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AbstractPrevious research suggests that individuals with 22q11.2 deletion syndrome (DS) have an increased risk of bleeding following cardiac surgery. However, current guidelines for management of patients with 22q11.2DS do not provide specific recommendations for perioperative management. This study sought to identify specific risk factors for bleeding in this patient population. Examine the factors determining bleeding and transfusion requirements in patients with 22q11.2DS undergoing cardiac surgery. This was a single center review of patients who underwent cardiac surgery at the Children’s Hospital of Philadelphia from 2000 to 2016. Data was extracted from the medical record. Frequency of bleeding events, laboratory values, and transfusion requirements were compared. We included 226 patients with 22q11.2DS and 506 controls. Bleeding events were identified in 13 patients with 22q11.2DS (5.8%) and 27 controls (5.3%). Platelet counts were lower among patients with 22q11.2DS than in control patients, but not statistically different comparing bleeding to not bleeding. Patients with 22q11.2DS received more transfusions (regardless of bleeding status). However, multivariate analysis showed only procedure type was associated with increased risk of bleeding (p = .012). The overall risk of bleeding when undergoing cardiac surgery is not different in patients with 22q11.2DS compared to non-deleted patients. Though platelet counts were lower in patients with 22q11.2DS, only procedure type was significantly associated with an increased risk of bleeding.

Summary: Background: This study evaluates whether there are ethnic differences in time to surgery in women with early-stage (1–3a) breast cancer in four NZ urban regions between 2000 and 2020 pre- and post- Faster Cancer Treatment (FCT) implementation, which was introduced to address inequities in cancer outcomes. Methods: This retrospective analysis used Te Rēhita Mate Ūtaetae (Breast Cancer Foundation National Register), a prospectively maintained database of breast cancers from 2000 to 2020. Women with stage 3b, 3c, metastatic or bilateral cancers were excluded. Logistic regression models evaluated ethnic differences in time to surgery (≤31/>31 days as per FCT plan) with sequential adjustment for potential contributing factors (demographic, mode of diagnosis, tumour, treatment facility type and treatment). Subgroup analyses by pre- and post-FCT implementation date were undertaken. Findings: Of the 16,365 women included, 74.1% were NZ European (NZE), 10.2% were Māori, 6.1% were Pacific, and 9.2% were Asian. Wāhine Māori (Māori women) and Pacific women were more likely to experience delays in surgery >31 days, compared to NZE (maximally adjusted OR: 1.18; 95% CI:1.05, 1.33 and OR:1.42; 95% CI:1.22, 1.65, respectively)–deprivation and treatment facility type contributed most to this. Wāhine Māori experienced delay in the public system only. The associations did not differ between the pre- and post- FCT periods. Interpretation: Ethnic inequities exist with respect to time to surgery for women with early-stage breast cancer and these differences persist after FCT implementation. Funding: LB is supported by the Richard Stewart scholarship, the Royal Australasian College of Surgeons and Oxford Population Health.

Abstract This study explored the acceptability of a novel pharmacist‐led pharmacogenetics (PGx) screening program among patients with cancer and healthcare professionals (HCPs) taking part in a multicenter clinical trial of PGx testing (PACIFIC‐PGx ANZCTR:12621000251820). Medical oncologists, oncology pharmacists, and patients with cancer from across four sites (metropolitan/regional), took part in an observational, cross‐sectional survey. Participants were recruited from the multicenter trial. Two study‐specific surveys were developed to inform implementation strategies for scaled and sustainable translation into routine clinical care: one consisting of 21 questions targeting HCPs and one consisting of 17 questions targeting patients. Responses were collected from 24 HCPs and 288 patients. The 5‐to‐7‐day PGx results turnaround time was acceptable to HCP (100%) and patients (69%). Most HCPs (92%) indicated that it was appropriate for the PGx clinical pharmacist to provide results to patients. Patients reported equal preference for receiving PGx results from a doctor/pharmacist. Patients and HCPs highly rated the pharmacist‐led PGx service. HCPs were overall accepting of the program, with the majority (96%) willing to offer PGx testing to their patients beyond the trial. HCPs identified that lack of financial reimbursements (62%) and lack of infrastructure (38%) were the main reasons likely to prevent/slow the implementation of PGx screening program into routine clinical care. Survey data have shown overall acceptability from patients and HCPs participating in the PGx Program. Barriers to implementation of PGx testing in routine care have been identified, providing opportunity to develop targeted implementation strategies for scaled translation into routine practice.

Background: Breast reconstruction (BR) improves women's health-related quality of life (HRQOL) following mastectomy for breast cancer, yet factors contributing to improved HRQOL remain unclear. This study aimed to explore the overall impact of mastectomy with or without BR on participants' perceptions of HRQOL over time in a cohort of women with high-risk breast cancer; to examine differences in mean HRQOL scores between immediate BR, delayed BR and no BR groups; to assess the influence of patient characteristics potentially associated with HRQOL scores; and to determine the feasibility of long-term collection of patient-reported outcome measures in clinical settings. Methods: A prospective, longitudinal study of 100 women with high-risk breast cancer who underwent mastectomy with or without breast reconstruction and were likely to require post-mastectomy radiotherapy. Four validated patient-reported questionnaires, comprising 21 outcome measures relating to HRQOL, administered at baseline and up to 4 years post-mastectomy. Demographic, clinical and surgical data extracted from patient medical records. Results: Consistently significant declines in perceptions of future health and arm symptoms, consistently significant improvements in treatment side effects, breast symptoms and fatigue, as well as significant improvements, compared to baseline, in social functioning and financial difficulties at 48 months. No significant differences in mean HRQOL scores between women given a choice of reconstructive options. Conclusion: Similar trajectories of HRQOL scores were found in women with high-risk breast cancer who were offered a choice of BR. Informed choice may be an independent contributing factor in long-term maintenance of most HRQOL indicators at their pre-mastectomy levels.

