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Purpose: To explore whether patients with BRCA1/2-mutated or homologous recombination deficient (HRD) ovarian cancers benefitted from atezolizumab in the phase III IMagyn050 (NCT03038100) trial. Patients and Methods: Patients with newly diagnosed ovarian cancer were randomized to either atezolizumab or placebo with standard chemotherapy and bevacizumab. Programmed death-ligand 1 (PD-L1) status of tumor-infiltrating immune cells (IC) was determined centrally (VENTANA SP142 assay). Genomic alterations, including deleterious BRCA1/2 alterations, genomic loss of heterozygosity (gLOH), tumor mutation burden (TMB), and microsatellite instability (MSI), were evaluated using the FoundationOne assay. HRD was defined as gLOH ≥ 16%, regardless of BRCA1/2 mutation status. Potential associations between progression-free survival (PFS) and genomic biomarkers were evaluated using standard correlation analyses and log-rank of Kaplan–Meier estimates. Results: Among biomarker-evaluable samples, 22% (234/1,050) harbored BRCA1/2 mutations and 46% (446/980) were HRD. Median TMB was low irrespective of BRCA1/2 or HRD. Only 3% (29/1,024) had TMB ≥10 mut/Mb, and 0.3% (3/1,022) were MSI-high. PFS was better in BRCA2-mutated versus BRCA2–non-mutated tumors and in HRD versus proficient tumors. PD-L1 positivity (≥1% expression on ICs) was associated with HRD but not BRCA1/2 mutations. PFS was not improved by adding atezolizumab in BRCA2-mutated or HRD tumors; there was a trend toward enhanced PFS with atezolizumab in BRCA1-mutated tumors. Conclusions: Most ovarian tumors have low TMB despite BRCA1/2 mutations or HRD. Neither BRCA1/2 mutation nor HRD predicted enhanced benefit from atezolizumab. This is the first randomized double-blind trial in ovarian cancer demonstrating that genomic instability triggered by BRCA1/2 mutation or HRD is not associated with improved sensitivity to immune checkpoint inhibitors. See related commentary by Al-Rawi et al., p. 1645

PFS by treatment arm according to TMB status (stratified by treatment approach, disease stage, and ECOG PS). A, TMB-low population. B, TMB-high population. CPB, paclitaxel, carboplatin, and bevacizumab.

Purpose:To explore whether patients with BRCA1/2-mutated or homologous recombination deficient (HRD) ovarian cancers benefitted from atezolizumab in the phase III IMagyn050 (NCT03038100) trial.Patients and Methods:Patients with newly diagnosed ovarian cancer were randomized to either atezolizumab or placebo with standard chemotherapy and bevacizumab. Programmed death-ligand 1 (PD-L1) status of tumor-infiltrating immune cells (IC) was determined centrally (VENTANA SP142 assay). Genomic alterations, including deleterious BRCA1/2 alterations, genomic loss of heterozygosity (gLOH), tumor mutation burden (TMB), and microsatellite instability (MSI), were evaluated using the FoundationOne assay. HRD was defined as gLOH ≥ 16%, regardless of BRCA1/2 mutation status. Potential associations between progression-free survival (PFS) and genomic biomarkers were evaluated using standard correlation analyses and log-rank of Kaplan–Meier estimates.Results:Among biomarker-evaluable samples, 22% (234/1,050) harbored BRCA1/2 mutations and 46% (446/980) were HRD. Median TMB was low irrespective of BRCA1/2 or HRD. Only 3% (29/1,024) had TMB ≥10 mut/Mb, and 0.3% (3/1,022) were MSI-high. PFS was better in BRCA2-mutated versus BRCA2–non-mutated tumors and in HRD versus proficient tumors. PD-L1 positivity (≥1% expression on ICs) was associated with HRD but not BRCA1/2 mutations. PFS was not improved by adding atezolizumab in BRCA2-mutated or HRD tumors; there was a trend toward enhanced PFS with atezolizumab in BRCA1-mutated tumors.Conclusions:Most ovarian tumors have low TMB despite BRCA1/2 mutations or HRD. Neither BRCA1/2 mutation nor HRD predicted enhanced benefit from atezolizumab. This is the first randomized double-blind trial in ovarian cancer demonstrating that genomic instability triggered by BRCA1/2 mutation or HRD is not associated with improved sensitivity to immune checkpoint inhibitors.See related commentary by Al-Rawi et al., p. 1645

