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To reduce the harmful impact of railway transport on the environment and ensure environmental safety, railway enterprises develop and implement a wide range of environmentally effective measures annually. First, it concerns the protection of the territories adjacent to the railroad tracks from various types of pollution. These forest plantations are created for the protection of the railroad track from adverse climatic factors, as well as for the reduction of the railway's impact on the surrounding territories - to reduce the various types of pollution, and to protect from adverse aerodynamic effects. In order to investigate the protective properties of forest plantations, we presented their detailed characteristics on the section of the Lviv-Sambir railway line. This is the busiest railway line in terms of the number of trains, which connects the eastern industrial regions of Ukraine with the western part of the European Union. It transports the largest volumes of cargo, including hazardous ones. The effect of afforestation on reducing the heavy metals content in the soil of the impact area of the railway was determined experimentally. In all samples, the concentrations of heavy metals in the soil do not exceed the maximum permissible concentration standards: Cu-100, Zn-100, Pb-30, Cd-3.0 mg/kg3. However, there is a decrease in the heavy metals' content with the distance from the track. Differences in ingredient pollution depending on the placement of plantations were established. Thus, the concentration of heavy metals is higher on average from 2.6% to 29.9% in the areas on the windward side compared to the areas on the opposite leeward side. Therefore, forest vegetation intensively retains heavy metals and performs the function of a filter for the natural environment. Research has established a reduction in the parametric impact of railway transport. The level of protective plantings' effect on noise reduction along railway lines was determined. The highest noise levels of electric trains were determined at 95-94 dBA near the track, at a distance of 50-100 m the noise level remained high at 90-82 dBA, and at a distance of 150-200 m the noise ranged from 86 to 65 dBA; the highest noise levels of passenger trains were determined near the track of 92-91 dBA; freight trains ‒ near the track 93-92 dBA. The dependence of the noise level on the structure and condition of the plantations was determined. Thus, it can be stated that the existing forest plantations perform their phytomelioration functions and reduce the negative ingredient and parametric impact of railway transport. In order to protect the territories adjacent to the railway from pollution successfully, it is necessary to monitor transport sections constantly to ensure the sustainable development of the railway industry.

Background: Endocrine therapy (ET) is the mainstay of ER+ BC treatment. However; up to 20% of ER+ BC tumors progress into metastatic disease and develop ET resistance, underscoring the need for combination therapies. Preclinical data suggest that combining phosphatidylinositol 3-kinase (PI3K) inhibitors with ET may overcome resistance. OPPORTUNE, a preoperative phase II window trial, evaluated whether the combination of the PI3K inhibitor pictilisib with anastrozole (PIC+ANA) can increase the antitumor effect of ANA in newly diagnosed operable ER+ BC. Early results showed greater suppression of tumor Ki67 in patients treated with PIC+ANA versus ANA alone. Here, we present gene expression analysis from tumors collected pre- and post-treatment, and their associations with Ki67 outcomes. Methods: Postmenopausal women with newly diagnosed operable ER+/HER2-negative BC were randomly allocated (2:1, favoring the combination) to 2 weeks of preoperative treatment with ANA 1 mg once per day (n = 47) or the combination of ANA 1 mg with PIC 260 mg once per day (n = 89). The primary end point was inhibition of tumor cell proliferation measured by change in Ki67 protein expression via IHC between tumor samples taken pre- and post-treatment. Samples were analyzed by RNA-sequencing—ER pathway activity, PAM50 intrinsic subtypes, and pathway analyses were assessed by Ki67 outcomes. Elastic net regression analysis and transcription factor activity inference with Dorothea were performed to identify features strongly associated with Ki67 outcomes. Results: 124 patients (ANA, n=43; PIC+ANA, n=81) had paired tumor samples at baseline/week 2 that were evaluable for both Ki67 and RNA-seq. PIC+ANA showed improved suppression of Ki67 compared to ANA alone (-83.78% vs -73.85%, p=0.012) and a greater proportion of patients achieved complete cell cycle arrest (CCCA, as defined by Ki67< 2.7%) in the PIC+ANA arm (45.68% vs 36.59%). ER pathway activity suppression was comparable between treatments. PAM50 classification based on RNA-seq showed that 83.0% of tumors were luminal (Lum) A at baseline and 12.9% were LumB, with the remainder being classified as Normal-like. PIC+ANA showed greater suppression of Ki67 in LumB tumors compared to LumA (-92.29% vs -81.62%). This effect was much greater in the PIC+ANA arm compared to LumB tumors treated with ANA alone (-92.29% vs -37.87%); however, given the low number of LumB tumors in the ANA arm (n=3), we could not determine statistical significance. Bioinformatic analysis of RNA-seq from baseline specimens showed that MYBL2 activity was associated with resistance to ANA (as defined by Ki67≥7.5% at week2). Tumors in the top quartile of MYBL2 activity at baseline showed improved Ki67 outcomes in the PIC+ANA arm compared to ANA alone (-91.71% vs -51.44%), while no differences were observed between treatments for tumors with lower MYBL2 activity (-79.16% vs -76.72%). Single-nucleus (sn)-RNA-seq from untreated ER+ BC tumors showed that MYBL2 was enriched in a single cluster of tumor cells, which also had the highest expression of a subset of actionable targets (including CDK1, CDK2, CDK4, EZH2, and AKT1), as compared to other tumor cells. Expression data from DepMap and drug-sensitivity data from ER+ BC cell lines show a positive trend between high MYBL2 expression and sensitivity to the ER degrader, giredestrant. Conclusions: PIC exhibited greater antiproliferative effects in combination with ANA in ER+/HER2- early BC compared to ANA alone, particularly in LumB and MYBL2-high tumors. Furthermore, the transcriptional profile and in vitro response of tumor cells with high MYBL2 expression suggest potential sensitivity to other combination therapies. Citation Format: Alejandro Martinez Chibly, Alice Shia, Radia Johnson, Michael S. Hwang, Marc Hafner, Ciara Metcalfe, Kalpit Shah, Michal Slyper, Chris Bolen, Sarah E. Pinder, Alastair M. Thompson, Steven Gendreau, Peter Schmid. PD10-06 Clinical outcomes and exploratory gene expression analysis of OPPORTUNE: a phase II window-of-opportunity study to evaluate pictilisib+anastrozole versus anastrozole alone in ER-positive breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD10-06.

