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The Last Interglaciation (~ 130 to 116 ka) is a time period with a strong astronomicallyinduced seasonal forcing of insolation compared to modern. Proxy records indicate a significantly different climate to that of the modern, in particular Arctic summer warming and higher eustatic sea level. Because the forcings are relatively well constrained, it provides an opportunity to test numerical models which are used for future climate prediction. In this paper, we compile a set of climate model simulations of the early Last Interglaciation (130 to 125 ka), encompassing a range of model complexity. We compare the models to each other, and to a recently published compilation of Last Interglacial temperature estimates. We show that the annual mean response of the models is rather small, with no clear signal in many regions. However, the seasonal response is more robust, and there is significant agreement amongst models as to the regions of warming vs. cooling. However, the quantitative agreement of the models with data is poor, with the models in general underestimating the magnitude of response seen in the proxies. Taking possible seasonal biases in the proxies into account improves the agreement marginally, but the agreement is still far from perfect. However, a lack of uncertainty estimates in the data does not allow us to draw firm conclusions. Instead, this paper points to several ways in which both modeling and data could be improved, to allow a more robust model-data comparison. [ABSTRACT FROM AUTHOR]

We studied the midbrain SERT availability in patients with major depression and assessed the relation of SERT occupancy by citalopram to the treatment response. 21 non-medicated patients with major depression and 13 healthy controls were examined by [123I]-ADAM SPECT. The midbrain SERT availability (SERT V3″) was calculated using individual MRI scans. In 13/21 patients SPECT was repeated 7 days after oral medication with citalopram (10 mg/day). We found no significant difference in the mean midbrain SERT availability between the studied patients with major depression and healthy controls (0.86 ± 0.27 vs. 0.71 ± 0.44, p = 0.069). The mean SERT occupancy accounted to 61%. The degree of SERT blockade by citalopram did not correlate with the reduction in HAMD total score. Treatment with low-dosed citalopram caused individually variable occupancy of the midbrain-SERT and a rapid clinical improvement in 54% of the investigated patients. [ABSTRACT FROM AUTHOR]

In this case report, we present the treatment outcomes of the first patient enrolled in the LuDO-N trial. The patient is a 21-month-old girl diagnosed with high-risk neuroblastoma (NB) and widespread skeletal metastasis. The patient initially underwent first-line therapy according to SIOPEN HRNBL-1 but was switched to second-line treatments due to disease progression, and she was finally screened for enrollment in the LuDO-N trial due to refractory disease. Upon enrollment, the patient received two rounds of the radiolabeled somatostatin analogue lutetium-177 octreotate ( 177 Lu-DOTATATE), which was well tolerated. A dosimetry analysis revealed a heterogeneous uptake across tumor lesions, resulting in a significant absorbed dose of 54 Gy in the primary tumor, but only 2 Gy at one of the metastatic sites in the distal femur. While the initial treatment response showed disease stabilization, the distal femoral metastasis continued to progress, leading to the eventual death of the patient. A tissue analysis of the biopsies collected throughout the course of the disease revealed heterogeneous drug target expression of somatostatin receptor 2 (SSTR2) across and within tumor lesions. Furthermore, genomic profiling revealed a novel KIAA1549 :: BRAF fusion oncogene amplification in the distal femoral metastasis at recurrence that might be related with resistance to radiation, possibly through the downregulation of SSTR2. This case report demonstrates a mixed response to molecular radiotherapy (MRT) with 177 Lu-DOTATATE. The observed variation in SSTR2 expression between tumor lesions suggests that heterogeneous target expression may have been the reason for treatment failure in this patient's case. Further investigation within the LuDO-N trial will give a more comprehensive understanding of the correlation between SSTR2 expression levels and treatment outcomes, which will be important to advance treatment strategies based on MRT for children with high-risk NB., Competing Interests: JJES is affiliated with the companies Expression Analytics Oy and Trifma Oy. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors declare that this study received funding from the Swedish Childhood Cancer Fund, Swedish Cancer Society, Region Stockholm, and Advanced Accelerator Applications/Novartis (AAA). AAA had the following involvement in the study: financial support of the trial, provision of the investigational medicinal product (IMP) as well as non-IMPs free of charge., (Copyright © 2024 Park, Fransson, Sundquist, Nilsson, Grybäck, Wessman, Strömgren, Djos, Fagman, Sjögren, Georgantzi, Herold, Kogner, Granberg, Gaze, Martinsson, Karlsson and Stenman.)

