CO2 Adsorption/Desorption in FAU Zeolite Nanocrystals: In Situ Synchrotron X-ray Powder Diffraction and in Situ Fourier Transform Infrared Spectroscopic Study

International audienceThe host–guest and guest–guest interactions governing the CO2 adsorption/desorption in two nanosized zeolite samples with FAU framework type and different Si/Al ratios (Na–X Si/Al = 1.24 and Na–Y Si/Al = 2.54) and cation distribution were investigated by in situ synchrotron high-resolution X-ray powder diffraction (XRPD) and in situ Fourier transform infrared (FTIR) spectroscopy. The two complementary techniques allow probing the CO2 adsorption/desorption in the FAU zeolites at different levels, that is, average structure by XRPD versus local structure by FTIR spectroscopy . The presence of physisorbed CO2 molecules in both zeolites was detected by XRPD, whereas only a high amount of chemisorbed CO2 in the Na–X zeolite was found. The presence of unshielded Na cations and H2O molecules in the supercage of the Na–X sample induces the formation of stable bidentate bicarbonate groups. Evacuating CO2-loaded samples resulted in the efficient removal of physisorbed CO2 from both nanosized zeolites; on the contrary, high temperature is required to remove the chemisorbed species from the nanosized Na–X zeolite. Understanding the CO2 sorption behavior and capacity of nanosized zeolites is of great importance in broadening their use in environmental, clinical, and biomedical applications

A quality-of-life mapping function developed from a grass pollen sublingual immunotherapy trial to a tree pollen sublingual immunotherapy trial.

Aims: Allergic rhinitis is caused by sensitivity to environmental allergens that can significantly impact quality-of-life. The objective of this analysis was to estimate health state utilities and quality-adjusted life days (QALDs) for a tree allergy immunotherapy trial, TT-04 (EudraCT No.2015-004821-15). Health-state utilities are a measure of patient preference for health states and are necessary to derive QALDs for cost-utility analysis. Preference-based utilities were not collected in the TT-04 trial, so a mapping algorithm was developed based on a similar grass allergy immunotherapy trial, GT-08 (EudraCT No. 2004-000083-27), to estimate utilities.Methods: A two-part model was developed to predict utilities for the GT-08 trial and applied to the TT-04 trial to estimate the difference in mean utility and QALDs between SQ tree sublingual immunotherapy (SLIT)-tablet and placebo.Results: Mean utility difference between SQ tree SLIT-tablet and placebo was 0.030 [95% CI = 0.015-0.046] during the birch pollen season (BPS), 0.019 [95% CI = 0.007-0.030] during the tree pollen season (TPS) and 0.018 [95% CI = 0.007-0.030] during the full trial. The treatment showed a QALD benefit of 1.26 [95% CI = 0.619-1.917] during the BPS, 1.90 [95% CI = 0.692-3.047] during the TPS, and 2.47 [95% CI = 0.930-4.101] during the full trial.Limitations: The generalizability of this algorithm is limited to allergy trials containing the same covariates as those present in the model. The analysis also assumes that grass and tree pollen allergy have the same relationship with EQ5D utilities, which is supported by the fact that both grass and tree pollen induce similar symptoms.Conclusions: Application of the mapping function enabled the calculation of QALDs associated with the treatment, with the caveat that data were extrapolated from grass seasonal allergy to tree seasonal allergy. The results showed a significant QALD benefit of the treatment over placebo in treatment of tree pollen-induced rhinoconjunctivitis

Does Team Leader Gender Matter? A Bayesian Reconciliation of Leadership and Patient Care During Trauma Resuscitations