Background: Mammographic screening programmes reduce breast cancer mortality, but detect many small tumours with favourable biological features which may not progress during a woman’s lifetime. Screen-detected cancers are treated with standard surgery and adjuvant therapies, with associated morbidities. There is a need to reduce overtreatment of good prognosis tumours and numerous studies have evaluated the omission of radiotherapy in this context. However, there is little evidence to support surgical de-escalation, although percutaneous minimally invasive treatment approaches have been described. Vacuum-assisted excision (VAE) is in widespread use for management of benign lesions and lesions of uncertain malignant potential. SMALL (ISRCTN 12240119) is designed to determine the feasibility of using this approach for treatment of small invasive tumours detected within the UK NHS Breast Screening Programme (BSP). Methods: SMALL is a phase III multicentre randomised trial comparing standard surgery with VAE for screen-detected good prognosis cancers. The main eligibility criteria are age ≥47 years, unifocal grade 1 tumours with maximum diameter 15mm, which are strongly ER/PR+ve and HER2-ve, with negative clinical/radiological axillary staging. Patients are randomised 2:1 in favour of VAE or surgery; with no axillary surgery in the VAE arm. Completeness of excision is assessed radiologically, and if excision is incomplete, patients undergo open surgery. Adjuvant radiotherapy and endocrine therapy are mandated in the VAE arm but may be omitted following surgery. Co-primary end-points are: 1. Non-inferiority comparison of the requirement for a second procedure following excision 2. Single arm analysis of local recurrence (LR) at 5 years following VAE Recruitment of 800 patients will permit demonstration of 10% non-inferiority of VAE for requirement of a second procedure. This ensures sufficient patients for single arm analysis of LR rates, where expected LR free survival is 99% at 5 years, with an undesirable survival probability after VAE of 97%. To ensure that the trial as a whole only has 5% alpha, the significance level for each co-primary outcome is set at 2.5% with 90% power. The Data Monitoring Committee will monitor LR events to ensure these do not exceed 3% per year. Secondary outcome measures include time to ipsilateral recurrence, overall survival, complications, quality of life and health economic analysis. A novel feature of SMALL is the integration of a QuinteT Recruitment Intervention (QRI), which aims to optimise recruitment to the study. Recruitment challenges are identified by analysing recruiter/patient interviews and audio-recordings of trial discussions, and by review of trial screening logs, eligibility and recruitment data and study documentation. Solutions to address these are developed collaboratively, including individual/group recruiter feedback and recruitment tips documents. Results: SMALL opened in December 2019, but recruitment halted in 2020 for 5 months due to COVID-19. At 7st July 2022, 142 patients had been randomised from 26 centres, with a randomisation rate of approximately 45%, and a per site recruitment rate of 0.4-0.5 patients/month, approaching the feasibility recruitment target of 144 patients. Drawing from preliminary QRI findings and insights from patient representatives, a recruitment tips document has been circulated (on providing balanced information about treatments, encouraging recruiters to engage with patient preferences, and explaining randomisation). Individual recruiter feedback has commenced, with wider feedback delivered across sites via recruitment training workshops. Conclusion: Despite pandemic-related challenges, SMALL has an excellent recruitment rate to date and is expected to have a global impact on treatment of breast cancer within mammographic screening programmes. SMALL is funded by the UK NIHR HTA programme, award 17/42/32 Citation Format: Stuart A. McIntosh, Charlotte E. Coles, David Dodwell, Kenneth Elder, Jessica Foster, Claire Gaunt, Amanda Kirkham, Iain Lyburn, Jenna Morgan, Sangeetha Paramasivan, Sarah E. Pinder, Sarah Pirrie, Shelley Potter, Tracy Roberts, Nisha Sharma, Hilary Stobart, Elizabeth Southgate, Sian Taylor-Phillips, Matthew Wallis, Daniel Rea. SMALL: Open Surgery versus Minimally invasive vacuum-Assisted excision for smaLL screen-detected breast cancer – a UK phase III randomised multi-centre trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT3-20-02.

Reproductive characteristics are known risk factors for breast cancer but, other than recent birth, their role as prognostic factors is less clear, and has not been studied in Sub-Saharan Africa (SSA). In this setting, we examined whether reproductive factors independently influence breast cancer survival in a subset of the African Breast Cancer – Disparities in Outcomes cohort study. In 1485 women with incident breast cancer recruited between 2014 and 2017, we examined birth cohort changes in reproductive factors, and used Cox models to examine whether reproductive characteristics were associated with all-cause mortality after adjusting for confounders (age, stage, treatment, HIV, and social factors). Four years after diagnosis, 822 (56%) women had died. Median parity was 4 (IQR=2, 6) and 209 (28%) of premenopausal women had had a recent birth (less than three years prior to cancer diagnosis). Each pregnancy was associated with a 5% increase (95% CI: 2%, 8%) in mortality rates, which held among postmenopausal women (5%, (1%-9%)). Pre-menopausal women with a recent birth had 52% (20%, 92%) higher mortality rates. Fertility trends by birth cohort showed declining parity, increasing age at first birth and declining age at last birth, however the impact of these population-level changes on future average survival was predicted to be very small (