Context: There is an increasing population of childhood cancer survivors (CCS) at risk for treatment-related toxicities, including skeletal morbidities. Bone mineral density (BMD) is a proxy for bone health and reductions are associated with osteoporosis and fractures., Objective: To investigate bone health in CCS by conducting a systematic review and meta-analysis of BMD after completed treatments., Data Sources: We searched Medline, Embase, Cochrane, and Web of Science in May 2019 and updated in May 2023., Study Selection: Studies reporting BMD Z-scores measured with dual-energy x-ray absorptiometry in CCS after treatment completion., Data Extraction: We performed a pooled analysis of studies reporting BMD Z-scores and thereafter we analyzed studies comparing BMD in survivors and healthy controls. All analyses were performed based on the site of BMD measurement., Results: Of 4243 studies, 84 were included (N = 8106). The mean time off-treatment across the studies ranged from 2 months to 24 years. The overall pooled mean Z-score was -0.57 (95% confidence interval [CI] -0.59 to -0.55) in the whole-body, -0.84 (95% CI -0.86 to -0.83) in the lumbar spine, -0.79 (95% CI -0.81 to -0.77) in the femoral neck and -0.14 (95% CI -0.18 to -0.11) in the total hip. When comparing survivors with controls, BMD was significantly lower in survivors at all sites., Limitations: English publications, study-level meta-analysis., Conclusions: We showed a significant reduction of BMD Z-scores in CCS. Given the increased fracture risk already within -1 SD, these results emphasize the need for BMD surveillance and secondary prevention in CCS., (Copyright © 2024 by the American Academy of Pediatrics.)

Background: Per- and polyfluoroalkyl Substances (PFAS) are synthetic chemicals widely detected in humans and the environment. Exposure to perfluorooctanesulfonic acid (PFOS) or perfluorohexanesulfonic acid (PFHxS) was previously shown to cause dark-phase hyperactivity in larval zebrafish., Objectives: The objective of this study was to elucidate the mechanism by which PFOS or PFHxS exposure caused hyperactivity in larval zebrafish., Methods: Swimming behavior was assessed in 5-d postfertilization (dpf) larvae following developmental (1-4 dpf) or acute (5 dpf) exposure to 0.43 - 7.86 μ M PFOS, 7.87 - 120 μ M PFHxS, or 0.4% dimethyl sulfoxide (DMSO). After developmental exposure and chemical washout at 4 dpf, behavior was also assessed at 5-8 dpf. RNA sequencing was used to identify differences in global gene expression to perform transcriptomic benchmark concentration-response ( BMC T ) modeling, and predict upstream regulators in PFOS- or PFHxS-exposed larvae. CRISPR/Cas9-based gene editing was used to knockdown peroxisome proliferator-activated receptors (ppars) pparaa/ab , pparda/db , or pparg at day 0. Knockdown crispants were exposed to 7.86 μ M PFOS or 0.4% DMSO from 1-4 dpf and behavior was assessed at 5 dpf. Coexposure with the ppard antagonist GSK3787 and PFOS was also performed., Results: Transient dark-phase hyperactivity occurred following developmental or acute exposure to PFOS or PFHxS, relative to the DMSO control. In contrast, visual startle response (VSR) hyperactivity only occurred following developmental exposure and was irreversible up to 8 dpf. Similar global transcriptomic profiles, BMC T estimates, and enriched functions were observed in PFOS- and PFHxS-exposed larvae, and ppars were identified as putative upstream regulators. Knockdown of pparda/db , but not pparaa/ab or pparg , blunted PFOS-dependent VSR hyperactivity to control levels. This finding was confirmed via antagonism of ppard in PFOS-exposed larvae., Discussion: This work identifies a novel adverse outcome pathway for VSR hyperactivity in larval zebrafish. We demonstrate that developmental, but not acute, exposure to PFOS triggered persistent VSR hyperactivity that required ppard function. https://doi.org/10.1289/EHP13667.

