the-art methods. Denoised micrographs exhibit less noise in the tilt-series tomography reconstructions, ultimately reducing the visual dominance of noise in direct volume rendering of microscopy tomograms.Comment: Version 2: Page 10: Fix the rendering problem in in Line 12 of Algorithm 2 Page 12: Table 2: Fix wrong data entries in the tabl