In this insight article, we aim to challenge current thinking regarding coaching and spark new ideas by demonstrating how high-performance Paralympic sport contexts provide rich environments for innovation. We propose an innovative approach to enhance coach learning and introduce coaches and practitioners to three interconnected areas of opportunity emerging in research: (a) reframing the role and harnessing the work of skill acquisition specialists, (b) the use of a design thinking approach, and (c) the implementation of technology-enhanced learning. Specifically, we demonstrate how using these three strategies can better facilitate cocreated coach learning in situ. Whilst we acknowledge that each of these areas is not necessarily new, we propose that when addressed and applied collectively by practitioners they can provide effective and efficient coach learning opportunities, where the result of the integration of ideas means the impact can be greater than simply the sum of the parts. We highlight how this approach has emerged out of challenging high-performance Paralympic sport contexts, and could have impact on research, practice, and coach development experiences across a wider range of contexts along the performance pathway in both Paralympic and nondisabled sports.

Background Survival rates for ovarian cancer remain poor, and monitoring and prediction of therapeutic response may benefit from additional markers. Ovarian cancers frequently overexpress Folate Receptor alpha (FRα) and the soluble receptor (sFRα) is measurable in blood. Here we investigated sFRα as a potential biomarker. Methods We evaluated sFRα longitudinally, before and during neo-adjuvant, adjuvant and palliative therapies, and tumour FRα expression status by immunohistrochemistry. The impact of free FRα on the efficacy of anti-FRα treatments was evaluated by an antibody-dependent cellular cytotoxicity assay. Results Membrane and/or cytoplasmic FRα staining were observed in 52.7% tumours from 316 ovarian cancer patients with diverse histotypes. Circulating sFRα levels were significantly higher in patients, compared to healthy volunteers, specifically in patients sampled prior to neoadjuvant and palliative treatments. sFRα was associated with FRα cell membrane expression in the tumour. sFRα levels decreased alongside concurrent tumour burden in patients receiving standard therapies. High concentrations of sFRα partly reduced anti-FRα antibody tumour cell killing, an effect overcome by increased antibody doses. Conclusions sFRα may present a non-invasive marker for tumour FRα expression, with the potential for monitoring patient response to treatment. Larger, prospective studies should evaluate FRα for assessing disease burden and response to systemic treatments.

This study uses published and unpublished data to create a comprehensive and up-to-date synthesis of available information on a little-known group of invertebrates, namely, non-marine giant ostracods (cypridids ≥3 mm long). Approximately 8% of the ∼1000 living cypridid species are identified as ‘giant’. They occur in a range of subfamilies, in all zoogeographic regions, except Antarctica, and mainly in small standing-water ecosystems. Only those in the subfamily Mytilocypridinae are reasonably well studied. This subfamily is endemic to Australia and comprises a diverse range of giant species (∼29 species in 6 genera), mainly in temporary habitats, mostly salt lakes, including in extreme conditions. We evaluate the current taxonomy of the Mytilocypridinae, analyse patterns in the field distributions and abiotic tolerances of species, and review the general biology of these ostracods. We also identify those species most in need of consideration in conservation planning, highlight critical gaps in knowledge and show how these ostracods could serve as useful models for testing ecological and evolutionary theories. The results of this study can be used to inform conservation planning for giant ostracods and direct further study of these unique invertebrates, which are an important component of the biodiversity of small standing-water ecosystems.

Genome sequencing of cancers often reveals mosaics of different subclones present in the same tumour1–3. Although these are believed to arise according to the principles of somatic evolution, the exact spatial growth patterns and underlying mechanisms remain elusive4,5. Here, to address this need, we developed a workflow that generates detailed quantitative maps of genetic subclone composition across whole-tumour sections. These provide the basis for studying clonal growth patterns, and the histological characteristics, microanatomy and microenvironmental composition of each clone. The approach rests on whole-genome sequencing, followed by highly multiplexed base-specific in situ sequencing, single-cell resolved transcriptomics and dedicated algorithms to link these layers. Applying the base-specific in situ sequencing workflow to eight tissue sections from two multifocal primary breast cancers revealed intricate subclonal growth patterns that were validated by microdissection. In a case of ductal carcinoma in situ, polyclonal neoplastic expansions occurred at the macroscopic scale but segregated within microanatomical structures. Across the stages of ductal carcinoma in situ, invasive cancer and lymph node metastasis, subclone territories are shown to exhibit distinct transcriptional and histological features and cellular microenvironments. These results provide examples of the benefits afforded by spatial genomics for deciphering the mechanisms underlying cancer evolution and microenvironmental ecology.

Background: This study examined self-reported physical activity (PA) participation, well-being, and perceived needs of Canadians with disabilities during the COVID-19 pandemic. In addition, we assessed physical and mental health and the extent to which pre-identified needs were being met or unmet. Methods: Two iterations of the COVID-19 Disability Survey were conducted during two pandemic timeframes: June–December 2020 (iteration 1, n = 599) and December 2020–September 2021 (iteration 2, n = 528). PA participation was assessed with the International Physical Activity Questionnaire. Physical and mental health were assessed with the PROMIS Global-10 questionnaire. A needs assessment was conducted on 11 needs pre-identified in partnership with community organizations. Results: Approximately 50% of respondents to both iterations reported that they did not do any moderate-vigorous intensity PA. While physical health was not different between timeframes, mental health was worse during iteration 2 than iteration 1 (p = 0.028). During both timeframes, access to recreation and leisure facilities was the greatest unmet need. Conclusion: These data highlight the low levels of PA and the perceived changes in PA, mental health, and recreational needs of Canadians with disabilities during the pandemic. The findings of the Survey were used to support policy change to remove barriers to PA participation for people with disabilities in Ontario.