Objective: The effect of atrial fibrillation (AF) patterns on outcomes remains controversial. This study aims to evaluate the influence of AF type on the risk of cardiocerebrovascular events after left atrial appendage closure (LAAC) at long-term follow-up., Methods: AF was categorized as paroxysmal AF (PAF) and non-PAF (NPAF). The baseline characteristics, procedural data, peri-procedural complications, and long-term outcomes between patients with PAF and NPAF after LAAC were compared., Results: We analyzed 410 AF patients (mean age 74.8 ± 8.2 years; 271 male; 144 with PAF, 266 NPAF). The NPAF group tended to be older (≥75 years), male, and have chronic kidney disease (CKD) compared with the PAF group. The procedural data and peri-procedural complications were comparable. During 2.2 ± 1.5 years of follow-up, the incidences of thromboembolism, major bleeding, and device-related thrombus (DRT) did not differ between the two groups. The observed risk of thromboembolism and major bleeding was significantly lower than the estimated risk based on the CHA 2 DS 2 -VASc and HAS-BLED scores, respectively, in patients who underwent LAAC, regardless of the AF type. NPAF patients were associated with a higher risk of all-cause mortality, non-cardiovascular mortality, and combined efficacy endpoints. This association disappeared after propensity score matching (PSM) analysis., Conclusions: The risk of thromboembolism and major bleeding was lower in patients who underwent LAAC, regardless of the AF type. Although NPAF often coexists with multiple risk factors, it was not associated with worse long-term outcomes after LAAC when compared with PAF., Competing Interests: JY is a consultant to Boston Scientific and LifeTech Scientific. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Zhao, Yu, Hou, Post, Zhang, Xu, Herold and Walsleben.)

Abstract: Sterile alpha motif and histidine-aspartate (HD) domain-containing protein 1 (SAMHD1) is a deoxynucleoside triphosphate triphosphohydrolase with ara-CTPase activity that confers cytarabine (ara-C) resistance in several hematological malignancies. Targeting SAMHD1's ara-CTPase activity has recently been demonstrated to enhance ara-C efficacy in acute myeloid leukemia. Here, we identify the transcription factor SRY-related HMG-box containing protein 11 (SOX11) as a novel direct binding partner and first known endogenous inhibitor of SAMHD1. SOX11 is aberrantly expressed not only in mantle cell lymphoma (MCL), but also in some Burkitt lymphomas. Coimmunoprecipitation of SOX11 followed by mass spectrometry in MCL cell lines identified SAMHD1 as the top SOX11 interaction partner, which was validated by proximity ligation assay. In vitro, SAMHD1 bound to the HMG box of SOX11 with low-micromolar affinity. In situ crosslinking studies further indicated that SOX11-SAMHD1 binding resulted in a reduced tetramerization of SAMHD1. Functionally, expression of SOX11 inhibited SAMHD1 ara-CTPase activity in a dose-dependent manner resulting in ara-C sensitization in cell lines and in a SOX11-inducible mouse model of MCL. In SOX11-negative MCL, SOX11-mediated ara-CTPase inhibition could be mimicked by adding the recently identified SAMHD1 inhibitor hydroxyurea. Taken together, our results identify SOX11 as a novel SAMHD1 interaction partner and its first known endogenous inhibitor with potentially important implications for clinical therapy stratification., (© 2024 American Society of Hematology. Published by Elsevier Inc. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

