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The lower limb of the Atlantic meridional overturning circulation (AMOC) is the equatorward flow of dense waters formed through the cooling and freshening of the poleward‐flowing upper limb. In the subpolar North Atlantic (SPNA), upper limb variability is primarily set by the North Atlantic Current, whereas lower limb variability is less well understood. Using observations from a SPNA mooring array, we show that variability of the AMOC's lower limb is connected to poleward flow in the interior Irminger Sea. We identify this poleward flow as the northward branch of the Irminger Gyre (IG), accounting for 55% of the AMOC's lower limb variability. Over 2014–2018, wind stress curl fluctuations over the Labrador and Irminger Seas drive this IG and AMOC variability. On longer (>annual) timescales, however, an increasing trend in the thickness of intermediate water, from 2014 to 2020, within the Irminger Sea coincides with a decreasing trend in IG strength. Plain Language Summary: In the subpolar North Atlantic, warm salty waters get transported northwards by the upper branch of the meridional overturning circulation. As they travel northwards, they transform: cooling, densifying, and sinking. The cooler deeper waters then get transported back southwards toward the equator in the lower branch of the overturning circulation. The transformation and transport of these waters plays a critical role in our climate system. However, the lower branch of the overturning circulation and the mechanisms controlling how it changes are still not well understood. Observations from a fixed array of moorings between Greenland and Scotland are used here to identify the interior (away from land boundaries) Irminger Sea as a region important for the overturning's lower branch. Specifically, we find that a closed system of currents in the western Irminger Sea, known as the Irminger Gyre, plays an important role in the overturning's variability. Gyre strength is then linked to the recirculation of newly transformed waters that get exported as part of the overturning's lower branch. Finally, we investigate the impact of the atmosphere on Irminger Sea circulation and find that fluctuations of the winds are important drivers of change in this gyre and the overturning. Key Points: The interior Irminger Sea, where the poleward limb of the Irminger Gyre (IG) dominates, is a hotspot for the overturning's lower limb variabilityA trend in IG transport is linked to deep intermediate water masses found in the Irminger SeaWind stress curl over the Labrador and Irminger Seas drives IG and Atlantic meridional overturning circulation variability [ABSTRACT FROM AUTHOR]

Competing Interests: Disclosure CS has reported non-remunerated activities as Coordinator Gynecological Programme for the European School of Oncology. JB has reported fees for advisory board membership for AstraZeneca and Pfizer; fees paid to her institute for roles as local principal investigator for AstraZeneca, MedSire and Pfizer. SLB has reported fees as an author for UpToDate. She has also reported non-remunerated activities as the chair of the Scientific Network on Female Sexual Health and Cancer (academic organisation). MJC has reported fees as an invited speaker for Roche (industry-sponsored symposium in National Conference). She has also reported non-remunerated activities as a member of the Board of Directors of EUSOMA, faculty member of ESO, project lead/lead investigator for the Breast Research Group of INESC TEC and President of MAMA Help (non-profit association for breast cancer patients in Portugal). She serves as a Specialty Editor for The Breast. NC has reported fees for advisory board membership for AstraZeneca, BIOCAD, Clovis Oncology, Eisai, GlaxoSmithKline (GSK), ImmunoGen, Mersana, Merck Sharp & Dohme (MSD)/Merck, Nuvation Bio, OncXerna, Pfizer, PharmaMar, Pieris and Roche; fees as an invited speaker for AstraZeneca, Clovis Oncology, GSK and MSD/Merck; institutional research grants from AstraZeneca, PharmaMar and Roche. She has also reported non-remunerated activities as member of the ESMO Guidelines Steering Committee and chair of the Scientific Committee of Alleanza contro il Tumore Ovarico (ACTO). GC has reported fees for advisory board membership for AstraZeneca, Bristol Myers Squibb (BMS), Celcuity, Daiichi Sankyo, Ellipsis, Exact Sciences, Lilly, Merck, Pfizer, Roche and Veracyte; fees as an invited speaker for AstraZeneca, Daiichi Sankyo, Novartis, Pfizer and Roche; fees for a writing engagement from Pfizer; institutional research grant from Merck for an investigator-initiated trial; institutional funding for phase I studies from Astellas, AstraZeneca, Blueprint Medicine, BMS, Daiichi Sankyo, Kymab, Novartis, Philogen, Relay Therapeutics, (coordinating principal investigator), Roche and Sanofi. He has also reported non-remunerated activities as an Italian National Health Council as Advisor for Ministry of Health (Consiglio Superiore di Sanità), member of the Scientific Council for the patient advocacy association Europa Donna, advisory role at the Fondazione Beretta cancer research foundation, member of the Board of Directors for Lega Italian Lotta ai Tumori (public national company for cancer prevention) and member of the Advisory Council of EUSOMA. SMD has reported personal honoraria from AstraZeneca, BMS and Clovis; fees paid to her institute as