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Adjuvant Atezolizumab for Early Triple-Negative Breast Cancer:The ALEXANDRA/IMpassion030 Randomized Clinical Trial
Get PDFIMPORTANCE Triple-negative breast cancer is an aggressive subtype with a high incidence in young patients, a high incidence in non-Hispanic Black women, and a high risk of progression to metastatic cancer, a devastating sequela with a 12- to 18-month life expectancy. Until recently, one strategy for treating early-stage triple-negative breast cancer was chemotherapy after surgery. However, it was not known whether the addition of immune therapy to postsurgery chemotherapy would be beneficial. OBJECTIVE To evaluate the addition of immune therapy in the form of atezolizumab to postoperative chemotherapy in patients with the high-risk triple-negative breast cancer subtype. DESIGN, SETTING, AND PARTICIPANTS In this open-label international randomized phase 3 trial conducted in more than 330 centers in 31 countries, patients undergoing surgery as initial treatment for stage II or III triple-negative breast cancer were enrolled between August 2, 2018, and November 11, 2022. The last patient follow-up was on August 18, 2023. INTERVENTIONS Patients were randomized (1:1) to receive standard chemotherapy for 20 weeks with (n = 1101) or without (n = 1098) the immune therapy drug atezolizumab for up to 1 year. MAIN OUTCOMES AND MEASURES The primary end point was invasive disease-free survival (time between randomization and invasive breast cancer in the same or opposite breast, recurrence elsewhere in the body, or death from any cause). RESULTS The median age of enrolled patients was 53 years and most self-reported as being of Asian or White race and neither Latino nor Hispanic ethnicity. The study independent data monitoring committee halted enrollment at 2199 of 2300 planned patients. All patients stopped atezolizumab following a planned early interim and futility analysis. The trial continued to a premature final analysis. With invasive disease-free survival events in 141 patients (12.8%) treated with atezolizumab-chemotherapy and 125 (11.4%) with chemotherapy alone (median follow-up, 32 months), the final stratified invasive disease-free survival hazard ratio was 1.11 (95% CI, 0.87-1.42; P = .38). Compared with chemotherapy alone, the regimen of atezolizumab plus chemotherapy was associated with more treatment-related grade 3 or 4 adverse events (54% vs 44%) but similar incidences of fatal adverse events (0.8% vs 0.6%) and adverse events leading to chemotherapy discontinuation. Chemotherapy exposure was similar in the 2 treatment groups. CONCLUSIONS AND RELEVANCE The addition of the immune therapy drug atezolizumab to chemotherapy after surgery did not provide benefit among patients with triple-negative breast cancer who are at high risk of recurrent disease.</p
The syntactic constraint on English auxiliary contraction
Get PDFWe offer a new explanation for the difference between cases where an auxiliary verb can and cannot contract, such as Kim is coming versus Kim is. Rather than a banning constraint, we argue that there is a positive syntactic licensing constraint. We consider, and reject, both the familiar Gap restriction and a range of phonological explanations. Our analysis rests on the category of grammatical relations, valent, which includes all non-adjuncts (i.e. all subjects and complements); the analysis consists of a single claim, the Following Valent Constraint: that a contracted auxiliary has an overt following valent. We show how this analysis explains the full range of data that has been discussed in the literature and how a minor variant of the constraint captures the data of the Scots Locative Discovery Expressions. We also propose a sociolinguistic explanation for the inability of auxiliaries to contract in certain environments such as after a preposed negative. Finally, we suggest a functional explanation for the proposed constraint: it allows the hearer to predict the presence of a following valent and thereby to manage the burden of processing
The East Asian portfolio glut and the rise of unconventional exchange rate management
Get PDFIn recent years, non-bank financial actors such as pension funds and life insurance corporations from Japan, Korea, and Taiwan have emerged as sizable investors in global bond and equity markets. What explains the rapid internationalisation of institutional investors? As this article shows, East Asian investors’ global search for yield is far from a purely market-driven development. Public authorities actively ‘de-risked’—that is, facilitated and made viable—this internationalization, notably by channelling public funds abroad, by easing regulatory restrictions on foreign currency trading, and by experimenting with new forms of central bank support for foreign exchange markets. From a policy perspective, promoting portfolio outflows allowed authorities to show markets the intention to depreciate their currencies, yet without having to resort to highly politicized official interventions. In drawing on market mechanisms to align private-sector profit interests with broader policy goals, this leveraging of portfolio flows for macroeconomic policy purposes constitutes a novel and unconventional form of exchange rate management. While highly effective in the decade following the global financial crisis, the pivot to global monetary tightening from 2021 onwards presents new challenges for states seeking to coordinate macroeconomic policy with private profit interests
Exploring the relationship between maternal wellbeing, infant development, smartphone use, and mother-infant responsiveness
Get PDFEmerging evidence suggests smartphone use has adverse effects on mother-infant relationships. However, while research suggests that maternal responsiveness is reduced when using a smartphone, little research has been undertaken with infants. This study used cross-sectional data to explore associations between infant social-emotional development, maternal mental health outcomes, smartphone use, and mother-infant responsiveness. We recruited 450 mothers with infants aged 3–9 months, in the UK. Data were collected between October 2021–April 2022, during the COVID-19 pandemic. Validated self-report scales measured predictor variables and an outcome variable of mother-infant responsiveness. Hierarchical linear multiple regression identified a final model (R2 = .385, F (3,432) = 17.33, p < .001), with four significant predictors for mother-infant responsiveness: infant social-emotional development, birth parity, perceived social support in the form of appraisal, and likelihood of maternal smartphone use when the infant may be perceived as passive. These results suggest that within this sample, suboptimal infant social-emotional development, additional children in the family, lack of appraisal support for mothers, as well as maternal smartphone use during critical periods of parenting all demonstrate a negative association with mother-infant responsiveness. The results have implications for planning early support for mothers in the first months of their infant’s life