This study presents a high-dimensional immunohistochemistry approach to assess human γδ T cell subsets in their native tissue microenvironments at spatial resolution, a hitherto unmet scientific goal due to the lack of established antibodies and required technology. We report an integrated approach based on multiplexed imaging and bioinformatic analysis to identify γδ T cells, characterize their phenotypes, and analyze the composition of their microenvironment. Twenty-eight γδ T cell microenvironments were identified in tissue samples from fresh frozen human colon and colorectal cancer where interaction partners of the immune system, but also cancer cells were discovered in close proximity to γδ T cells, visualizing their potential contributions to cancer immunosurveillance. While this proof-of-principle study demonstrates the potential of this cutting-edge technology to assess γδ T cell heterogeneity and to investigate their microenvironment, future comprehensive studies are warranted to associate phenotypes and microenvironment profiles with features such as relevant clinical characteristics., Competing Interests: Conflict of interest statement. M.W.L. reports personal fees from Boehringer Ingelheim for lectures/consultancy and is listed as a co-inventor on several patents owned by Immatics Biotechnologies, concerning peptides for use in immunotherapies., (© The Author(s) 2024. Published by Oxford University Press on behalf of Society for Leukocyte Biology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Childhood cancer predisposition (ChiCaP) syndromes are increasingly recognized as contributing factors to childhood cancer development. Yet, due to variable availability of germline testing, many children with ChiCaP might go undetected today. We report results from the nationwide and prospective ChiCaP study that investigated diagnostic yield and clinical impact of integrating germline whole-genome sequencing (gWGS) with tumor sequencing and systematic phenotyping in children with solid tumors., Methods: gWGS was performed in 309 children at diagnosis of CNS (n = 123, 40%) or extracranial (n = 186, 60%) solid tumors and analyzed for disease-causing variants in 189 known cancer predisposing genes. Tumor sequencing data were available for 74% (227/309) of patients. In addition, a standardized clinical assessment for underlying predisposition was performed in 95% (293/309) of patients., Findings: The prevalence of ChiCaP diagnoses was 11% (35/309), of which 69% (24/35) were unknown at inclusion (diagnostic yield 8%, 24/298). A second-hit and/or relevant mutational signature was observed in 19/21 (90%) tumors with informative data. ChiCaP diagnoses were more prevalent among patients with retinoblastomas (50%, 6/12) and high-grade astrocytomas (37%, 6/16), and in those with non-cancer related features (23%, 20/88), and ≥2 positive ChiCaP criteria (28%, 22/79). ChiCaP diagnoses were autosomal dominant in 80% (28/35) of patients, yet confirmed de novo in 64% (18/28). The 35 ChiCaP findings resulted in tailored surveillance (86%, 30/35) and treatment recommendations (31%, 11/35)., Interpretation: Overall, our results demonstrate that systematic phenotyping, combined with genomics-based diagnostics of ChiCaP in children with solid tumors is feasible in large-scale clinical practice and critically guides personalized care in a sizable proportion of patients., Funding: The study was supported by the Swedish Childhood Cancer Fund and the Ministry of Health and Social Affairs., Competing Interests: BT, FA, ET, and AN received support from the Swedish Childhood Cancer Fund (BT: TJ2018-0042; FA: KP2021-0010; ET: TJ2021-0125; AN: KP2019-0024, PR2019-0027, TJ2019-0013) and the Swedish Cancer Fund (FA: 21 1540 Fk 01 H; ET: 22 2451Fk; AN: 22 2057Pj). BT, ET and AN received support from Region Stockholm (BT: FoUI-985957; ET: FoUI-973659; AN: 5010124 ALF, 520136 ALF). AN received support from The Swedish Research Council (2021-02860). MB received honoraria for lectures by the Swedish Childhood Cancer Fund. GS served as advisor for trial design for Cyxone AB, Sweden. NH served as Chair of NOPHO Scientific Committee and Young NOPHO without retribution. RR received honoraria from AbbVie, AstraZeneca, Janssen, Illumina, and Roche. DG received grants from Swedish Ministry of Health and Social Affairs for GMS Childhood Cancer and is Vice dean for internationalization and recruitment, Faculty of Medicine, Lund University. AN received also funding from the Cancer Society of Stockholm, Stiftelsen Frimurare Barnhuset i Stockholm, Hållsten research foundation, Berth von Kantzow foundation and is board member of Sävstaholm foundation, Ågrenska foundation, Sällsyntafonden. All other authors have no conflict of interest to declare., (© 2024 The Author(s).)