Abstract Objectives The objective of this study is to investigate the influence of diabetes on breast cancer‐specific survival among women with breast cancer in Aotearoa/New Zealand. Methods This study included women diagnosed with invasive breast cancer between 2005 and 2020, with their information documented in the Te Rēhita Mate Ūtaetae—Breast Cancer Foundation National Register. Breast cancer survival curves for women with diabetes and those without diabetes were generated using the Kaplan–Meier method. The hazard ratio (HR) of breast cancer‐specific mortality for women with diabetes compared to women without diabetes was estimated using the Cox proportional hazards model. Results For women with diabetes, the 5‐year and 10‐year of cancer‐specific survival were 87% (95% CI: 85%–88%) and 79% (95% CI: 76%–81%) compared to 89% (95% CI: 89%–90%) and 84% (95% CI: 83%–85%) for women without diabetes. The HR of cancer‐specific mortality for patients with diabetes compared to those without diabetes was 0.99 (95% CI: 0.89–1.11) after adjustment for patient demographics, tumor characteristics, and treatments. Age at cancer diagnosis and cancer stage had the biggest impact on the survival difference between the two groups. When stratified by cancer stage, the cancer‐specific mortality between the two groups was similar. Conclusions While differences in survival have been identified for women with diabetes when compared to women without diabetes, these are attributable to age and the finding that women with diabetes tend to present with more advanced disease at diagnosis. We did not find any difference in survival between the two groups due to differences in treatment.

The three language versions of Ian Campbell's poem series about the old jacaranda tree in a university coutryard presented here comprise a poem series in which he first wrote a poem in French in 1989, then an Indonesian language version which was published in the literary pages of an Indonesian newspaper (in Bandung, West Java) in 2004, and finally in English. Campbell regards this whole process as emblematic of his explorations in trilingual poetics, namely what does a 'concept'/poem idea look like if done in three of the languages with which he has some degree of written knowledge or fluency: English, French and Indonesian. This mirrors the three-pronged approach he took in an earlier edition of PORTAL - Vol. 14, No 1, April 2017, where the three language versions he wrote on a single theme were in English, Spanish, and Indonesian.

Abstract Background Women with early breast cancer who meet guideline-based criteria should be offered breast conserving surgery (BCS) with adjuvant radiotherapy as an alternative to mastectomy. New Zealand (NZ) has documented ethnic disparities in screening access and in breast cancer treatment pathways. This study aimed to determine whether, among BCS-eligible women, rates of receipt of mastectomy or radiotherapy differed by ethnicity and other factors. Methods The study assessed management of women with early breast cancer (ductal carcinoma in situ [DCIS] and invasive stages I-IIIA) registered between 2010 and 2015, extracted from the recently consolidated New Zealand Breast Cancer Registry (now Te Rēhita Mate Ūtaetae NZBCF National Breast Cancer Register). Specific criteria were applied to determine women eligible for BCS. Uni- and multivariable analyses were undertaken to examine differences by demographic and clinicopathological factors with a primary focus on ethnicity (Māori, Pacific, Asian, and Other; the latter is defined as NZ European, Other European, and Middle Eastern Latin American and African). Results Overall 22.2% of 5520 BCS-eligible women were treated with mastectomy, and 91.1% of 3807 women who undertook BCS received adjuvant radiotherapy (93.5% for invasive cancer, and 78.3% for DCIS). Asian ethnicity was associated with a higher mastectomy rate in the invasive cancer group (OR 2.18; 95%CI 1.72–2.75), compared to Other ethnicity, along with older age, symptomatic diagnosis, advanced stage, larger tumour, HER2-positive, and hormone receptor-negative groups. Pacific ethnicity was associated with a lower adjuvant radiotherapy rate, compared to Other ethnicity, in both invasive and DCIS groups, along with older age, symptomatic diagnosis, and lower grade tumour in the invasive group. Both mastectomy and adjuvant radiotherapy rates decreased over time. For those who did not receive radiotherapy, non-referral by a clinician was the most common documented reason (8%), followed by patient decline after being referred (5%). Conclusion Rates of radiotherapy use are high by international standards. Further research is required to understand differences by ethnicity in both rates of mastectomy and lower rates of radiotherapy after BCS for Pacific women, and the reasons for non-referral by clinicians.