Despite organizations increasingly seeking talent to identify data to make better business decisions, many assignments provide the data for the students. This article encourages curriculum to introduce data and information request dimensions, identify data sources, write data and information requests, and reflect on data request examples. We propose a three-step writing exercise with a data and information request rubric. A pilot study for an operations management data and information request revealed that participants struggled to specify four data request dimensions: an appropriate recipient, adequate data, a data format, and an information security level.

Trigger finger is a common condition affecting the hand. Therapeutic variability surrounds the management of trigger finger, especially in the mild cases. The aim of this study was to survey secondary care surgeons to describe the current management of trigger fingers. The steering group developed a survey for hand surgeons. Following piloting, the survey was distributed to hand surgeons in the United Kingdom and The Netherlands. A total of 713 plastic surgeons and orthopaedic surgeons were invited to participate in the online survey and 440 (62%) surgeons completed the survey. In both mild and moderate cases of trigger finger, steroid injection was the preferred treatment option. Open surgery was the treatment of choice for severe cases. However, there was variation in delivery of care, including type and dosage of steroid, site of injection, interval between injections, maximum number of injections, type of incision and treatment of patients with diabetes or rheumatoid arthritis. This highlights the need for a better evidence base for the treatment of trigger fingers.

Practical and theoretical frameworks centred around skill acquisition (SA) aim to provide opportunities and techniques to enhance athletes’ learning. Recent moves to embed SA practitioners in daily performance environments allows for insight into current coaching practices, and a means to enhance talent development pathways. While calls for more embedded coach support are not new, Para sport contexts may in fact be frontrunners in translation of knowledge for coach and athlete development. In this chapter, we highlight some of the ways applied SA support and research programs can achieve this in Para sport, using case-study insights from Great Britain and Australia. The examples provided highlight the importance of the coach-athlete-practitioner relationship, suggest that big shifts in thinking can occur over a relatively short period of time, and provide opportunities to reduce some of the barriers associated with coach and athlete development in high-performance Para sport environments.

Ductal carcinoma in-situ (DCIS) accounts for 20-25% of all new breast cancer diagnoses. DCIS has an uncertain risk of progression to invasive breast cancer and a lack of predictive biomarkers may result in relatively high levels (~ 75%) of overtreatment. To identify unique prognostic biomarkers of invasive progression, crystallographic and chemical features of DCIS microcalcifications have been explored. Samples from patients with at least 5-years of follow up and no known recurrence (174 calcifications in 67 patients) or ipsilateral invasive breast cancer recurrence (179 microcalcifications in 57 patients) were studied. Significant differences were noted between the two groups including whitlockite relative mass, hydroxyapatite and whitlockite crystal maturity and, elementally, sodium to calcium ion ratio. A preliminary predictive model for DCIS to invasive cancer progression was developed from these parameters with an AUC of 0.797. These results provide insights into the differing DCIS tissue microenvironments, and how these impact microcalcification formation.

Chromosome 17 alterations affect the assessment of HER2 gene amplification in breast cancer (BC), but its clinical significance remains unclear. This study aimed to identify the prevalence of centromere enumeration probe 17 (CEP17) alterations, and its correlation with response to neoadjuvant therapy (NAT) in BC patients with human epidermal growth factor receptor 2 (HER2) immunohistochemistry-equivocal score.A large BC cohort (n = 6049) with HER2 immunohistochemistry score 2+ and florescent in-situ hybridisation (FISH) results was included to assess the prevalence of CEP17 alterations. Another cohort (n = 885) with available clinicopathological data was used to evaluate the effect of CEP17 in the setting of NAT. HER2-amplified tumours with monosomy 17 (CEP17 copy number 1.5 per nucleus), normal 17 (CEP17 1.5- 3.0) and polysomy 17 (CEP17 ≥ 3.0) were observed in 16, 59 and 25%, respectively, compared with 3, 74 and 23%, respectively, in HER2-non-amplified tumours. There was no significant relationship between CEP17 alterations and pathological complete response (pCR) rate in both HER2-amplified and HER2-non-amplified tumours. The independent predictors of pCR were oestrogen (ER) negativity in HER2-amplified tumours [ER negative versus positive; odds ratio (OR) = 11.80; 95% confidence interval (CI) = 1.37-102.00; P = 0.02], and histological grade 3 in HER2 non-amplified tumours (3 versus 1, 2; OR = 5.54; 95% CI = 1.61-19.00; P = 0.007).The impacts of CEP17 alterations are not as strong as those of HER2/CEP17 ratio and HER2 copy number. The hormonal receptors status and tumour histological grade are more useful to identify BC patients with a HER2 immunohistochemistry-equivocal score who would benefit from NAT.

College students faced many challenges due to the coronavirus disease 2019 (COVID-19) pandemic that are unique to them (eg, sudden relocation, interruption in their education and transition to virtual learning, and having to find a mental health provider licensed in their home state when returning home for school closure) and adjunct to challenges faced by the general population (eg, economic strains, racial discrimination, health disparities, and sense of social isolation). Previous studies consistently reported increased stress, mood, and anxiety symptoms and even suicidal ideation among college students since the COVID-19 outbreak. Anecdotally, many students have also shared concerns and anxiety due to returning to normal college life. To better prepare for potential future disruptions and/or other similar challenges, schools need to consider proactive steps for supporting student mental health in their transition not only to virtual learning but also to having them back on campus. [ Psychiatr Ann . 2022;52(8):323–327.]