This paper discusses a practical, multidisciplinary approach used to embed employability skills in a new postgraduate (PGT) Engineering course at the University of Bath. Informed by relevant professional bodies, key transferable skills were identified and embedded in the curriculum with discipline-specific content. Students worked on a series of hands-on activities in which they integrated and applied principles and methodologies from various areas (linguistics, information, etc.), complementary to their technical expertise, as in the working environment. This was facilitated by a multidisciplinary team comprised of Academic and Professional Services staff at the University of Bath. The organisational context and rationale for the approach presented, including the practical implementation and initial outcomes in the new PGT course, are provided.

In the context of aircraft system performance assessment, deep learning technologies allow to quickly infer models from experimental measurements, with less detailed system knowledge than usually required by physics-based modeling. However, this inexpensive model development also comes with new challenges regarding model trustworthiness. This work presents a novel approach, physics-guided adversarial machine learning (ML), that improves the confidence over the physics consistency of the model. The approach performs, first, a physics-guided adversarial testing phase to search for test inputs revealing behavioral system inconsistencies, while still falling within the range of foreseeable operational conditions. Then, it proceeds with physics-informed adversarial training to teach the model the system-related physics domain foreknowledge through iteratively reducing the unwanted output deviations on the previously-uncovered counterexamples. Empirical evaluation on two aircraft system performance models shows the effectiveness of our adversarial ML approach in exposing physical inconsistencies of both models and in improving their propensity to be consistent with physics domain knowledge.

Background: A large proportion of children in the UK do not engage in the recommended amount of physical activity. Schools are an environment where children spend a considerable portion of their time and have the potential to facilitate more physical activity. There has been little exploration of the specific school environment factors that are most pertinent to child physical activity and sedentary behaviour. This study was intended to fill this important gap. Methods: Data were collected between March 2017 and May 2018 from 50 schools and 1223 children who participated in the B-Proact1v cohort study. School level measures were the built environment (e.g. playground equipment, cycling parking, allotments), physical activity-related policies (e.g. policy to encourage active travel) and the use of physical activity in the curriculum (e.g. regular physical activity breaks throughout day). Children’s weekday moderate-to-vigorous physical activity (MVPA) was estimated via Actigraph GT3X accelerometers. Associations between school context measures and children’s weekday MVPA were analysed using linear multilevel models, with children nested within schools, adjusted for individual characteristics. Results: On average, children at schools with allotments, a larger amount of playground equipment and where cycle training was offered, engaged in higher levels of MVPA. PE being compromised due to space was associated with lower levels of MVPA. Conclusions: Whilst there is a need for further exploration, the findings suggest that school-based provision and policies for active travel, sport and active play may be important to encouraging more primary school children to be more active more regularly.