Abstract Internationally, population breast cancer screening is moving towards a risk-stratified approach and requires engagement and acceptance from current and future screening clients. A decision aid ( www.defineau.org ) was developed based on women’s views, values, and knowledge regarding risk-stratified breast cancer screening. This study aims to evaluate the impact of the decision aid on women’s knowledge, risk perception, acceptance of risk assessment and change of screening frequency, and decision-making. Here we report the results of a pre and post-survey in which women who are clients of BreastScreen Victoria were invited to complete an online questionnaire before and after viewing the decision aid. 3200 potential participants were invited, 242 responded with 127 participants completing both surveys. After reviewing the decision aid there was a significant change in knowledge, acceptance of risk-stratified breast cancer screening and of decreased frequency screening for lower risk. High levels of acceptance of risk stratification, genetic testing and broad support for tailored screening persisted pre and post review. The DEFINE decision aid has a positive impact on acceptance of lower frequency screening, a major barrier to the success of a risk-stratified program and may contribute to facilitating change to the population breast screening program in Australia.

Background: Sentinel node-based management (SNBM) is the international standard of care for early breast cancer that is clinically node-negative based on randomised trials comparing it with axillary lymph node dissection (ALND) and reporting similar rates of axillary recurrence (AR) without distant disease. We report all ARs, overall survival, and breast cancer-specific survival at 10-years in SNAC1. Methods: 1.088 women with clinically node-negative, unifocal breast cancers 3 cm or less in diameter were randomly assigned to either SNBM with ALND if the sentinel node (SN) was positive, or to SN biopsy followed by ALND regardless of SN involvement. Results: First ARs were more frequent in those assigned SNBM rather than ALND (11 events, cumulative risk at 10-years 1·85%, 95% CI 0·95–3.27% versus 2 events, 0·37%, 95% CI 0·08–1·26%; HR 5·47, 95% CI 1·21–24·63; p = 0·013). Disease-free survival, breast cancer-specific survival, and overall survival were similar in those assigned SNBM versus ALND. Lymphovascular invasion was an independent predictor of AR (HR 6·6, 95% CI 2·25–19·36, p

Abstract The growth kinetics of localized corrosion, e.g. pits, in corrosive environments often controls the service life of metallic components. Yet, our understanding of these kinetics is largely based on coupon-level, e.g. mass-loss, studies which provide limited insights into the evolution of individual damage events. It is critical to relate observed cumulative loss trends, such as links between changing humidity and mass loss rates, to the growth kinetics of individual pits. Towards this goal, we leverage in-situ X-ray computed tomography to measure the growth rates of over sixty pits in aluminum in four different humid, chloride environments over ≈3 days of exposure. Pit growth rates and final volumes increased with increasing droplet volume, which was observed to increase with increasing humidity and salt loading. Two factors, droplet spreading and oxide jacking, dramatically increased pit growth rates and final volumes.

Abstract Our objective was to test whether p53 expression status is associated with survival for women diagnosed with the most common ovarian carcinoma histotypes (high‐grade serous carcinoma [HGSC], endometrioid carcinoma [EC], and clear cell carcinoma [CCC]) using a large multi‐institutional cohort from the Ovarian Tumor Tissue Analysis (OTTA) consortium. p53 expression was assessed on 6,678 cases represented on tissue microarrays from 25 participating OTTA study sites using a previously validated immunohistochemical (IHC) assay as a surrogate for the presence and functional effect of TP53 mutations. Three abnormal expression patterns (overexpression, complete absence, and cytoplasmic) and the normal (wild type) pattern were recorded. Survival analyses were performed by histotype. The frequency of abnormal p53 expression was 93.4% (4,630/4,957) in HGSC compared to 11.9% (116/973) in EC and 11.5% (86/748) in CCC. In HGSC, there were no differences in overall survival across the abnormal p53 expression patterns. However, in EC and CCC, abnormal p53 expression was associated with an increased risk of death for women diagnosed with EC in multivariate analysis compared to normal p53 as the reference (hazard ratio [HR] = 2.18, 95% confidence interval [CI] 1.36–3.47, p = 0.0011) and with CCC (HR = 1.57, 95% CI 1.11–2.22, p = 0.012). Abnormal p53 was also associated with shorter overall survival in The International Federation of Gynecology and Obstetrics stage I/II EC and CCC. Our study provides further evidence that functional groups of TP53 mutations assessed by abnormal surrogate p53 IHC patterns are not associated with survival in HGSC. In contrast, we validate that abnormal p53 IHC is a strong independent prognostic marker for EC and demonstrate for the first time an independent prognostic association of abnormal p53 IHC with overall survival in patients with CCC.

Abstract Assessing the lifetimes of alloys in humid, corrosive environments requires growth kinetic information regarding individual instances of damage, e.g. pit growth rates. Corrosion rates measured at the continuum scale using mass change convolute the rate of pit nucleation and growth, providing limited information on local kinetics. The current study used in-situ X-ray computed tomography to measure growth rates of individual pits in aluminum over 100 h of exposure in a humid, chloride environment. While pits grew at relatively constant rates over the first hours after nucleation, significant growth-rate nonlinearities subsequently occurred. These were linked to both droplet spreading, which altered the cathode size, and changes in the mode of pit growth. Pit morphology appeared to influence the dominant growth mode and the duration of pit growth. Post-mortem serial sectioning revealed pits preferentially attacked grain-boundary triple junctions and dislocation boundaries.