Purpose: To investigate the associations of childhood adversities (CAs) with lifetime onset and transitions across suicidal thoughts and behaviors (STB) among incoming college students. Methods: Web-based self-report surveys administered to 20,842 incoming college students from nine countries (response rate 45.6%) assessed lifetime suicidal ideation, plans and attempts along with seven CAs: parental psychopathology, three types of abuse (emotional, physical, sexual), neglect, bully victimization, and dating violence. Logistic regression estimated individual- and population-level associations using CA operationalizations for type, number, severity, and frequency. Results: Associations of CAs with lifetime ideation and the transition from ideation to plan were best explained by the exact number of CA types (OR range 1.32–52.30 for exactly two to seven CAs). Associations of CAs with a transition to attempts were best explained by the frequency of specific CA types (scaled 0–4). Attempts among ideators with a plan were significantly associated with all seven CAs (OR range 1.16–1.59) and associations remained significant in adjusted analyses with the frequency of sexual abuse (OR = 1.42), dating violence (OR = 1.29), physical abuse (OR = 1.17) and bully victimization (OR = 1.17). Attempts among ideators without plan were significantly associated with frequency of emotional abuse (OR = 1.29) and bully victimization (OR = 1.36), in both unadjusted and adjusted analyses. Population attributable risk simulations found 63% of ideation and 30–47% of STB transitions associated with CAs. Conclusion: Early-life adversities represent a potentially important driver in explaining lifetime STB among incoming college students. Comprehensive intervention strategies that prevent or reduce the negative effects of CAs may reduce subsequent onset of STB.

BACKGROUND: Comprehensive breast cancer management is essential to achieve high breast cancer survival; however, detailed reports of the treatment regimens received by patients are scarce in sub-Saharan Africa where survival is low. We aimed to examine treatment initiation, guideline concordance, and abandonment in patients with non-metastatic breast cancer in sub-Saharan Africa from the African Breast Cancer-Disparities in Outcomes (ABC-DO) prospective cohort. METHODS: The ABC-DO prospective cohort study recruited women (aged ≥18 years) with newly diagnosed invasive breast cancer in eight hospitals across five sub-Saharan African countries (Namibia, Nigeria, Uganda, South Africa, and Zambia). We analysed treatments received by women who were classified as non-metastatic (M0) at the initial presentation. Data on surgery, radiotherapy, and systemic therapies were obtained from medical records and a self-reported follow-up questionnaire at 6 months after the diagnosis, follow-up calls every 3 months, and a baseline questionnaire. Initiation, completion, and abandonment of treatment modalities and combined therapy regimens were examined overall, by country-specific groups, and by clinical factors relevant for guideline-based treatment. FINDINGS: Of 2313 women recruited into the ABC-DO study between Sept 10, 2014, and Dec 31, 2017, 2226 had histologically or clinically confirmed breast cancer. Of these 2226 women, 510 were excluded from the present analysis because 378 had metastatic disease, 37 were prevalent cases (defined as those previously diagnosed with breast cancer >2 years before baseline), 82 had unknown TNM stage, and 13 were White or Asian women in South Africa (number was too small for analysis). After a median follow-up of 5·2 years (IQR 4·6-5·9), 1163 (68%) of 1716 women underwent breast cancer surgery. Surgery and systemic therapy (ie, multimodality treatment) with radiotherapy was initiated in 370 (36%) of 1028 women with localised tumours versus 156 (23%) of 688 women with locally advanced tumours, whereas multimodality treatment without radiotherapy was initiated in 386 (38%) versus 167 (24%) women, respectively. Of 1530 patients requiring chemotherapy (which excludes 105 who died within 6 months after baseline), 1013 (66%) initiated treatment of neoadjuvant chemotherapy or surgery within 3 months after baseline, which was adequately completed by 359 (35%) of 1013 women, marginally completed by 284 (28%), abandoned by 200 (20%), and unknown in 151 (15%). 19 (2%) women died within 6 months after chemotherapy initiation. Of 1375 women in whom endocrine therapy was indicated, this treatment was initiated in 920, and lasted at least 3 years in 367 (40%) women. Treatment disparities between country-specific groups were substantial for all therapy regimens. INTERPRETATION: A high proportion of patients with non-metastatic breast cancer did not initiate, did not fully complete, or abandoned treatment with surgery, systemic therapy, radiotherapy, or an appropriate combination of these, highlighting the need for improved treatment access and completion in sub-Saharan Africa to potentially prevent premature breast cancer deaths. FUNDING: National Institutes of Health (National Cancer Institute), Susan G Komen, and the International Agency for Research on Cancer.

Conceptual engineering is sometimes presented as an alternative to conceptual analysis. But one important objection to conceptual analysis threatens to carry across: that philosophy investigates phenomena—knowledge, truth, freedom, etc.—rather than concepts of those phenomena. This poses a prima facie problem insofar as conceptual engineering targets concepts or terms rather than phenomena. Call it the ‘phenomenon objection’. I begin by examining recent discussions of the phenomenon objection by Cappelen and Scharp, rejecting their responses. I then clarify and strengthen the objection, discussing the challenge that the ‘strong phenomenon objection’ poses to conceptual engineers. Finally, I develop a new response to the strong phenomenon objection. In doing so, I motivate, articulate and defend an account of philosophy and its problems on which conceptual engineering is the appropriate method for tackling many philosophical problems—as well as, perhaps surprisingly, some problems in the sciences.