To meet the increasing energy demands of portable devices and electric vehicles, high-nickel lithium-ion cathode materials with the general formula Li(NixMnyCoz)O2 (NMCXYZ) have been extensively researched. Currently, NMC811 is used commercially due to its high capacity and low cobalt content. However, capacity fade is still a prominent issue, with a variety of degradation mechanisms responsible. Of particular interest is secondary particle cracking, where the stress-strain effect of c-parameter expansion in the NMC crystal lattice leads to fractures. Boundaries between the primary particle grain that make up the secondary particle structure act as nucleation points for particle cracking. The exposed surface then reacts with the liquid electrolyte, leading to oxygen evolution and capacity loss. Single-crystal materials have shown promise as a method of improving cycle life, as the lack of agglomerated primary grains appear to make the monocrystalline particles more resilient to the mechanical strain of expansion during charging1. In parallel with the cycle life concerns, attention over battery safety continues to increase as instances of catastrophic battery failure are publicised across the world. While the specific steps that lead to battery thermal runaway have been extensively researched, the safety and thermal stability of degraded cells remains a scarcely investigated topic2. To that end, the goal of this work is to characterise the safety properties of different NMC morphologies, and study how charge-discharge cycling affects the thermal stability of these materials. In this work, we have combined accelerating rate calorimetry (ARC) with lab-based, post-mortem macro, micro and nano X-ray CT to observe the influence of cell structure on thermal runaway of NMC811 pouch cells with single-crystal and polycrystalline cathode materials in both the pristine and aged state. The results presented show that when pristine, the larger surface area of single-crystal materials provides more reaction sites and leads to a lower self-heating onset and thermal runaway initiation temperature compared to polycrystalline, suggesting a lower thermal stability. However, as polycrystalline particles break up during thermal runaway, the fragments create fresh surface to react with the electrolyte and continue the series of exothermic reactions, leading to a higher peak temperature. Macro-CT has revealed how the wound jellyroll structure of the cell focuses the force of the explosion through the flat sides of the cells, possibly increasing the likelihood of failure propagation. It has also been observed that the polycrystalline materials show a greater material ejection out from the centre of the cell, reinforcing the findings from the ARC investigations that although polycrystalline cells are more thermally stable initially, the peak temperatures produced during catastrophic failure are higher due to particle fracture. Micro and nano-CT are used to probe this idea further, revealing that polycrystalline particles show significant damage and fracturing during failure, whereas single-crystal materials remain largely intact. Both polycrystalline and single-crystal morphologies were cycled to 80% capacity retention, with EIS and diagnostic cycles used to identify prevalent degradation modes for both particle structures. As previously found, the single-crystal cells showed superior cycle life to the polycrystalline materials3. The same combination of ARC and X-ray CT was then applied to aged cells, where it was found that aged cells show lower thermal stability than their pristine counterparts. Overall, this work aims to build understanding of the interplay between material structure, safety and degradation of nickel-rich cathodes, with the goal of informing future material development to produce batteries that are safer throughout their lifetimes. G. Qian et al., Energy Storage Mater., 27, 140–149 (2020) https://doi.org/10.1016/j.ensm.2020.01.027. X. Feng et al., Energy Storage Mater., 10, 246–267 (2018) https://doi.org/10.1016/j.ensm.2017.05.013. D. Ren et al., eTransportation, 2, 100034 (2019) https://doi.org/10.1016/j.etran.2019.100034.