The risk of germline copy number variants (CNVs) in BRCA1 and BRCA2 pathogenic variant carriers in breast cancer is assessed, with CNVs overlapping SULT1A1 decreasing breast cancer risk in BRCA1 carriers.

Abstract Background Mitochondrial disease is a heterogenous group of rare, complex neurometabolic disorders. Despite their individual rarity, collectively mitochondrial diseases represent the most common cause of inherited metabolic disorders in the UK; they affect 1 in every 4300 individuals, up to 15,000 adults (and a similar number of children) in the UK. Mitochondrial disease manifests multisystem and isolated organ involvement, commonly affecting those tissues with high energy demands, such as skeletal muscle. Myopathy manifesting as fatigue, muscle weakness and exercise intolerance is common and debilitating in patients with mitochondrial disease. Currently, there are no effective licensed treatments and consequently, there is an urgent clinical need to find an effective drug therapy. Aim To investigate the efficacy of 12-week treatment with acipimox on the adenosine triphosphate (ATP) content of skeletal muscle in patients with mitochondrial disease and myopathy. Methods AIMM is a single-centre, double blind, placebo-controlled, adaptive designed trial, evaluating the efficacy of 12 weeks’ administration of acipimox on skeletal muscle ATP content in patients with mitochondrial myopathy. Eligible patients will receive the trial investigational medicinal product (IMP), either acipimox or matched placebo. Participants will also be prescribed low dose aspirin as a non-investigational medical product (nIMP) in order to protect the blinding of the treatment assignment. Eighty to 120 participants will be recruited as required, with an interim analysis for sample size re-estimation and futility assessment being undertaken once the primary outcome for 50 participants has been obtained. Randomisation will be on a 1:1 basis, stratified by Fatigue Impact Scale (FIS) (dichotomised as < 40, ≥ 40). Participants will take part in the trial for up to 20 weeks, from screening visits through to follow-up at 16 weeks post randomisation. The primary outcome of change in ATP content in skeletal muscle and secondary outcomes relating to quality of life, perceived fatigue, disease burden, limb function, balance and walking, skeletal muscle analysis and symptom-limited cardiopulmonary fitness (optional) will be assessed between baseline and 12 weeks. Discussion The AIMM trial will investigate the effect of acipimox on modulating muscle ATP content and whether it can be repurposed as a new treatment for mitochondrial disease with myopathy. Trial registration EudraCT2018-002721-29 . Registered on 24 December 2018, ISRCTN 12895613. Registered on 03 January 2019, https://www.isrctn.com/search?q=aimm

Abstract The classical paradigm of the ‘big magma tank’ chambers in which the melt differentiates, is replenished, and occasionally feeds the overlying volcanos has recently been challenged on various grounds. An alternative school of thought is that such large, long-lived and largely molten magma chambers are transient to non-existent in Earth’s history. Our study of stratiform chromitites in the Bushveld Complex—the largest magmatic body in the Earth’s continental crust—tells, however, a different story. Several chromitites in this complex occur as layers up to 2 m in thickness and more than 400 kms in lateral extent, implying that chromitite-forming events were chamber-wide phenomena. Field relations and microtextural data, specifically the relationship of 3D coordination number, porosity and grain size, indicate that the chromitites grew as a 3D framework of touching chromite grains directly at the chamber floor from a basaltic melt saturated in chromite only. Mass-balance estimates imply that a few km thick column of this melt is required to form each of these chromitite layers. Therefore, an enormous volume of melt appears to have been involved in the generation of all the Bushveld chromitite layers, with half of this melt being expelled from the magma chamber. We suggest that the existence of thick and laterally extensive chromitite layers in the Bushveld and other layered intrusions supports the classical paradigm of big, albeit rare, ‘magma tank’ chambers.

Summary: Plasma metabolomics represents a potentially powerful approach to understand the biochemical mechanisms of nutrition and metabolism in asthma. This study aims to acquire knowledge on plasma metabolites in asthma, which may provide avenues for nutrition therapy, as well as explanations for the observed effects in existing therapies. This study investigated 249 metabolites from 18 metabolite groups in a large cohort of African American population, including 602 pediatric patients with asthma and 593 controls, using a nuclear magnetic resonance (NMR) metabolomics platform. Decreased levels of citrate, ketone bodies, and two amino acids histidine (His) and glutamine (Gln), were observed in asthma cases compared to controls. Metabolites for lipid metabolism lost significance after controlling for comorbid obesity. For the first time, this study depicts a broad panorama of lipid metabolism and nutrition in asthma. Supplementation or augmentation of nutrients that are deficient may be beneficial for asthma care.

This suite of short poems with Latin American references draws from original versions written in Spanish in 2008 and early 2011. It now follows on from other poems with Latin American refrerences written by the poet in languages other than Spanish as part of the poet's interest in 'trilingual poetics'. Spanish is not the first language of the writer nor is the poet of Latin American heritage. It is part of a 'corpus' of poems which aims to explore the potentialities of multiple language perspectives associated with or derived from a single poetic theme or set of themes. It is also part of the poet's explorations of what can be derived from some identification as a poet 'of the south'.