OBJECTIVE: Team leadership facilitates teamwork and is important to patient care. It is unknown whether physician gender-based differences in team leadership exist. The objective of this study was to assess and compare team leadership and patient care in trauma resuscitations led by male and female physicians. METHODS: We performed a secondary analysis of data from a larger randomized controlled trial using video recordings of emergency department trauma resuscitations at a Level 1 trauma center from April 2016 to December 2017. Subjects included emergency medicine and surgery residents functioning as trauma team leaders. Eligible resuscitations included adult patients meeting institutional trauma activation criteria. Two video-recorded observations for each participant were coded for team leadership quality and patient care by 2 sets of raters. Raters were balanced with regard to gender and were blinded to study hypotheses. We used Bayesian regression to determine whether our data supported gender-based advantages in team leadership. RESULTS: A total of 60 participants and 120 video recorded observations were included. The modal relationship between gender and team leadership (β = 0.94, 95% highest density interval [HDI], -.68 to 2.52) and gender and patient care (β = 2.42, 95% HDI, -2.03 to 6.78) revealed a weak positive effect for female leaders on both outcomes. Gender-based advantages to team leadership and clinical care were not conclusively supported or refuted, with the exception of rejecting a strong male advantage to team leadership. CONCLUSIONS: We prospectively measured team leadership and clinical care during patient care. Our findings do not support differences in trauma resuscitation team leadership or clinical care based on the gender of the team leader

A novel prostate cell type-specific gene signature to interrogate prostate tumor differentiation status and monitor therapeutic response (running title: Phenotypic classification of prostate tumors)

In this study, we extracted prostate cell-specific gene sets (metagenes) to define the epithelial differentiation status of prostate cancers and, using a deconvolution-based strategy, interrogated thousands of primary and metastatic tumors in public gene profiling datasets. We identified a subgroup of primary prostate tumors with low luminal epithelial enrichment (LumElow). LumElow tumors were associated with higher Gleason score and mutational burden, reduced relapse-free and overall survival, and were more likely to progress to castration-resistant prostate cancer (CRPC). Using discriminant function analysis, we generate a predictive 10-gene classifier for clinical implementation. This mini-classifier predicted with high accuracy the luminal status in both primary tumors and CRPCs. Immunohistochemistry for COL4A1, a low- luminal marker, sustained the association of attenuated luminal phenotype with metastatic disease. We found also an association of LumE score with tumor phenotype in genetically engineered mouse models (GEMMs) of prostate cancer. Notably, the metagene approach led to the discovery of drugs that could revert the low luminal status in prostate cell lines and mouse models. This study describes a novel tool to dissect the intrinsic heterogeneity of prostate tumors and provide predictive information on clinical outcome and treatment response in experimental and clinical samples

Phase 2 Multicenter Study of Gantry-Based Stereotactic Radiotherapy Boost for Intermediate and High Risk Prostate Cancer (PROMETHEUS)

Objectives: To report feasibility, early toxicity, and PSA kinetics following gantry-based, stereotactic radiotherapy (SBRT) boost within a prospective, phase 2, multicenter study (PROMETHEUS: ACTRN12615000223538).Methods: Patients were treated with gantry-based SBRT, 19–20 Gy in two fractions delivered 1 week apart, followed by conventionally fractionated IMRT (46 Gy in 23 fractions). The study mandated MRI fusion for RT planning, rectal displacement, and intrafraction image guidance. Toxicity was prospectively graded using the Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4).Results: Between March 2014 and July 2018, 135 patients (76% intermediate, 24% high-risk) with a median age of 70 years (range 53–81) were treated across five centers. Short course (≤6 months) androgen deprivation therapy (ADT) was used in 36% and long course in 18%. Rectal displacement method was SpaceOAR in 59% and Rectafix in 41%. Forty-two and ninety-three patients were treated at the 19 Gy and 20 Gy dose levels, respectively. Median follow-up was 24 months. Acute grade 2 gastrointestinal (GI) and urinary toxicity occurred in 4.4 and 26.6% with no acute grade 3 toxicity. At 6, 12, 18, 24, and 36 months post-treatment the prevalence of late grade ≥2 gastrointestinal toxicity was 1.6, 3.7, 2.2, 0, and 0%, respectively, and the prevalence of late grade ≥2 urinary toxicity was 0.8, 11, 12, 7.1, and 6.3%, respectively. Three patients experienced grade 3 late toxicity at 12 to 18 months which subsequently resolved to grade 2 or less. For patients not receiving ADT the median PSA value pre-treatment was 7.6 ug/L (1.1–20) and at 12, 24, and 36 months post-treatment was 0.86, 0.36, and 0.20 ug/L.Conclusions: Delivery of a gantry-based SBRT boost is feasible in a multicenter setting, is well-tolerated with low rates of early toxicity and is associated with promising PSA responses. A second transient peak in urinary toxicity was observed at 18 months which subsequently resolved. Follow-up is ongoing to document late toxicity, long-term patient reported outcomes, and tumor control with this approach