T-helper cell phenotypes are repeatable, positively correlated and associated with helminth infection in wild Soay sheep
Get PDFT-helper (Th) cells co-ordinate immune responses to ensure that infections with diverse parasites are controlled effectively. Helminth parasites such as gastro-intestinal nematodes (GIN) are generally associated with T-helper type 2 (Th2) responses, while intracellular parasites are associated with Th1 responses. Although laboratory models have reported that Th1 and Th2 can be antagonistic, this has been challenged by studies of natural infections.Between 2019 and 2022 we completed 759 captures of 538 wild Soay sheep (1-4 captures per animal) and monitored body weight, parasite egg counts, Th phenotypes, cytokines and GIN-specific antibodies.While different Th cell counts, cytokines and antibody isotypes were generally positively correlated with each other, no strong positive associations were observed between these measurements. Cell counts had low repeatability (among-individual variation) across four years, while antibody levels were highly repeatable. The Th1 and Th2 cytokines IFN-γ and IL-4 were moderately repeatable and were positively correlated at both the between- and within-individual levels independent of body condition or parasite exposure. IL-4 was negatively associated with GIN faecal egg count, while IFN-γ was negatively associated with coccidian faecal oocyst count, suggesting that these cytokines reflect resistance to these parasites. None of our immune markers were strongly associated with lamb survival.Our results provide insights into how different aspects of immune function interact to produce effective responses to complex infections but suggest longer term data collection is required to address the causes of these interactions and to detect fitness consequences of variation in T cell phenotypes under natural conditions
Artificial Intelligence and creativity
Get PDFThe question of whether machines can be creative has been at the centre of debates among scholars and practitioners well before the inception of Artificial Intelligence (AI) as a recognised field of research. This paper reviews how some of the key thinkers in the fields of creativity and AI have approached this question, contextualising their views within the ebbs and flows of AI technological developments, from the 1950s until now. The thread of this overview is Margaret Boden’s identification of novelty, surprisingness, and value, as the three cardinal features of creativity. This review will retrace the steps of the quest of Artificial Intelligence researchers as they strive to replicate each of these three properties within human-made machines. The paper closes with a reflection on how the third of these properties, value, prompts us to consider societal challenges raised by the widespread adoption of AI for creativity that transcend the question: “Can AI be creative?”
Delivery of blended learning models for veterinary paraprofessionals:Lessons learned
Get PDFThrough an innovative continuous professional development training programme, “Growing your business through preventive livestock healthcare”, the Food and Agriculture Organization of the United Nations (FAO) has aimed to address private sector veterinary paraprofessionals’ skills gaps and support them to develop successful businesses providing preventive livestock health services to small-scale farmers and pastoralists. These training courses were piloted in Nigeria, South Africa and Uganda in 2023 using a blended learning approach. This document will detail some of the lessons learned from the delivery of this training in Nigeria and Uganda covering the training design process, its implementation and the initial impact
Impact of household size and co-resident multimorbidity on unplanned hospitalisation and transition to care home
Get PDFThe ability to manage ill health and care needs might be affected by who a person lives with. This study examined how unplanned hospitalisation and transition to living in a care home vary according to household size and co-resident multimorbidity. Here we show results from a cohort study using Welsh nationwide linked healthcare and census data and multilevel multistate models accounting for competing risk of death and clustering within households. The highest rates of unplanned hospitalisation and care home transition were in those living alone. Event rates were lower in all shared households and lowest when co-residents did not have multimorbidity. These differences were more substantial for care home transition. Therefore, living alone or with co-residents with multimorbidity poses additional risk for unplanned hospitalisation and care home transition beyond an individual’s sociodemographic and health characteristics. Understanding the mechanisms behind these associations is needed to inform targeted inte
Pathways to a Diagnosis of Trigeminal Neuralgia: a Qualitative Study of Patients’ Experiences
No full textBackgroundTrigeminal Neuralgia (TN) is a rare disorder which causes episodes of intense facial pain and has been described as the ‘suicide disease’. Hence, prompt diagnosis and timely initiation of treatment is vital. However, delays to diagnosis and high rates of misdiagnosis are common, particularly within primary care. To date, most research has focused upon treatment options rather than improving diagnostic experiences. This study sought to explore patients’ experiences of the events leading up to their TN diagnosis and their views about the care and support they received when they were diagnosed to provide recommendations for improving the TN diagnostic pathway.MethodsThis was a qualitative, exploratory study using in-depth interviews. Interviews were conducted with (n=25) UK-based people with TN recruited via online forums. Data were analysed thematically.ResultsFollowing the onset of their TN pain, most participants described an arduous and uncertain journey to diagnosis, with many encountering significant delays, misdiagnoses and receiving inappropriate referrals and treatment. As a consequence, participants reported experiencing profound distress, anxiety, depression and, in extreme cases, suicidal ideation; some also described drug and alcohol misuse during this time. Most participants conveyed relief upon finally receiving a diagnosis. However, this was often by eclipsed by what they saw as poor and insensitive communication and inadequate information provisioning. ConclusionsThe present study highlights the importance of developing bespoke training for primary care and other professionals to facilitate timely recognition of TN symptomatology and ensure that they deliver a TN diagnosis in clear, sensitive and empathetic ways
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