The safety of concerns of lithium-ion batteries continues to be a prevalent obstacle toward their widespread application from vehicle electrification to space exploration. Aside from the highly oxidising and reducing electrode materials, their safety is compounded by an inherent drawback of poor heat dissipation [1]. High-speed imaging with in-situ/operando X-ray CT has been used extensively to study various lithium-ion battery safety features and failure mechanisms [2][3], including thermal failure [4]. However, these are exclusively using synchrotron X-ray sources which are limited in terms of both access and data recording capabilities: high frame rates require the data collection window to be restricted to a few seconds. During lithium-ion battery failure, there are several changes to a cell structure leading up to thermal runaway (TR) which can take minutes, and as a result are often missed. Here, we present an instrument that simulates thermal failure for lab-based radiography at slower imaging speeds and longer recording lengths, which has been validated by correlative synchrotron measurements. The failure mechanisms within a fully charged (100 % SOC, 4.2 V) commercially available LiCoO2 cathode and graphite anode pouch cell (651628-2C, AA Portable Power Corp) rated at 210 mAh are investigated. Three samples are studied using lab-based radiography at a frame rate of 3.75 fps with a 16.1 µm pixel resolution and, for comparison, an additional three samples are studied using synchrotron X-ray sources at a higher speed of 20,000 fps with a 13.3 µm pixel resolution. For the six samples investigated, the total time taken from a start temperature of 80 °C to TR is approximately 20 minutes and the onset temperatures for TR are recorded within the range of 196 °C to 210 °C. The beginning of the TR event (defined as a sample temperature increase greater than 15 °C s-1), where the effects to the electrode structure are the most catastrophic, lasts for approximately 1 s. Operando radiographic images during this event reveal that the structural displacement of electrode layers begins at the centre of the cell and propagates outwards in a wave-like motion. The electrode displacement, as a result, is quantified by cross-correlating Gabor signals and spatiotemporal mapping [5] in both types of datasets. For the lab-based radiography, data is recorded from the start temperature to TR (lasting approximately 20 minutes), and reactions such as the electrolyte decomposition, ca. 105 °C, and separator melting, ca.130 °C are characterised in the context of electrode deformation and gas evolution. Investigations of pre- and post-failure 3D X-ray CT images further verify the uniformity of the pristine (or pre-failure) cell assembly as well as the estimated post-failure behaviour between samples. Finally, by comparison with correlative synchrotron measurements, the instrument for inducing thermal failure for lab-based X-ray CT is proven to be a viable and more accessible method to investigate thermal failure within a 210 mAh pouch cell. While synchrotron data has a higher-speed imaging advantage, it is limited to only recording the short TR event at a high temporal resolution. Whereas continuous imaging in lab-based radiography has the benefit of measuring the slower architectural changes taking place up to TR, albeit at a marginally lower spatial resolution. References [1] D. H. Doughty and E. P. Roth, Interface Mag., 21, 37–44 (2012). [2] D. P. Finegan, M. Scheel, J. B. Robinson, B. Tjaden, M. Di Michiel, G. Hinds, D. J. L. Brett, and P. R. Shearing, Phys. Chem. Chem. Phys., 18, 30912–30919 (2016). [3] D. P. Finegan, M. Scheel, J. B. Robinson, B. Tjaden, I. Hunt, T. J. Mason, J. Millichamp, M. Di Michiel, G. J. Offer, G. Hinds, D. J. L. Brett, and P. R. Shearing, Nat. Commun., 6, 6924 (2015). [4] M. T. M. Pham, J. J. Darst, D. P. Finegan, J. B. Robinson, T. M. M. Heenan, M. D. R. Kok, F. Iacoviello, R. Owen, W. Q. Walker, O. V. Magdysyuk, T. Connolley, E. Darcy, G. Hinds, D. J. L. Brett, and P. R. Shearing, J. Power Sources, 470, 228039 (2020). [5] A. N. P. Radhakrishnan, M. Buckwell, M. Pham, D. P. Finegan, A. Rack, G. Hinds, D. J. L. Brett, and P. R. Shearing, ChemRxiv (2021).