This article studies the cognitive and communicative effects of typographical iconicity in poetry from the perspective of relevance theory. It argues that the visual aspect pertaining to an instance of typographical iconicity conveys a sensory impression, which perceptually resembles elements of the semantic material represented via the typographical iconicity’s lexical aspect. It is suggested that the non-propositional information relating to this impression can trigger the derivation of a wide array of weak implicatures which can combine to form an impressionistic and indeterminate cognitive state described within relevance theory as a poetic effect. Furthermore, since the added effort, which the typographical iconicity requires to be perceived and processed, is offset by the derived implicatures, the use of typographical iconicity may be said to produce an optimally relevant level of processing.

This article examines the meaning of the ‘impolitical’ regarding cases of impolitical theatre and associated critical discourse, with reference to Rodolfo Usigli and Raymond Williams, among others. It is argued that ‘impolitical’ theatre represents social relations from the standpoint of the ideal of culture. The analysis starts with Richard Schechner’s critique of the original Broadway production of Edward Albee’s Who’s Afraid of Virginia Woolf? and discusses this play, segueing into The Performance Group’s Dionysus in 69. The author indicates the differences of theatre practice between the examples chosen, and shows that these theatres nevertheless participate in the same form of theatrical representation as they broach similar social questions of moment in the Unites States in the 1960s. John Yves Pinder has recently received his PhD from the University of Leeds. He is currently teaching at Leuphana University of Lüneberg.

BACKGROUND: Studies have shown increased mortality among women living with HIV diagnosed with breast cancer compared with HIV-negative women with breast cancer. We aimed to examine how this HIV differential varies by patient or breast tumour characteristics. METHODS: The African Breast Cancer-Disparities in Outcomes (ABC-DO) study is a prospective cohort of women (aged ≥18 years) with incident breast cancer recruited consecutively at diagnosis (2014-17) from hospitals in Namibia, Nigeria, South Africa, Uganda, and Zambia. Detailed clinical and epidemiological data, including self-reported or tested HIV status, were collected at baseline. Participants were actively followed up via telephone calls every 3 months. The primary outcome was all-cause mortality, assessed in all women who had at least one updated vital status after baseline interview. Using Cox regression, we examined differences in overall survival by HIV status in the cohort, and across country and patient subgroups, adjusted for age, tumour grade, and tumour stage at cancer diagnosis. FINDINGS: Between Sept 8, 2014, and Dec 31, 2017, we recruited 2154 women with primary breast cancer, 519 of whom were excluded due to their countries having small numbers of women with HIV for comparison. Among the remaining 1635 women, 313 (19%) were living with HIV, 1184 (72%) were HIV negative, and 138 (9%) had unknown HIV status. At breast cancer diagnosis, women with HIV were younger and had lower body-mass index (BMI) than their HIV-negative counterparts, but had similar tumour stage, grade, and receptor subtypes. At the end of the follow-up (Jan 1, 2019), a higher proportion of women with HIV (137 [44%] of 313) had died than had HIV-negative women (432 [37%] of 1184). Crude 3-year survival was 9% lower for women with HIV (46% [95% CI 40-53]) than for HIV-negative women (55% [52-59]; hazard ratio (HR) 1·41 [1·15-1·74]). The HIV survival differential did not differ by age, BMI, tumour subtype, or tumour grade, but was stronger in women with non-metastatic disease (3-year survival 52% HIV-positive vs 63% HIV-negative women, adjusted HR 1·65 [1·30-2·10]), whereas women with metastatic cancer had low survival, regardless of HIV status. INTERPRETATION: The larger survival deficit among women with HIV with non-metastatic breast cancer calls for a better understanding of the reasons underlying this differential (eg, biological mechanisms, health behaviours, detrimental HIV-breast cancer treatment interactions, or higher HIV background mortality) to inform strategies for reducing mortality among this patient group. FUNDING: Susan G Komen, International Agency for Research on Cancer, National Cancer Institute, and UK-Commonwealth Scholarships.

The microplastic loads in elvers of the critically endangered European eel Anguilla anguilla, sampled in the lower reaches of three English rivers, were very low (incidence: 3.3%, mean ± s.d.: 0.03 ± 0.18 particles) and did not vary with body length or between rivers. Particles were mostly black, polyolefins, fibres and fragments of size 101–200 μm. Current levels indicate a low contamination pressure locally and, consequently, management efforts might prioritise mitigating the effects of other stressors affecting the species.

Grace Hibshman has developed a new explanation for why narrative self-conceptions might contribute to one’s flourishing: conceiving of one’s life narratively, she argues, can facilitate an improved self-understanding. In this short paper, we argue that, pace Hibshman, life narratives tend to misrepresent and mislead. So while they may give the impression of an improved self-understanding, that impression is typically mistaken. In this respect, conceiving of one’s life narratively hinders flourishing.

Expression cloning of fully human monoclonal antibodies (hmAbs) is seeing powerful utility in the field of vaccinology, especially for elucidating vaccine-induced B-cell responses and novel vaccine candidate antigen discovery. Precision of the hmAb cloning process relies on efficient isolation of hmAb-producing plasmablasts of interest. Previously, a novel immunoglobulin-capture assay (ICA) was developed, using single protein vaccine antigens, to enhance the pathogen-specific hmAb cloning output. Here, we report a novel modification of this single-antigen ICA using formalin-treated, fluorescently stained whole cell suspensions of the human bacterial invasive pathogens, Streptococcus pneumoniae and Neisseria meningitidis. Sequestration of IgG secreted by individual vaccine antigen-specific plasmablasts was achieved by the formation of an anti-CD45-streptavidin and biotin anti-IgG scaffold. Suspensions containing heterologous pneumococcal and meningococcal strains were then used to enrich for polysaccharide- and protein antigen-specific plasmablasts, respectively, during single cell sorting. Following application of the modified whole-cell ICA (mICA), ~61% (19/31) of anti-pneumococcal polysaccharide hmAbs were cloned compared to 14% (8/59) obtained using standard (non-mICA) methods – representing a ~4.4-fold increase in hmAb cloning precision. A more modest ~1.7-fold difference was obtained for anti-meningococcal vaccine hmAb cloning; ~88% of hmAbs cloned via mICA versus ~53% cloned via the standard method were specific for a meningococcal surface protein. VDJ sequencing revealed that cloned hmAbs reflected an anamnestic response to both pneumococcal and meningococcal vaccines; diversification within hmAb clones occurred by positive selection for replacement mutations. Thus, we have shown successful utilisation of whole bacterial cells in the ICA protocol enabling isolation of hmAbs targeting multiple disparate epitopes, thereby increasing the power of approaches such as reverse vaccinology 2.0 (RV 2.0) for bacterial vaccine antigen discovery.