UWE Science Communication Postgraduate Papers

ForewordThis second volume in the Postgraduate Papers series has been produced as part of the celebrations of ten years of Science Communication postgraduate programmes in the Faculty of Health and Applied Sciences, University of the West of England, Bristol.Every year, some fifteen to twenty students undertake a Master’s level project as part of their MSc studies. These papers represent just a small selection of the projects carried out between 2009 and 2013 but they persuasively demonstrate the wide range of subjects tackled by our students and the innovative research they conduct.Bonnie Buckley, Jennifer Garrett and Melanie Davies looked at aspects of science communication in science centres and museums. Bonnie examined the motivations that lead people to be volunteers in science centres; Jennifer investigated how science centres can play a role in communicating environmental sustainability and Melanie explored how science centres can use a range of activities to sustain and develop creativity. The Internet offers new modes and new routes for dialogue and science communication. Felicity Liggins, Mathieu Ranger and Robin Longdin undertook projects in this dynamic medium. Felicity explored attitudes to blogging in the UK Met Office, while Mathieu looked at the particular challenges faced by science bloggers and Robin investigated whether online interaction with scientists could positively affect school students’ attitudes to science.Amy Seakins, Maya Herbolzheimer and Sarah Venugopal’s projects were all based in the lively and diverse world of festivals. Spanning the worlds of traditional and online communication, Amy considered how citizen science projects could make the most effective use of the media; Maya investigated the effectiveness of a Festival of Nature in engaging a wide range of attendees with nature conservation, while Sarah examined the relationship between arts and science at a science event embedded in an arts festival.The final two papers, by Michal Jane Filtness and Alexander Brown defy grouping but clearly illustrate the variety of audiences our students address. Michal investigated researchers’ views of the Pathways to Impact tool created by the UK Research Councils to increase the public impact of research, while Alexander evaluated the impact on school students’ attitudes to science among young people who had undertaken work experience placements at a UK research council. We want to congratulate those graduates whose research is included in this volume and thank them for the time and care they have taken in creating their contributions. Thanks should also go to the graduates’ academic supervisors, who are the co-authors on these papers; in particular Dr Karen Bultitude and Dr Helen Featherstone, who are now based at other institutions. We would also like to thank the many organisations whose support made these projects possible.We are honoured to share in our graduates’ success and delighted to have this opportunity to open up their work to a wider audience. We wish all our graduates every success in their careers as science communicators

POTs: Protective Optimization Technologies

Algorithmic fairness aims to address the economic, moral, social, and political impact that digital systems have on populations through solutions that can be applied by service providers. Fairness frameworks do so, in part, by mapping these problems to a narrow definition and assuming the service providers can be trusted to deploy countermeasures. Not surprisingly, these decisions limit fairness frameworks' ability to capture a variety of harms caused by systems. We characterize fairness limitations using concepts from requirements engineering and from social sciences. We show that the focus on algorithms' inputs and outputs misses harms that arise from systems interacting with the world; that the focus on bias and discrimination omits broader harms on populations and their environments; and that relying on service providers excludes scenarios where they are not cooperative or intentionally adversarial. We propose Protective Optimization Technologies (POTs). POTs provide means for affected parties to address the negative impacts of systems in the environment, expanding avenues for political contestation. POTs intervene from outside the system, do not require service providers to cooperate, and can serve to correct, shift, or expose harms that systems impose on populations and their environments. We illustrate the potential and limitations of POTs in two case studies: countering road congestion caused by traffic-beating applications, and recalibrating credit scoring for loan applicants.Comment: Appears in Conference on Fairness, Accountability, and Transparency (FAT* 2020). Bogdan Kulynych and Rebekah Overdorf contributed equally to this work. Version v1/v2 by Seda G\"urses, Rebekah Overdorf, and Ero Balsa was presented at HotPETS 2018 and at PiMLAI 201