To meet the increasing energy demands of portable devices and electric vehicles, high-nickel lithium-ion cathode materials with the general formula Li(NixMnyCoz)O2 (NMC) have been extensively researched. Currently NMC811 is used commercially for high-energy applications. The energy density of NMC also comes with concerns over cycle life and safety1,2. To improve the cycle life of NMC-based cells, single-crystal materials have recently gained attention to tackle the particle cracking issues found in polycrystalline cathodes3. However, for successful introduction to the lithium-ion battery market, inherent safety over a material’s lifetime also needs to be proven. Failure and degradation mechanisms both need to be fully understood to improve the stability of future cathode materials. Abusive testing, such as overheating, overcharge and nail penetration, has been used in conjunction with in-situ and ex-situ X-ray computed tomography (CT) 3D imaging to perform post-mortem studies and understand the relationship between thermal failure and cathode microstructure4,5. However, the interplay between safety characteristics, microstructural properties and material degradation remains unclear. This work first aims to compare the safety performance of polycrystalline and single-crystal NMC811 in 200 mAh pouch cells. Accelerating rate calorimetry (ARC) with a heat-wait-search (HWS) technique is used to heat cells and determine the onset of self-heating, onset of thermal runaway and the peak thermal runaway temperature. Laboratory-based pre- and post-mortem in-situ and ex-situ X-ray CT is also used for non-destructive imaging at multiple length scales to determine how failure propagates through the cells and the impacts on the electrodes and microstructure. Pouch cells containing polycrystalline and single-crystal NMC811 cathode and graphite anode are electrochemically cycled to induce material degradation. EIS measurements and diagnostic cycles are performed to identify prevalent degradation modes in both types of cathode materials. Finally, the same ARC and X-ray CT characterisations are performed on the aged cells to determine how degradation and changes to the material structure affect the safety performance in high-nickel cathode materials. The results of this work will improve the current understanding of capacity fade in high-nickel cathodes and the safety behaviour over the lifetime of a battery cell. This information can then be used to inform future materials development and strategies for mitigating thermal runaway in batteries. References L. Ma, M. Nie, J. Xia, and J. R. Dahn, J. Power Sources, 327, 145–150 (2016). H. J. Noh, S. Youn, C. S. Yoon, and Y. K. Sun, J. Power Sources, 233, 121–130 (2013). J. Langdon and A. Manthiram, Energy Storage Mater., 37, 143–160 (2021). D. Patel, J. B. Robinson, S. Ball, and D. J. L. Brett, (2020). D. P. Finegan et al., Phys. Chem. Chem. Phys., 18, 30912–30919 (2016).

Background Physical activity is associated with improved health. Girls are less active than boys. Pilot work showed that a peer-led physical activity intervention called PLAN-A was a promising method of increasing physical activity in secondary school age girls. This study examined the effectiveness and cost-effectiveness of the PLAN-A intervention. Methods We conducted a cluster randomised controlled trial with Year 9 (13–14 year old) girls recruited from 20 secondary schools. Schools were randomly assigned to the PLAN-A intervention or a non-intervention control group after baseline data collection. Girls nominated students to be peer leaders. The top 18 % of girls nominated by their peers in intervention schools received three days of training designed to prepare them to support physical activity. Data were collected at two time points, baseline (T0) and 5–6 months post-intervention (T1). Participants wore an accelerometer for seven days to assess the primary outcome of mean weekday minutes of moderate-to-vigorous physical activity (MVPA). Multivariable mixed effects linear regression was used to estimate differences in the primary outcome between the two arms on an Intention-to-Treat (ITT) basis. Resource use and quality of life were measured and a within trial economic evaluation from a public sector perspective was conducted. Results A total of 1558 girls were recruited to the study. At T0, girls in both arms engaged in an average of 51 min of MVPA per weekday. The adjusted mean difference in weekday MVPA at T1 was − 2.84 min per day (95 % CI = -5.94 to 0.25) indicating a slightly larger decline in weekday MVPA in the intervention group. Results were broadly consistent when repeated using a multiple imputation approach and for pre-specified secondary outcomes and sub-groups. The mean cost of the PLAN-A intervention was £2817 per school, equivalent to £31 per girl. Economic analyses indicated that PLAN-A did not lead to demonstrable cost-effectiveness in terms of cost per unit change in QALY. Conclusions This study has shown that the PLAN-A intervention did not result in higher levels of weekday MVPA or associated secondary outcomes among Year 9 girls. The PLAN-A intervention should not be disseminated as a public health strategy. Trial registration ISRCTN14539759–31 May, 2018.

Strategies to address declining physical activity levels among children and adolescents have focused on ‘individual-level’ approaches which often fail to demonstrate impact. Recent attention has been on an alternative ‘whole-school’ approach to increasing physical activity that involves promoting physical activity throughout all aspects of the school environment. There is, however, a lack of evidence on how whole-school physical activity approaches could be implemented in the UK. This qualitative study explored perspectives of key stakeholders on potential reasons for the lack of impact of individual-level school-based interventions on children’s physical activity, and key considerations for adopting a whole-school approach. Nineteen semi-structured interviews were conducted with a range of stakeholders involved in the implementation of physical activity programmes in UK schools. Data were analysed using an inductive approach. Respondents suggested that individual-level school-based interventions to increase physical activity often failed to consult end users in the design and were typically implemented in environments unsupportive of long-term change. They subsequently outlined specific barriers and key facilitators for the adoption and implementation of whole-school approaches in UK settings and recommended a shift in research foci towards building an evidence base around educational outcomes and whole-school implementation insights.