This thesis investigates how and why luxury brand stores articulate, establish, and perpetuate luxury brand identity in the airport. Through the construction of luxury narratives, spaces, display, and services, the luxury sensory environments must be able to attract and engage airport passengers. This thesis discusses how the airport is considered transitory and unique, which means that the identity of luxury brands must remain stable and familiar, in an environment which has opportunities to diffuse luxury. Furthermore, the airport in contemporary consciousness is driven by notions of luxury, leisure, pleasure, and the exotic. They are places of possibility and desire, which drives the need for luxury experiences. This is the first study of its kind to explore how luxury branded spaces in the airport are constructed, and how through methods of the expression of luxury display, they renegotiate what luxury means to consumers. Previous research has failed to consider how the perception of luxury is influenced in unique transitory environments, such as the airport.International airports are now considered luxury shopping destinations in themselves. Since the first duty-free store was established in 1947 at Shannon airport in Ireland, retail in the airport has grown to seventy six billion dollars, and will reach one hundred and twelve billion dollars by 2025 (Adroit Research, 2019). Airport retail proves to be the most resilient global market, and globe travellers are four times more likely to spend on luxury purchases in the airport than in non-airport stores (Blue, 2019)1. Therefore, luxury brands have realised that they can provide a unique offering, experience, and sensory engagement within the airport environment, which act as a microcosm for the retail world.This thesis offers a set of recommendations for luxury brand practitioners, airport managers and academics in the realm of luxury, and suggests that for an airport luxury brand store to be deemed luxury and important, there are special measures which must be in place. These are window display, store interior design, and sensory experience, which help construct, articulate, and reposition luxury in the airport. This is important, because the airport is a distinct, non-place, transitory environment, which, due to historical associations with glamour, carries with it expectations of luxury experiences. Therefore, to raise levels of luxuriousness, spatial constructs must be in place. The results suggest that luxury in the airport must appear exclusive, at the same time inclusive, through the democratisation of the luxury experience. I reveal that the appearance of luxury brands in the airport has repositioned luxury as an accessible and democratic space to experience luxurious things.Key words: airport, transitory, luxury, space, display, accessible, experience

Due to significant advances in instrumentation, many previously specialized techniques have become “routine” in user facilities. However, detailed knowledge held by experts has often not been relayed to general users, so they often rely on entry-level information, basic principles, and comparison with literature results for data analysis. As a result, major errors in the data analysis of multiple surface and material analysis techniques, including in x-ray photoelectron spectroscopy (XPS), have been appearing in the scientific literature. Representative examples of serious errors in XPS data analysis are shown in this work. We suggest that surface and material analysis, and perhaps even science in general, are in a state of “pre-crisis.” We use two (logistic) models from population biology to suggest that bad analyses self-correct if they remain below a critical number. However, beyond a threshold, the literature can become useless because of the perpetuation of faulty analyses and concomitant loss of its self-correcting ability. XPS is used by scientists in many communities because of the power of the technique and high-quality instrumentation that is commercially available. Those who make new surfaces and materials face unique challenges because of the large number of surface and material analytical techniques that are often needed to characterize their materials. Graduate students and post-docs are often provided with only minimal instruction on using surface and material characterization methods. High fees for instruments may affect both the quality and the quantity of the data people collect. The Prisoner's Dilemma is a model from game theory that describes situations with reward structures that encourage uncooperative behavior and lead to suboptimal outcomes. However, the outcomes of Prisoner's Dilemma are not inevitable—their consequences change if their reward structures change. The current system does not appear to incentivize detailed learning of surface and material characterization techniques and careful material characterization. Prisoner's dilemmas appear to lead to other undesirable consequences in science. The concerns raised in this work suggest that many manuscripts are incompletely reviewed at present. The different stakeholders in this problem, including authors, research advisers, subject matter experts, reviewers, scientists who notice examples of faulty data analysis, editors, journals and publishers, funding agencies, scientific societies, leaders at universities and research centers, and instrument vendors, can improve the current situation. This work provides specific recommendations for each of these stakeholders. For example, we believe that authors are primarily responsible for the correctness of their work, not reviewers or editors; we question the wisdom of listing the names of the editor and reviewers on a paper; we are grateful for the significant contributions that have been made by subject matter experts to produce standards and tutorial information; the high cost of instrument time at some institutions may limit student access and result in suboptimal analyses; staff scientists often need to be better recognized for their intellectual contributions to studies; publishers may wish to allow selective reviewing of specific sections of papers related to material characterization; the reviewing at some open access journals may be inadequate; while it had its shortcomings, the pre-open access model of publishing incentivized the production and publication of high-quality work; audits of the products (scientific papers) of funding agencies may be necessary; collaboration needs to be encouraged to a greater extent at some institutions; and instrument vendors should not suggest to potential customers that surface characterization, e.g., by XPS, is trivial or simple.