coordinating principal investigator for AstraZeneca. DGE has reported fees for advisory board membership for Recursion, SpringWorks and Syantra; consultancy fees for a writing engagement for AstraZeneca. DF has declared no conflicts of interest. NH has reported fees for advisory board membership for Aptitude Health, AstraZeneca, Daiichi Sankyo, Gilead, Novartis, Pfizer, Roche, Sandoz-Hexal, Sanofi and SeaGen; fees as an invited speaker for Art Tempi, AstraZeneca, Daiichi Sankyo, Exact Sciences, Gilead, Lilly, Medscape, MSD, Novartis, Onkowissen, Pierre Fabre, Roche, Sanofi and SeaGen; institutional funding from AstraZeneca, BMS, Daiichi Sankyo, Lilly, MSD, Novartis, Palleos, Pierre Fabre, Roche, SeaGen, TRIO and WSG; ownership interest in the West German Study Group. She has also reported non-remunerated activities as a member of the AGO Breast Guideline Committee and member of the ESO/ESCO Breast Cancer Educational Programs. She is the Founding Editor of the Breast Care journal. CK has reported fees for advisory board membership for Guerbet; fees as an invited speaker for Bayer and Bracco. BL has reported fees received from the Rising Tide Foundation as a patient reviewer. She has also reported non-remunerated activities as a member of the European Society of Gynaecological Oncology (ESGO) ENGAGe (Past Executive Board Member) and chair of KIU—Danish Patient Organisation for Women with Gynaecological Cancer. ELL has reported employment as the Director of the Medical Genetics Institute of the Shaare Zedek Medical Center. She has also reported non-remunerated activity as the vice president of the Israel National Academy of Science in Medicine (non-profit). ML has reported fees for advisory board membership and speaker fees for AstraZeneca, Exact Sciences, Gilead, Lilly, MSD, Novartis, Roche and SeaGen; fees as an invited speaker for Ipsen, Knight, Libbs, Pfizer, Sandoz, SeaGen and Takeda. JAL has reported fees for advisory board membership for Artios Pharma, AstraZeneca, BMS, Clovis Oncology, Eisai, Ellipses, GSK, ImmunoGen, Merck/MSD, Nuvation, Pfizer and VBL Therapeutics; speaker fees from AstraZeneca, Clovis Oncology, GSK and Neopharm; fees related to an independent data monitoring committee for Regeneron; institutional research grants from AstraZeneca, Clovis Oncology, Eisai, GSK, MSD/Merck and Pfizer. He has also reported non-remunerated activities as vice president of the European Society of Gynaecological Oncology (2019-2021). He serves as an associate editor of Therapeutic Advances in Medical Oncology (Sage Publishing). SL has reported fees paid to her institute for advisory board membership for AbbVie, Amgen, AstraZeneca, BMS, Celgene, DSI, EirGenix, Gilead, GSK, Lilly, Merck, Novartis, Pfizer, Pierre Fabre, Relay Therapeutics, Roche, Sanofi and SeaGen; fees paid to her institute as an invited speaker for AstraZeneca, DSI, Gilead, Novartis, Pfizer and Roche; employment as the Chief Executive officer (CEO) of GBG Forschungs GmbH; licensing fees paid to her institute by VM Scope GmbH; research grants to her institute from AstraZeneca, Celgene, Daiichi Sankyo, Immunomedics/Gilead, Novartis, Pfizer and Roche; institutional funding from AbbVie and Molecular Health; fees paid to her institute as principal investigator (Penelope/Padma) from Pfizer; fees paid to her institute from AstraZeneca (SC Capitello), Daiichi Sankyo (SC Destiny B05), Immunomedics/Gilead (SC ASCENT), Novartis (SC SOLAR1), Pfizer (SC PALOMA3), Roche (SC Inavo and SC Katherine), SeaGen (SC HERCLIMB). She has also reported non-remunerated activities as principal investigator for Aphinity, advisory role to Arbeitsgemeinschaft Gynäkologische Onkologie (AGO) Kommission Mamma (group in Germany responsible for breast cancer guidelines), membership of AGO, Deutsche Krebsgesellschaft (DKG), American Society of Clinical Oncology (ASCO) and ESMO including membership of the ESMO Guidelines Committee and past chair of the ESMO Breast Congress. She has reported institutional patents for which she has no financial interests: EP14153692.0, EP21152186.9, EP15702464.7, EP19808852.8. K-AP has reported non-remunerated activities as advisory board member for AstraZeneca, Scientific Advisory Committee member for Breast Cancer Trials, project lead in Australia for the DECRESENDO and OlympiA studies, member of the Expert Advisory Group on Cancer Clusters for the Victorian Department of Health and Human Services, Strategic Advisory Committee member for Breast Cancer Network Australia, Cancer Genetics Reference Committee Member for New South Wales Cancer Institute; advisory role on the register of experts for breast and hereditary cancer for the Medical Oncology Group of Australia and breast cancer optimal care pathway committee member for Cancer Council Victoria. She is also a leadership fellow of the National Health and Medical Research Council (Australia) and a practitioner fellow of the National Breast Cancer Foundation (Australia). SP-S has reported fees paid to her institute for advisory board membership for AstraZeneca, Eli Lilly, Exact Sciences, Medison, Pfizer and Roche; fees paid to her institute as an invited speaker for AstraZeneca, Eli Lilly, Exact Sciences, Medison, Novartis, Pfizer and Roche; fees paid to her institute for consultancy for Medison; personal and institutional research grant for an request for proposal for independent research put out by Shared Progress in Cancer Care and Pfizer.