Background: Around one-third of pregnant women suffer from moderate to severe nausea and vomiting, causing physical and emotional distress and reducing their quality of life. There is no cure for nausea and vomiting in pregnancy. Management focuses on relieving symptoms and preventing morbidity, and often requires antiemetic therapy. National guidelines make recommendations about first-, second- and third-line antiemetic therapies, although care varies in different hospitals and women report feeling unsupported, dissatisfied and depressed. Objectives: To determine whether or not, in addition to intravenous rehydration, ondansetron compared with no ondansetron and metoclopramide compared with no metoclopramide reduced the rate of treatment failure up to 10 days after drug initiation; improved symptom severity at 2, 5 and 10 days after drug initiation; improved quality of life at 10 days after drug initiation; and had an acceptable side effect and safety profile. To estimate the incremental cost per treatment failure avoided and the net monetary benefits from the perspectives of the NHS and women. Design: This was a multicentre, double-dummy, randomised, double-blinded, dummy-controlled 2 × 2 factorial trial (with an internal pilot phase), with qualitative and health economic evaluations. Participants: Thirty-three patients (who were

Background Research identifying and returning clinically actionable germline variants offer a new avenue of access to genetic information. The psychosocial and clinical outcomes for women who have received this ‘genome-first care’ delivering hereditary breast and ovarian cancer risk information outside of clinical genetics services are unknown. Methods: An exploratory sequential mixed-methods case-control study compared outcomes between women who did (cases; group 1) and did not (controls; group 2) receive clinically actionable genetic information from a research cohort in Victoria, Australia. Participants completed an online survey examining cancer risk perception and worry, and group 1 also completed distress and adaptation measures. Group 1 participants subsequently completed a semi structured interview. Results: Forty-five participants (group 1) and 96 (group 2) completed the online survey, and 31 group 1 participants were interviewed. There were no demographic differences between groups 1 and 2, although more of group 1 participants had children (p = 0.03). Group 1 reported significantly higher breast cancer risk perception (p < 0.001) compared to group 2, and higher cancer worry than group 2 (p < 0.001). Some group 1 participants described how receiving their genetic information heightened their cancer risk perception and exacerbated their cancer worry while waiting for risk-reducing surgery. Group 1 participants reported a MICRA mean score of 27.4 (SD 11.8, range 9–56; possible range 0–95), and an adaptation score of 2.9 (SD = 1.1). Conclusion: There were no adverse psychological outcomes amongst women who received clinically actionable germline information through a model of ‘genome-first’ care compared to those who did not. These findings support the return of clinically actionable research results to research participants.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Abstract An association between genetic variants in the vitamin D receptor (VDR) gene and epithelial ovarian cancer (EOC) was previously reported in women of African ancestry (AA). We sought to examine associations between genetic variants in VDR and additional genes from vitamin D biosynthesis and pathway targets (EGFR, UGT1A, UGT2A1/2, UGT2B, CYP3A4/5, CYP2R1, CYP27B1, CYP24A1, CYP11A1, and GC). Genotyping was performed using the custom‐designed 533,631 SNP Illumina OncoArray with imputation to the 1,000 Genomes Phase 3 v5 reference set in 755 EOC cases, including 537 high‐grade serous (HGSOC), and 1,235 controls. All subjects are of African ancestry (AA). Logistic regression was performed to estimate odds ratios (OR) and 95% confidence intervals (CI). We further evaluated statistical significance of selected SNPs using the Bayesian False Discovery Probability (BFDP). A significant association with EOC was identified in the UGT2A1/2 region for the SNP rs10017134 (per allele OR = 1.4, 95% CI = 1.2‐1.7, P = 1.2 × 10−6, BFDP = 0.02); and an association with HGSOC was identified in the EGFR region for the SNP rs114972508 (per allele OR = 2.3, 95% CI = 1.6‐3.4, P = 1.6 × 10−5, BFDP = 0.29) and in the UGT2A1/2 region again for rs1017134 (per allele OR = 1.4, 95% CI = 1.2‐1.7, P = 2.3 × 10−5, BFDP = 0.23). Genetic variants in the EGFR and UGT2A1/2 may increase susceptibility of EOC in AA women. Future studies to validate these findings are warranted. Alterations in EGFR and UGT2A1/2 could perturb enzyme efficacy, proliferation in ovaries, impact and mark susceptibility to EOC.

Abstract Background Recurrent and persistent infections are known to affect airways of patients with Primary Immunodeficiency despite appropriate replacement immunoglobulin serum levels. Interestingly, patients with Chronic Obstructive Pulmonary Disease or with non-CF bronchiectasis also show similar susceptibility to such infections. This may be due to the limited availability of immunoglobulins from the systemic circulation in the conductive airways, resulting in local immunodeficiency. Topical application of nebulized plasma-derived immunoglobulins may represent a means to address this deficiency. In this study, we assessed the feasibility of nebulizing plasma-derived immunoglobulins and delivering them into the airways of rats and non-human primates. Methods Distinct human plasma-derived immunoglobulin isotype preparations were nebulized with an investigational eFlow® nebulizer and analyzed in vitro or deposited into animals. Biochemical and immunohistological analysis of nebulized immunoglobulins were then performed. Lastly, efficacy of topically applied human plasma-derived immunoglobulins was assessed in an acute Streptococcus pneumoniae respiratory infection in mice. Results Characteristics of the resulting aerosols were comparable between preparations, even when using solutions with elevated viscosity. Neither the structural integrity nor the biological function of nebulized immunoglobulins were compromised by the nebulization process. In animal studies, immunoglobulins levels were assessed in plasma, broncho-alveolar lavages (BAL) and on lung sections of rats and non-human primates in samples collected up to 72 h following application. Nebulized immunoglobulins were detectable over 48 h in the BAL samples and up to 72 h on lung sections. Immunoglobulins recovered from BAL fluid up to 24 h after inhalation remained structurally and functionally intact. Importantly, topical application of human plasma-derived immunoglobulin G into the airways of mice offered significant protection against acute pneumococcal pneumonia. Conclusion Taken together our data demonstrate the feasibility of topically applying plasma-derived immunoglobulins into the lungs using a nebulized liquid formulation. Moreover, topically administered human plasma-derived immunoglobulins prevented acute respiratory infection.