Queer pedagogical theory might be best thought of as a mindset to approaching the classroom derived from the lived experience of queerness. Starting with a consideration of what is to be queer, one can begin to develop an understanding of how queerness as an identity might inform a decentering of classroom spaces that allows for marginalized positionalities to disrupt normative assumptions about how we approach myriad aspects of classroom experiences. After tracing the theoretical lineage of queer pedagogy and the theory that informs it, specific pedagogical aspects such as method, texts, and assessment can be cast in a queer context. With openness, fluidity, and the embracing of the unknown, the queer pedagogue holds space for new sites of epistemological inquiry which moves toward not inclusion, rather a disruption of the colonized lineage of the classroom.

Culture-independent and meta-omics sequencing methods have shed considerable light on the so-called “microbial dark matter” of Earth’s environmental microbiome, improving our understanding of phylogeny, the tree of life, and the vast functional diversity of microorganisms. This influx of sequence data has led to refined and reimagined hypotheses about the role and importance of microbial biomass, that paradoxically, sequencing approaches alone are unable to effectively test. Post-genomic approaches such as metabolomics are providing more sensitive and insightful data to unravel the fundamental operations and intricacies of microbial communities within aquatic systems. We assert that the implementation of integrated post-genomic approaches, specifically metabolomics and metatranscriptomics, is the new frontier of environmental microbiology and ecology, expanding conventional assessments toward a holistic systems biology understanding. Progressing beyond siloed phylogenetic assessments and cataloging of metabolites, toward integrated analysis of expression (metatranscriptomics) and activity (metabolomics) is the most effective approach to provide true insight into microbial contributions toward local and global ecosystem functions. This data in turn creates opportunity for improved regulatory guidelines, biomarker discovery and better integration of modeling frameworks. To that end, critical aquatic environmental issues related to climate change, such as ocean warming and acidification, contamination mitigation, and macro-organism health have reasonable opportunity of being addressed through such an integrative approach. Lastly, we argue that the “post-genomics” paradigm is well served to proactively address the systemic technical issues experienced throughout the genomics revolution and focus on collaborative assessment of field-wide experimental standards of sampling, bioinformatics and statistical treatments.

There are three goals of insurance rate regulation. Rates must be: 1) adequate; 2) not excessive; and 3) not unfairly discriminatory. Rates that are adequate yet not excessive are overall high enough to pay claims and expenses, yet not so high overall that they result in unreasonable profiteering by insurers. The third regulatory goal—that rates are not unfairly discriminatory—is the topic of interest in our research. The concept of unfair discrimination in an insurance context—determining what constitutes fairness in pricing—can differ substantially from the thinking on fairness in a societal context. As a result, the term “discrimination” may be used quite differently in these two contexts. Discrimination, with negative societal connotations, is endemic in our world broadly and largely unjustifiable, yet in the narrower world of insurance, it is the basis for the entire industry’s viability and sustainability. In the insurance context, we can receive the term “discrimination” in a neutral manner, simply taking it to mean different treatment for different groups having different characteristics, without it necessarily connoting any negative intent or outcome. Indeed, the purpose in insurance for engaging in “fair discrimination” —that is, discrimination that price differentiates between discernibly different levels of risk—is itself rooted in economic fairness. An insurance carrier charges differential prices for its products based on differentials in risk. Nevertheless, when risk transfer to an insurer is priced based on uncontrollable and/or immutable classifications such as race and gender, there can be profoundly different views of what constitutes fairness. In many areas of U.S. law, discrimination on either the basis of gender or sexual identity is prohibited in a number of jurisdictions for a number of consumer situations. Yet the broad concept of societal fairness and the much narrower concept of actuarial fairness differ, and so within insurance markets, U.S. law has historically set insurance apart from other products in speaking to issues of fairness and discrimination (West, 2013). Within the last year, several states have enhanced their recognition of nonbinary or genderqueer identities by implementing a Gender X option on driver’s licenses. Insurance carriers are left with minimal direction on how to appropriately price this emerging class within the three goals of rate regulation. Additionally, as diversity and inclusion continue to be a strategic initiative within the insurance market, the insurance industry and its regulatory environment have to navigate carefully between the business imperatives for adequate pricing and inclusion efforts. This paper addresses the potential for unfair discrimination in some lines of business—with special focus on auto insurance—should gender-based rating be continued into the future. It also explores an immediate opportunity to enhance the insurance industry’s social compact with its insureds via recognition of the Gender X identity. Part I gives a primer on nonbinary and trans-identity followed by a brief history of the role of gender in insurance pricing, Part II discusses nonbinary, transgender, and the introduction of Gender X as an additional categorical level of the gender identify rating factor as used in insurance pricing. Part III and Part IV dive into the economic and social implications of movement in U.S. law toward more gender inclusivity.

