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Ramzi Lakhdar,1 Dagmara McGuinness,2 Ellen M Drost,1 Paul G Shiels,2 Ricardo Bastos,3 William MacNee,1,4 Roberto A Rabinovich1,4 1ELEGI Colt Laboratory, MRC Centre for Inflammation Research, The Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, UK; 2Wolfson Wohl Translational Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, UK; 3IDIBAPS, University of Barcelona, Barcelona, Spain; 4Respiratory Department, Royal Infirmary of Edinburgh, Edinburgh, UK Purpose: Skeletal muscle wasting is an independent predictor of health-related quality of life and survival in patients with COPD, but the complexity of molecular mechanisms associated with this process has not been fully elucidated. We aimed to determine whether an impaired ability to repair DNA damage contributes to muscle wasting and the accelerated aging phenotype in patients with COPD. Patients and methods: The levels of phosphorylated H2AX (γH2AX), a molecule that promotes DNA repair, were assessed in vastus lateralis biopsies from 10 COPD patients with low fat-free mass index (FFMI; COPDL), 10 with preserved FFMI and 10 age- and gender-matched healthy controls. A panel of selected markers for cellular aging processes (CDKN2A/p16ink4a, SIRT1, SIRT6, and telomere length) were also assessed. Markers of oxidative stress and cell damage and a panel of pro-inflammatory and anti-inflammatory cytokines were evaluated. Markers of muscle regeneration and apoptosis were also measured. Results: We observed a decrease in γH2AX expression in COPDL, which occurred in association with a tendency to increase in CDKN2A/p16ink4a, and a significant decrease in SIRT1 and SIRT6 protein levels. Cellular damage and muscle inflammatory markers were also increased in COPDL. Conclusion: These data are in keeping with an accelerated aging phenotype as a result of impaired DNA repair and dysregulation of cellular homeostasis in the muscle of COPDL. These data indicate cellular degeneration via stress-induced premature senescence and associated inflammatory responses abetted by the senescence-associated secretory phenotype and reflect an increased expression of markers of oxidative stress and inflammation. Keywords: COPD, skeletal muscle wasting, aging, inflammation, apoptosis

Postmortem single-cell studies have transformed understanding of lower respiratory tract diseases (LRTDs), including coronavirus disease 2019 (COVID-19), but there are minimal data from African settings where HIV, malaria and other environmental exposures may affect disease pathobiology and treatment targets. In this study, we used histology and high-dimensional imaging to characterize fatal lung disease in Malawian adults with (n = 9) and without (n = 7) COVID-19, and we generated single-cell transcriptomics data from lung, blood and nasal cells. Data integration with other cohorts showed a conserved COVID-19 histopathological signature, driven by contrasting immune and inflammatory mechanisms: in US, European and Asian cohorts, by type I/III interferon (IFN) responses, particularly in blood-derived monocytes, and in the Malawian cohort, by response to IFN-γ in lung-resident macrophages. HIV status had minimal impact on histology or immunopathology. Our study provides a data resource and highlights the importance of studying the cellular mechanisms of disease in underrepresented populations, indicating shared and distinct targets for treatment., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Dysphoric milk ejection reflex (D-MER) is a dysregulation of emotions (dysphoria) that can occur during the milk ejection reflex and during breastfeeding or expressing breast milk. Symptoms of D-MER present suddenly and can include hopelessness, sadness, nervousness, irritability, nausea, dread, palpitations, and a hollow feeling in the stomach. Although D-MER was first reported in 2007, it remains understudied to date and should not be confused with postnatal depression or anxiety disorders. Knowing that they are experiencing symptoms of a named condition is very supportive for women who experience D-MER. It is important that health care professionals who interact with the breastfeeding dyad be aware of D-MER so they can provide supportive care, manage symptoms, and protect the breastfeeding relationship. In this article, we describe the case of a woman who experienced D-MER while she breastfed her newborn., Competing Interests: Conflict of Interest The authors report no conflicts of interest or relevant financial relationships., (Copyright © 2024 AWHONN, the Association of Women’s Health, Obstetric and Neonatal Nurses. Published by Elsevier Inc. All rights reserved.)