Over 170 susceptibility loci have been identified by genome-wide association studies in breast cancer. Here, the authors interrogated the role of risk-associated variants from non-breast tissue, and using expression quantitative trait loci, identify potential target genes of known breast cancer susceptibility variants, as well as 11 regions not previously known to be associated with breast cancer risk.

Similarities in cancers can be studied to interrogate their etiology. Here, the authors use genome-wide association study summary statistics from six cancer types based on 296,215 cases and 301,319 controls of European ancestry, showing that solid tumours arising from different tissues share a degree of common germline genetic basis.

Abstract Background There is a growing interest in delivering more personalised, risk-based breast cancer screening protocols. This requires population-level validation of practical models that can stratify women into breast cancer risk groups. Few studies have evaluated the Gail model (NCI Breast Cancer Risk Assessment Tool) in a population screening setting; we validated this tool in a large, screened population. Methods We used data from 40,158 women aged 50–69 years (via the lifepool cohort) participating in Australia’s BreastScreen programme. We investigated the association between Gail scores and future invasive breast cancer, comparing observed and expected outcomes by Gail score ranked groups. We also used machine learning to rank Gail model input variables by importance and then assessed the incremental benefit in risk prediction obtained by adding variables in order of diminishing importance. Results Over a median of 4.3 years, the Gail model predicted 612 invasive breast cancers compared with 564 observed cancers (expected/observed (E/O) = 1.09, 95% confidence interval (CI) 1.00–1.18). There was good agreement across decile groups of Gail scores (χ2 = 7.1, p = 0.6) although there was some overestimation of cancer risk in the top decile of our study group (E/O = 1.65, 95% CI 1.33–2.07). Women in the highest quintile (Q5) of Gail scores had a 2.28-fold increased risk of breast cancer (95% CI 1.73–3.02, p

The principal argument of the article is that the architecture of the palaces of James V is more eclectic than previously assumed. The advanced French Renaissance character of parts of the Falkland Palace, dating from about 1537-41, is complemented by medieval elements in Falkland, Linlithgow and Stirling, and that this last also has stronger affinities with the buildings of the Habsburg dominions or Portugal than France. It also argues that the Linlithgow plan had a strong influence on the castle of Écouen and on Serlio's Ancy-le-Franc.

Development of large scale hydropower is proceeding rapidly in the Mekong basin without adequate consideration of the severe and cumulative impacts the dams and reservoirs will, and are already beginning to, have on biodiversity, livelihoods and the economies of the lower Mekong countries. Migratory aquatic species will be particularly affected, and global experience indicates that fishways proposed for large mainstream and tributary dams will not provide effective amelioration. An offset strategy of remediating small weirs, flood control devices, regulators and irrigation works on tributaries and flood plains is more likely to be an effective and economically efficient means of supplementing fisheries to compensate for the negative impact of mainstream dams. Mainstream hydropower developments may result in future stranded assets, high electricity costs and even threaten the sovereignty of lower Mekong countries.

Howard, D. A Review of Ludovica Galeazzo, 'Venezia e i margini urbani: L’insula dei Gesuiti in età moderna'. Memorie: Classe di scienze morali, lettere ed arti, vol. 144. Venice: Istituto veneto di scienze, lettere ed arti, 2018. Tosland, B. A Review of Łukasz Stanek, 'Architecture in Global Socialism: Eastern Europe, West Africa, and the Middle East in the Cold War'. Princeton and Oxford: Princeton University Press, 2020. Campbell, I. A Review of Mark McDonald, 'Architecture, Topography and Military Maps'. The Paper Museum of Cassiano dal Pozzo. Series C. Prints, Part 2, 3 vols. London: The Royal Collection Trust and The British Library in association with Harvey Miller Publishers, 2019. Wells, M.J. A Review of Torsten Schmiedeknecht and Andrew Peckham, eds., 'Modernism and the Professional Architecture Journal: Reporting, Editing, and Reconstructing in Post-War Europe'. London and New York: Routledge, 2019.