A multi-modal exploration of heterogeneous physico–chemical properties of DCIS breast microcalcifications

Ductal carcinoma in situ (DCIS) is frequently associated with breast calcification. This study combines multiple analytical techniques to investigate the heterogeneity of these calcifications at the micrometre scale. X-ray diffraction, scanning electron microscopy and Raman and Fourier-transform infrared spectroscopy were used to determine the physicochemical and crystallographic properties of type II breast calcifications located in formalin fixed paraffin embedded DCIS breast tissue samples. Multiple calcium phosphate phases were identified across the calcifications, distributed in different patterns. Hydroxyapatite was the dominant mineral, with magnesium whitlockite found at the calcification edge. Amorphous calcium phosphate and octacalcium phosphate were also identified close to the calcification edge at the apparent mineral/matrix barrier. Crystallographic features of hydroxyapatite also varied across the calcifications, with higher crystallinity centrally, and highest carbonate substitution at the calcification edge. Protein was also differentially distributed across the calcification and the surrounding soft tissue, with collagen and β-pleated protein features present to differing extents. Combination of analytical techniques in this study was essential to understand the heterogeneity of breast calcifications and how this may link crystallographic and physicochemical properties of calcifications to the surrounding tissue microenvironment.Cancer Research UK and by KWF Kankerbestrijding: C38317/A2404

ONC201 in combination with paxalisib for the treatment of H3K27-altered diffuse midline glioma

Diffuse midline gliomas (DMG), including diffuse intrinsic pontine gliomas (DIPGs), are the most lethal of childhood cancers. Palliative radiotherapy is the only established treatment, with median patient survival of 9-11 months. ONC201 is a DRD2 antagonist and ClpP agonist that has shown preclinical and emerging clinical efficacy in DMG. However, further work is needed to identify the mechanisms of response of DIPGs to ONC201 treatment and to determine whether recurring genomic features influence response. Using a systems-biological approach, we showed that ONC201 elicits potent agonism of the mitochondrial protease ClpP to drive proteolysis of electron transport chain and tricarboxylic acid cycle proteins. DIPGs harboring PIK3CA-mutations showed increased sensitivity to ONC201, while those harboring TP53-mutations were more resistant. Metabolic adaptation and reduced sensitivity to ONC201 was promoted by redox-activated PI3K/Akt signaling, which could be counteracted using the brain penetrant PI3K/Akt inhibitor, paxalisib. Together, these discoveries coupled with the powerful anti-DIPG/DMG pharmacokinetic and pharmacodynamic properties of ONC201 and paxalisib have provided the rationale for the ongoing DIPG/DMG phase II combination clinical trial NCT05009992

Transforming astrobiology research and innovation: embedding an ethos of engaged research

UK Research has been transformed over the past 10 years due to the staged introduction of the impact agenda; initially, as a requirement of applications to public funders, and then as an element of sector-wide research audits. We will begin this presentation with a brief review to explain these changes, drawing on selected theories of epistemology, and the findings from a recent research collaboration undertaken with a UK public funder. In response to the scale of these changes, UK Universities have been given opportunities by public funders to review and revise their organisational structures and cultural practices to adapt to the increased requirements to engage with ‘publics’ in ways that are meaningful to them. In the second section, we will briefly review the findings and key actions from a project undertaken at the Open University, UK to respond to these changes. These are embodied in our Senate-approved concept of ‘engaged research’, encompassing the different ways that researchers meaningfully interact with stakeholders, user communities, members of the public, facilitating engagement over any or all stages of a research process, from issue formulation, the production or co-creation of new knowledge, to knowledge evaluation and dissemination. The UK research landscape continues to evolve. In the final section, we will discuss how we have embedded theoretical concepts and practical approaches to promote ‘fairness in knowing’ and reduce ‘epistemic injustice’ in an ongoing project. The vehicle for this discussion is astrobiology, an emerging scientific field that encompasses 1) questions of whether life can exist beyond the Earth; 2) space governance and planetary protection; 3) inclusive innovation for international development; 4) commercially-viable microbiological solutions; and 5) educational innovation in developing nations. We will conclude by arguing that engaged research can transform research and innovation, moving science communicators beyond perennial arguments about theory vs. practice