Objectives: Genomically unstable tumors, characterized by BRCA1/2 alterations and homologous recombination deficiency (HRD), are hypothesized to be more mutated and potentially more sensitive to immune checkpoint inhibitors. To explore this hypothesis we analyzed outcomes in the IMagyn050 trial according to BRCA1/2, HRD, and PD-L1 status [Moore, ESMO 2020]. Methods: IMagyn050 (NCT03038100) is a double-blind randomized phase III trial evaluating the efficacy and safety of adding atezolizumab/placebo to carboplatin, paclitaxel, and bevacizumab (CPB) followed by maintenance bevacizumab plus atezolizumab/placebo. PD-L1 status was determined centrally using VENTANA SP142 (PD-L1+ defined as ≥1% tumor-infiltrating immune cells expressing PD-L1). Deleterious tumor germline/somatic BRCA1/2 alterations (BRCA1/2m), genomic loss of heterozygosity (gLOH), tumor mutation burden (TMB), and microsatellite instability (MSI) were evaluated using the FoundationOne assay (Foundation Medicine, Inc., Cambridge, MA). HRD and homologous recombination proficiency (HRP) were defined as gLOH ≥16% and Results: Among 1301 randomized patients, samples from 1050 were evaluable for BRCA1/2 (22% were BRCA1/2m, 78% BRCA1/2 nonmutant) and 980 were evaluable for gLOH (46% were HRD, 54% HRP). Median TMB was similarly low in BRCA1/2m and BRCA1/2 nonmutant (3.78 vs 2.52 Mut/Mb, respectively), and HRD and HRP (3.78 vs 2.52 Mut/Mb, respectively) tumors. Only 3% (29/1024) of evaluable tumors had TMB ≥10 Mut/Mb and 0.3% (3/1022) were MSI-high (1 mixed, 1 undifferentiated, 1 other). All high-grade serous cases were MS-stable. PFS prognosis (assessed in the placebo + CPB arm) was improved in patients with BRCA1/2m (hazard ratio [HR] 0.62, 95% CI 0.46–0.84) and HRD (HR 0.63, 95% CI 0.49–0.80) tumors. There was a suggested association between PD-L1+ and HRD (HRD prevalence: 40% vs 25% in PD-L1+ vs PD-L1– subgroups, respectively; exploratory Fisher's exact test p=0.0001) but not with BRCA1/2m (BRCA1/2m prevalence: 21% vs 14%, respectively; exploratory Fisher exact test p=0.064). Adding atezolizumab to CPB did not improve PFS, irrespective of BRCA1/2 or HRD status (table). In the PD-L1+ population, HRs were similar in BRCA1/2m and BRCA1/2 nonmutant subgroups, and in HRD and HRP subgroups. In the PD-L1– population, atezolizumab did not improve PFS. Download : Download high-res image (172KB) Download : Download full-size image Conclusions: We showed that the majority of ovarian tumors have low TMB scores regardless of BRCA1/2 or HRD. Neither BRCA1/2m nor HRD was associated with greater clinical benefit from adding atezolizumab to CPB. PD-L1 status was more reliably associated with numerically longer PFS with atezolizumab + CPB. This is the first randomized double-blind trial in ovarian cancer to demonstrate that genomic instability triggered by BRCA1/2m or HRD does not improve sensitivity to immune checkpoint inhibitors.