Background: Breast cancer has a significant heritable basis, of which ∼60% remains unexplained. Testing for BRCA1/BRCA2 offers useful discrimination of breast cancer risk within families, and identification of additional breast cancer susceptibility genes could offer clinical utility., Patients and Methods: We included 2135 invasive breast cancer cases recruited via the Breast and Ovarian Cancer Susceptibility study, a retrospective UK study of familial breast cancer., Eligibility Criteria: female, BRCA-negative, white European ethnicity, and one of: (i) breast cancer family history, (ii) bilateral disease, (iii) young age of onset (<30 years), and (iv) concomitant ovarian cancer. We undertook exome sequencing of cases and carried out gene-level burden testing of rare damaging variants against those from 51 377 ethnicity-matched population controls from gnomAD., Results: 159/2135 (7.4%) cases had a qualifying variant in an established breast cancer susceptibility gene, with minimal evidence of signal in other cancer susceptibility genes. Known breast cancer susceptibility genes PALB2, CHEK2, and ATM were the only genes to retain statistical significance after correcting for multiple testing. Due to the enrichment of hereditary cases in the series, we had good power (>80%) to detect a gene of BRCA1-like risk [odds ratio (OR) = 10.6] down to a population minor allele frequency of 4.6 × 10 -5 (1 in 10 799, less than one-tenth that of BRCA1)and of PALB2-like risk (OR = 5.0) down to a population minor allele frequency of 2.8 × 10 -4 (1 in 1779, less than half that of PALB2). Power was lower for identification of novel moderate penetrance genes (OR = 2-3) like CHEK2 and ATM., Conclusions: This is the largest case-control whole-exome analysis of enriched breast cancer published to date. Whilst additional breast cancer susceptibility genes likely exist, those of high penetrance are likely to be of very low mutational frequency. Contention exists regarding the clinical utility of such genes., Competing Interests: Disclosure The authors have declared no conflicts of interest., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Many women with increased lifetime risk of developing breast cancer, due to pathogenic gene variants or family history, choose to undergo bilateral risk reducing mastectomies (BRRM). Patient reported outcome measures (PROMS) are an increasingly important part of informed consent but are little studied in women undergoing BRRM., Methods: We used a validated PROMS tool for breast reconstruction (BREAST-Q) in 297 women who had BRRM and breast reconstruction, 81% of whom had no malignancy (Benign Group, BG) and 19% in whom a perioperative breast cancer was diagnosed (Cancer Group, CG). 128 women also completed a Hospital Anxiety & Depression Score (HADS) questionnaire to test if preoperative HADS score could predict PROMS outcomes., Results: Women in the CG had lower PROMS scores for satisfaction with their breasts, nipple reconstruction and sexual wellbeing. Both groups reported equal satisfaction with BRRM outcome and psychosocial well-being. Physical well-being PROMS of the abdomen and chest were high in women in both groups as were scores for satisfaction with the care they received. The CG group reported suboptimal quality of patient information. A higher presurgical HADS anxiety score predicted less favourable postoperative psychosocial well-being despite similar levels of satisfaction with aesthetic outcome., Conclusion: We show a high degree of patient reported satisfaction by woman undergoing BRRM and reconstruction. There was a negative association with a cancer diagnosis on quality of life PROMS and higher preoperative anxiety levels negatively affected postoperative psychosocial well-being. These important findings should be part of the informed consent process during preoperative counselling., Competing Interests: Declaration of Competing Interest All authors confirm the absence of any conflicts of interest relating to any aspect of the work presented above., (Copyright © 2021. Published by Elsevier Ltd.)