Background and Objective: In PROpel (NCT03732820), olaparib + abiraterone resulted in a statistically significant radiographic progression-free survival (rPFS) benefit and numerically prolonged overall survival (OS) versus placebo + abiraterone in first-line (1L) metastatic castration-resistant prostate cancer (mCRPC) patients. Here, we report post hoc exploratory subgroup analyses in patients with asymptomatic/mildly symptomatic or symptomatic disease at baseline., Methods: Patients were randomised 1:1 to olaparib (300 mg b.i.d.) or placebo with abiraterone (1000 mg o.d.) + prednisone/prednisolone (5 mg b.i.d.). For this post hoc exploratory analysis, patients with a Brief Pain Inventory-Short Form (BPI-SF) item 3 score of <4 and no opiate use were classified as asymptomatic/mildly symptomatic; those with a BPI-SF item 3 score of ≥4 and/or opiate use were classified as symptomatic. Subgroup analyses included investigator-assessed rPFS, OS, objective response rate, time to second progression or death, health-related quality of life, and safety., Key Findings and Limitations: The median rPFS in asymptomatic/mildly symptomatic patients (n = 560) was 27.6 mo for olaparib + abiraterone versus 19.1 mo for placebo + abiraterone (hazard ratio [HR], 0.59; 95% confidence interval [CI], 0.46-0.76). For symptomatic patients (n = 183), equivalent values were 14.1 versus 13.8 mo (HR, 0.78; 95% CI, 0.54-1.13). At the final planned OS analysis, the median OS in asymptomatic/mildly symptomatic patients was not reached for olaparib + abiraterone versus 39.5 mo for placebo + abiraterone (HR, 0.77; 95% CI, 0.59-1.00). For symptomatic patients, equivalent values were 22.9 versus 22.8 mo (HR, 0.82; 95% CI, 0.58-1.16). Other outcomes showed no meaningful differences between the subgroups., Conclusions and Clinical Implications: Olaparib + abiraterone provided efficacy benefits in 1L mCRPC patients with either asymptomatic/mildly symptomatic or symptomatic disease. A larger benefit occurred in asymptomatic/mildly symptomatic patients., Patient Summary: PROpel, a phase 3 clinical trial, looked at whether combining olaparib with abiraterone delays the progression of patients' cancer compared with placebo plus abiraterone. Patients with or without pain symptoms associated with metastatic castration-resistant prostate cancer were eligible for enrolment into the trial. Results showed that olaparib plus abiraterone reduced the risk of disease progression and death, with a larger benefit observed in patients without or with mild pain symptoms than in those with pain symptoms., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Breastfeeding is the optimal form of nutrition for infants and young children. The World Health Organization recommends that babies are breastfed exclusively for the first 6 months of life, and up to the age of 2 years or beyond in combination with complementary food. Breastfeeding initiation and continuation rates are suboptimal globally and very low in the Republic of Ireland where health promotion initiatives and healthcare professional support predominantly focus on the important phase of initiation and early months of the breastfeeding journey. This qualitative descriptive study aimed to explore the experiences of women who chose to breastfeed their children beyond 1 year of age in the Republic of Ireland. Fourteen women participated in semi-structured interviews. Interviews were transcribed verbatim and thematic analysis was conducted. The analysis generated three overarching themes: (1) Influences on breastfeeding beyond 1 year, (2) Sustaining breastfeeding and (3) Benefits of breastfeeding beyond 1 year. Family, friends, peers, culture and commercial milk formula marketing had an influence on breastfeeding journeys. Support, determination, knowledge, bed-sharing and Covid-19 pandemic social restrictions helped to sustain breastfeeding beyond 1 year. Benefits of breastfeeding beyond 1 year such as nutrition, strengthening of emotional bonds, development of a parenting tool, and protection of child and maternal health were identified. Our findings support the need for discussions and further research on the normalization of breastfeeding beyond 1 year in the Republic of Ireland, targeted health promotion initiatives and education programmes for healthcare professionals on supporting the continuation of breastfeeding., (© The Author(s) 2024. Published by Oxford University Press.)

Objective: To investigate the effectiveness of a multicomponent breastfeeding support intervention on breastfeeding prevalence at 3 months among women with a body mass index (BMI) >25 kg/m 2 ., Design: Multicentre multicomponent randomised controlled trial., Setting: Four maternity centres in Ireland., Population: A total of 225 primiparous women and their nominated support partners. Participants were aged 18 years and over, with BMI ≥25 kg/m 2 , carrying a singleton pregnancy and without contraindication for breastfeeding., Methods: The intervention included an antenatal group breastfeeding education session for participants and their support partners, followed by a planned postnatal breastfeeding assessment and telephone support for up to 6 weeks by a lactation consultant., Main Outcome Measures: Any breastfeeding at 3 months postpartum., Results: Any breastfeeding prevalence was 68.7% (n = 68) in the intervention group and 62.1% (n = 59) in the control group at 3 months postpartum (odds ratio 1.33, 95% confidence interval 0.72-2.46, p = 0.36). Any and exclusive breastfeeding rates did not significantly differ at any other time point. More women in the control group accessed support from private lactation consultants (intervention 23.5% [n = 12], control 45.3% [n = 24], p = 0.02)., Conclusions: The control group had higher than expected breastfeeding rates, and the study found no evidence of effect on the primary outcome. Providing comprehensive education and support for women intending to breastfeed remains of paramount importance., (© 2024 The Authors. BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd.)