Objective Children with anorectal malformations (ARM) have a high rate of renal anomalies and increased risk of urinary tract infection (UTI). We aimed to determine whether using routine Micturating Cystourethrogram (MCUG) to detect VUR is effective in reducing the incidence of UTI or renal scarring in children with ARM. Methods A retrospective study of consecutive children diagnosed with ARM in two centres with a minimum of 3 years follow-up was performed, excluding those with cloaca or an MCUG prior to ARM repair. Univariate and multivariate logistic regression analysis was used to determine variables which were associated with VUR, UTI and renal scarring. Associations are described as Odd's Ratio (OR), 95% Confidence Interval. Significance was taken as p Results 344 children were included with a median age of 8 years (IQR 5–11 years). 150 (44%) were female. 89 (26%) had renal anomalies and 101 (29%) had spine anomalies. 148 patients had routine MCUG and VUR was found in 62 (42%) of these children. Univariate analysis did not correlate any of the assessed variables with VUR or renal scarring. However, abnormal renal ultrasound - OR 6.18 (95% CI 2.99–13.07, p 0.0001) was associated with UTI whilst abnormal spine - OR 0.27 (95% CI 0.10–0.62, p 0.009), low ARM - OR 0.30 (CI 0.14–0.63, p 0.006) and intermediate ARM - OR 0.35 (CI 0.17–0.70, p 0.01) were associated with a reduced risk of UTI. On multivariate analysis, only abnormal renal USS retained a significant association with UTI (p Conclusions VUR is common in patients with ARM. Children with an abnormal R-USS are at increased risk of UTI. Performing routine MCUG does not reduce the risk of UTI in children with ARM.

Reducing the minimum load at which a unit can reliably operate is one method to manage changes in market demands and avoid inherent concerns over frequent on and off cycling. For this reason, it is now becoming common practice for plants to develop new lower minimum load levels that are well below conventional targets provided when the unit was first commissioned. For many plants, the criteria for successful operation were not based on optimizing minimum load levels. In fact, most conventional steam plants were commissioned during an era when full base load operation was expected throughout the life of the plant. Base load availability was the key driver not parameters that promoted unit flexibility. As a result, there are opportunities for plants to lower minimum load levels, but it is important for owners to understand the trade-offs and risks that come with such operation. TG Advisers (Turbine - Generator) and Tetra Engineering (Boiler) partnered on an analytical assessment and process simulation for a US site with four vintage boilers and steam turbines, the boilers having been converted from coal to gas-firing some years earlier. The boilers were modeled at different load points using boiler and power plant process simulation software. Key issues analyzed were superheat steam temperature, stability of natural circulation, and maintenance of minimum flow velocities. Secondary factors included cold end condensation and the potential for accumulation of dissolved solids in the circuit. Utilizing the results of Tetra’s boiler model, TGA completed off-design modeling and calculations for the steam turbine and balance of plant equipment. Examples of primary interest was the impact of the predicted steam conditions and superheat, resulting thermal transient cycles, and LP blading concerns influenced by moisture content and back pressure control. Finally, balance of plant equipment was reviewed to ensure acceptable operating points for key equipment such as boiler feed pumps, feedwater heaters, and hood spray systems. Following computer simulations, a plant testing plan was developed, and plant testing was completed. The paper will review analytical predictions and actual plant testing as well as overall lessons learned from the project. Through these analytical and testing efforts the minimum load was reduced from the current practice of 65 MW to 31 MW.