Notch pathway haploinsufficiency can cause severe developmental syndromes with highly variable penetrance. Currently, we have a limited mechanistic understanding of phenotype variability due to gene dosage. Here, we unexpectedly found that inserting an enhancer containing pioneer transcription factor sites coupled to Notch dimer sites can induce a subset of Notch haploinsufficiency phenotypes in Drosophila with wild type Notch gene dose. Using Drosophila genetics, we show that this enhancer induces Notch phenotypes in a Cdk8-dependent, transcription-independent manner. We further combined mathematical modeling with quantitative trait and expression analysis to build a model that describes how changes in Notch signal production versus degradation differentially impact cellular outcomes that require long versus short signal duration. Altogether, these findings support a ‘bind and discard’ mechanism in which enhancers with specific binding sites promote rapid Cdk8-dependent Notch turnover, and thereby reduce Notch-dependent transcription at other loci and sensitize tissues to gene dose based upon signal duration.

Abstract Background The only available predictive models for the outcome of breast cancer patients in New Zealand (NZ) are based on data in other countries. We aimed to develop and validate a predictive model using NZ data for this population, and compare its performance to a widely used overseas model, the Nottingham Prognostic Index (NPI). Methods We developed a model to predict 10-year breast cancer-specific survival, using data collected prospectively in the largest population-based regional breast cancer registry in NZ (Auckland, 9182 patients), and assessed its performance in this data set (internal validation) and in an independent NZ population-based series of 2625 patients in Waikato (external validation). The data included all women with primary invasive breast cancer diagnosed from 1 June 2000 to 30 June 2014, with follow up to death or Dec 31, 2014. We used multivariate Cox proportional hazards regression to assess predictors and to calculate predicted 10-year breast cancer mortality, and therefore survival, probability for each patient. We assessed observed survival by the Kaplan Meier method. We assessed discrimination by the C statistic, and calibration by comparing predicted and observed survival rates for patients in 10 groups ordered by predicted 10-year survival. We compared this NZ model with the Nottingham Prognostic Index (NPI) in this validation data set. Results Discrimination was good: C statistics were 0.84 for internal validity and 0.83 for an independent external validity. For calibration, for both internal and external validity the predicted 10-year survival probabilities in all groups of patients, ordered by predicted survival, were within the 95% confidence intervals (CI) of the observed Kaplan-Meier survival probabilities. The NZ model showed good discrimination even within the prognostic groups defined by the NPI. Conclusions These results for the New Zealand model show good internal and external validity, transportability, and potential clinical value of the model, and its clear superiority over the NPI. Further research is needed to assess other potential predictors, to assess the model’s performance in specific subgroups of patients, and to compare it to other models, which have been developed in other countries and have not yet been tested in NZ.

Puisi selatan is a small selection of Sydney poet Ian Campbell’s Indonesian language poems taken from the author’s larger collection titled Selatan-Sur-South of Indonesian language poems - which appeared in PORTAL in 2008 - but now supplemented, for the first time, with English language versions which have been rendered by the poet himself from the ‘starting point’ of these original four Indonesian language poems. In all there are here now eight poems – four in Indonesian and four in English – with the common thread, for the poet, of being written ‘in the south’. For the poet also, they now interact, across languages, as a set of poems which consider the ways in which the actions of ‘memorialising’ are often intertwined with specific responses to the natural environment. The poems ‘Semenanjung Bilgola’ and ‘Bilgola headland’ are poems reflecting upon the efforts the poet’s parents made in the late 1960s-early 1970s to restore the natural environment on a headland of one of Sydney’s northern beaches which had been donated to the National Trust. The Indonesian language original poem was read by the poet himself and by Indonesian poets in cities in West Java in 2004 and also at the first Ubud Writers Festival in 2004 by Indonesian female poet, Toeti Heraty, The poems ‘Berziarah di Punta de Lobos, Chile’ and ‘Pilgrimage to Punta de Lobos’ are also memorialising poems and reflect upon the idea of ’pilgimage’ to a natural location near Pichilemu on the Chilean coast which is popular with surfers. In contrast, the poems ‘Simfoni angin’ and ‘Symphony of the winds’ describe the sights and sounds of a rural area near Purranque in the south of Chile, but here too the poet reflects upon the ways in which present evokes past. The final poems ‘Buenos Aires’ - rendered as the title in both languages - explore the ways in which the Argentinian café becomes a place in which memories of the city are revealed anew through the processes of inversion of light and shadow, of internal and external shapes and sounds, as if through a camera lens. Puisi selatan can be rendered in English as ‘poetry of the south’ as all poems derive their impetus from settings in Australia or in Latin America, specifically either Chile or Argentina. They were originally written in Indonesian as part of the poet’s interest in using Bahasa Indonesia as a language of creative writing.

Although penetrating neck trauma (PNT) is uncommon, it is associated with the significant morbidity and mortality. The management of PNT has changed significantly over the past 50 years. A radiological assessment now is a vital part of the management with a traditional surgical exploration. A 22 years old male was assaulted by a screwdriver and sustained multiple penetrating neck injuries. A contrast CT scan revealed a focal pseudoaneurysm in the left common carotid artery bulb. There was no active bleeding or any other vascular injuries and the patient remained haemodynamically stable. In view of these findings, he was initially managed conservatively without an open surgical exploration. However, the patient was noted to have an acute drop in his hemoglobin count overnight post injury and the catheter directed angiography showed active bleeding from the pseudoaneurysm. Surgical exploration 40 hours following the initial injury revealed a penetrating injury through both arterial walls of the left carotid bulb which was repaired with a great saphenous vein patch. A percutaneous drain was inserted in the carotid triangle and a course of intravenous antibiotics for five days was commenced. The patient recovered well with no complications and remained asymptomatic at five months followup. Keywords: Penetrating neck trauma, Management penetrating neck trauma, Investigation penetrating neck trauma, Assessment penetrating neck trauma