HIV (human immunodeficiency virus) is a virus that infects different cell types in the immune system. While different monoclonal antibodies have been identified, because of the antigenic diversity of HIV, defining broad neutralising antibodies (bnAbs) it has been very challenging. Using the 10x Chromium technology partitioning system, we performed single-cell sequencing of the B cell repertoire and analysed a cohort of 48 HIV-negative subjects randomised into 4 groups each receiving a different HIV vaccine regime to investigate the type of antibody response to each of the proteins in the vaccine groups, namely ConM SOSIP, EDC ConM SOSIP, ConS UFO and EDC ConS UFO. We recovered over >300,000 single cells and reconstructed full-length antibody heavy- and light-chain variable regions from individual memory B cells, plasmablasts, naïve B cells and activated B cells as well as retrieved their transcriptome profile to correctly separate the different populations within each individual. We identified seven clonotypes representing functional antibodies against vaccine candidate proteins. We reconstructed their phylogenetic tree and confirmed they were novel antibodies in response to HIV. These were mainly antibodies in response to two of the four protein candidates, namely ConS UFO and EDC ConS UFO.

Phytoplankton have short generation times, flexible reproduction strategies, large population sizes, and high standing genetic diversity, traits that should facilitate rapid evolution under directional selection. We quantified local adaptation of copper tolerance in a population of the diatom Skeletonema marinoi from a mining exposed inlet in the Baltic Sea and in a non-exposed population 100 km away. We hypothesized that mining pollution has driven evolution of elevated copper tolerance in the impacted population of S. marinoi. Assays of 58 strains originating from sediment resting stages revealed no difference in the average tolerance to copper between the two populations. However, variation within populations was greater at the mining site, with three strains displaying hyper-tolerant phenotypes. In an artificial evolution experiment, we used a novel intraspecific metabarcoding locus to track selection and quantify fitness of all 58 strains during co-cultivation in one control and one toxic copper treatment. As expected, the hyper-tolerant strains enabled rapid evolution of copper tolerance in the mining exposed population through selection on available strain diversity. Within 42 days, in each experimental replicate a single strain dominated (30-99% abundance) but different strains dominated the different treatments. The reference population developed tolerance beyond expectations primarily due to slowly developing plastic response in one strain, suggesting that different modes of copper tolerance are present in the two populations. Our findings provide novel empirical evidence that standing genetic diversity of phytoplankton resting stage allows populations to evolve rapidly (20-50 generations) and flexibly on timescales relevant for seasonal bloom progressions.

Table S1

Table S2

Supplementary Figure S1. Frequency of genomic aberrations in the KCL TNBC cohort. Supplementary Figure S2. Conceptual diagrams of Scores of Chromosomal Instability Scarring (SCINS). Supplementary Figure S3. Extent and location of SCINS in TNBC. Supplementary Figure S4. Chromosome-wise distribution of SCINS across four TNBC cohorts. Supplementary Figure S5. SCINS-defined tumour classes identify HORMAD1 to be among the top genes linked with Hi-AiCNA/Hi-CnLOH in PrECOG TNBCs. Supplementary Figure S6. Gene expression signatures and HORMAD1 expression. Supplementary Figure S7. Immunofluorescent localisation of HORMAD1 in cell lines. Supplementary Figure S8. Expression of HORMAD1 in breast cancer cell lines and tumour samples. Supplementary Figure S9. HORMAD1 inhibits activity of the DR-GFP HR reporter. Supplementary Figure S10. Effect of HORMAD1 overexpression and knockdown on cell growth and proliferation. Supplementary Figure S11. HORMAD1 promotes activity of the EJ5 NHEJ reporter. Supplementary Figure S12. Effect of HORMAD1 knockdown on 53BP1 and RAD51 foci in HCC1143. Supplementary Figure S13. BRCA1/2 mutation, platinum sensitivity and genomic scarring or HORMAD1 expression. Supplementary Figure S14. Effect of HORMAD1 knockdown on drug sensitivity in HCC1143. Supplementary Figure S15. ROC analysis of PrECOG TNBCs. Supplementary Figure S16. HORMAD1 expression in unselected and BRCA1/2 wildtype TNBCs.

Supplementary Methods, Figure Legends, Table Legends

Table S4

Supplementary Table S1. KCL TNBC and breast cell line cohort characteristics. Supplementary Table S2. Categories of genomic segment used as the basis for measuring SCINS. Supplementary Table S3. Genes expressed in a SAM of different SCINS clusters. Supplementary Table S4. Gene expression signatures of genomic instability.

Table S5

Supplementary Data

SWEAVE document. R code for SCINS analysis.

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Table S3

Rural houses in sub-Saharan Africa are typically hot and allow malaria mosquitoes inside. We assessed whether passive or active ventilation can reduce house entry of malaria mosquitoes and cool a bedroom at night in rural Gambia. Two identical experimental houses were used: one ventilated and one unventilated (control). We evaluated the impact of (i) passive ventilation (solar chimney) and (ii) active ventilation (ceiling fan) on the number of mosquitoes collected indoors and environmental parameters (temperature, humidity, CO 2 , evaporation). Although the solar chimney did not reduce entry of Anopheles gambiae sensu lato , the ceiling fan reduced house entry by 91% compared with the control house. There were no differences in indoor nightly temperature, humidity or CO 2 between intervention and control houses in either experiment. The solar chimney did not improve human comfort assessed using psychrometric analysis. While the ceiling fan improved human comfort pre-midnight, in the morning it was too cool compared with the control house, although this could be remedied through provision of blankets. Further improvements to the design of the solar chimney are needed. High air velocity in the ceiling fan house probably reduced mosquito house entry by preventing mosquito flight. Improved ventilation in houses may reduce malaria transmission.