Abstract Background Obesity has been reported as an adverse prognostic factor in breast cancer, but inconsistently, and under-treatment with chemotherapy may occur. We provide the first assessment of obesity and breast cancer outcomes in a population-based, multi-ethnic cohort of New Zealand patients treated with chemotherapy. Methods All 3536 women diagnosed with invasive breast cancer in the Waikato region of New Zealand from 2000-2014 were registered and followed until last follow-up in specialist or primary care, death or Dec 2014; median follow-up 4.1 years. For the 1049 patients receiving chemotherapy, mortality from breast cancer, other causes, and all causes, and rates of loco-regional and of distant recurrence, were assessed by body mass index (BMI), recorded after diagnosis, adjusting for other clinico-pathological and demographic factors by Cox regression. Results BMI was known for 98% (n=1049); 33% were overweight (BMI 25-29.9), 21% were obese (BMI 30-34.9), and 14% were very obese (BMI 35+). There were no significant associations between obesity and survival, after adjustment for demographic and clinical factors (hazard ratios, HR, for very obese compared to BMI 21-24, for breast cancer deaths 0.96 (0.56-1.67), and for all deaths 1.03 (0.63-1.67), respectively, and only small non-significant associations for loco-regional or metastatic recurrence rates (HR 1.17 and 1.33 respectively). Subgroup analyses by age, menopausal status, ethnicity, stage, post-surgical radiotherapy, mode of diagnosis, type of surgery, and receptor status, showed no associations. No associations were seen with BMI as a continuous variable. The results in all patients irrespective of treatment but with recorded BMI data (n=2296) showed similar results. Conclusions In this population, obesity assessed post-diagnosis had no effect on survival or recurrence, based on 1049 patients with chemotherapy treatment with follow-up up to 14 years.

Abstract Background New Zealand has major ethnic disparities in breast cancer survival with Māori (indigenous people) and Pacific women (immigrants or descended from immigrants from Pacific Islands) faring much worse than other ethnic groups. This paper identified underlying factors and assessed their relative contribution to this risk differential. Methods This study involved all women who were diagnosed with primary invasive breast cancer in two health regions, covering about 40% of the national population, between January 2000 and June 2014. Māori and Pacific patients were compared with other ethnic groups in terms of demographics, mode of diagnosis, disease factors and treatment factors. Cox regression modelling was performed with stepwise adjustments, and hazards of excess mortality from breast cancer for Māori and Pacific patients were assessed. Results Of the 13,657 patients who were included in this analysis, 1281 (9.4%) were Māori, and 897 (6.6%) were Pacific women. Compared to other ethnic groups, they were younger, more likely to reside in deprived neighbourhoods and to have co-morbidities, and less likely to be diagnosed through screening and with early stage cancer, to be treated in a private care facility, to receive timely cancer treatment, and to receive breast conserving surgery. They had a higher risk of excess mortality from breast cancer (age and year of diagnosis adjusted hazard ratio: 1.76; 95% CI: 1.51–2.04 for Māori and 1.97; 95% CI: 1.67–2.32 for Pacific women), of which 75% and 99% respectively were explained by baseline differences. The most important contributor was late stage at diagnosis. Other contributors included neighbourhood deprivation, mode of diagnosis, type of health care facility where primary cancer treatment was undertaken and type of loco-regional therapy. Conclusions Late diagnosis, deprivation and differential access to and quality of cancer care services were the key contributors to ethnic disparities in breast cancer survival in New Zealand. Our findings underscore the need for a greater equity focus along the breast cancer care pathway, with an emphasis on improving access to early diagnosis for Māori and Pacific women.

Despite high response rates to initial chemotherapy, the majority of women diagnosed with High-Grade Serous Ovarian Cancer (HGSOC) ultimately develop drug resistance within 1–2 years of treatment. We previously identified the most common mechanism of acquired resistance in HGSOC to date, transcriptional fusions involving the ATP-binding cassette (ABC) transporter ABCB1, which has well established roles in multidrug resistance. However, the underlying biology of fusion-positive cells, as well as how clonal interactions between fusion-negative and positive populations influences proliferative fitness and therapeutic response remains unknown. Using a panel of fusion-negative and positive HGSOC single-cell clones, we demonstrate that in addition to mediating drug resistance, ABCB1 fusion-positive cells display impaired proliferative capacity, elevated oxidative metabolism, altered actin cellular morphology and an extracellular matrix/inflammatory enriched transcriptional profile. The co-culture of fusion-negative and positive populations had no effect on cellular proliferation but markedly altered drug sensitivity to doxorubicin, paclitaxel and cisplatin. Finally, high-throughput screening of 2907 FDA-approved compounds revealed 36 agents that induce equal cytotoxicity in both pure and mixed ABCB1 fusion populations. Collectively, our findings have unraveled the underlying biology of ABCB1 fusion-positive cells beyond drug resistance and identified novel therapeutic agents that may significantly improve the prognosis of relapsed HGSOC patients.