Vegetation and precipitation are known to fundamentally influence each other. However, this interdependence is not fully represented in climate models because the characteristics of land surface (canopy) conductance to water vapor and CO 2 are determined independently of precipitation. Working within a coupled atmosphere and land modelling framework (CAM6/CLM5; coupled Community Atmosphere Model v6/Community Land Model v5), we have developed a new theoretical approach to characterizing land surface conductance by explicitly linking its dynamic properties to local precipitation, a robust proxy for moisture available to vegetation. This will enable regional surface conductance characteristics to shift fluidly with climate change in simulations, consistent with general principles of co-evolution of vegetation and climate. Testing within the CAM6/CLM5 framework shows that climate simulations incorporating the new theory outperform current default configurations across several error metrics for core output variables when measured against observational data. In climate simulations for the end of this century the new, adaptive stomatal conductance scheme provides a revised prognosis for average and extreme temperatures over several large regions, with increased primary productivity through central and east Asia, and higher rainfall through North Africa and the Middle East. The new projections also reveal more frequent heatwaves than originally estimated for the south-eastern US and sub-Saharan Africa but less frequent heatwaves across east Europe and northeast Asia. These developments have implications for evaluating food security and risks from extreme temperatures in areas that are vulnerable to climate change., (© 2024 The Authors. Global Change Biology published by John Wiley & Sons Ltd.)

(1) Background : The isokinetic measurement (IM) of the leg muscles is well established but costly, whereas the Bunkie Test (BT) is a rarely investigated but easy-to-conduct functional test to evaluate the total posterior chain. Although the tests differ in aim and test structures, both have their justification in the assessment process. Therefore, this study evaluated the diagnostic accuracy of the BT and the IM. (2) Methods : 21 participants (9 female, 12 male; age, 26.2 ± 5.26 years; weight 73.8 ± 14.6 kg; height 176.0 ± 9.91 cm) and 21 patients (9 female, 12 male; age, 26.5 ± 5.56 years; weight, 72.6 ± 16.9 kg; height 177.0 ± 10.1 cm) with self-reported pain in the knee performed the IM and the BT. For IM, we calculated the ratio of the knee mean flexor/extensor peak torque (H/Q ratio) for 60°/s and 120°/s, and BT performance was measured in seconds. We classified the IM (<0.6 H/Q ratio) and the BT (leg difference ≥4 s) as binary results according to the literature. We calculated the sensitivity and specificity, which we compared with the Chi-Square test, and the 95% confidence intervals (CI). A p -value of ≤0.05 is considered significant. (3) Results : The sensitivity for the BT was 0.89, 95% CI [0.67, 0.99], and the specificity was 0.52 [0.30, 0.74]. For the IM, the sensitivity was 0.14 [0.03, 0.36] for 60°/s and 0.05 [0.00, 0.24] for 120°/s, and the specificity was 0.70 [0.46, 0.88] for 60°/s and 0.90 [0.68, 0.99] for 120°/s. The results of the Chi-Square tests were significant for the BT (χ 2 (1) = 6.17, p = 0.01) but not for the IM (60°/s: χ 2 (1) = 0.70, p = 0.40; 120°/s: χ 2 (1) = 0.00, p = 0.97). (4) Conclusions : Patients were more likely to obtain a positive test result for the BT but not for the IM.

The German Cancer Society (Deutsche Krebsgesellschaft DKG) has published a position paper to address the challenges of cancer patient care in the era of genomic medicine. The German Consortium Hereditary Breast and Ovarian Cancer (GC-HBOC) has implemented this recommendation in its care concept for families at risk. Core elements are the outcome-oriented evaluation of structured and standardized clinical measures and reporting recommendations derived therefrom to primary care providers and patients. A cross-sector network with certified breast cancer and gynecological cancer centers was founded in 2015, starting from the Cologne Center of the GC-HBOC. To guarantee the knowledge transfer for mainstream genetic counseling, the Cologne center has established an educational program for physicians and specialized nurses in order to pilot trans-sectoral knowledge transfer on risk assessment and risk-stratified care. It consists of face-to-face lectures with written knowledge test, attending a genetic case conference and genetic counseling sessions with the opportunity to counsel under supervision. The lectures were accompanied by a structured evaluation of the participants' satisfaction and feedback of the needs in mainstream genetic counseling. Thereby, the network ensures that genetic counseling and testing is provided according to state-of-the-art knowledge and allows physicians to participate in knowledge-generating care outside the university setting and patients to receive care close to home. After multiple feedback cycles to improve the educational program, the GC-HBOC, in cooperation with the German Cancer Society, has now adopted this concept and developed a common and uniform online curriculum funded by the Federal Ministry of Health. https://www.krebsgesellschaft.de/fortbildung-familiaerer-krebs.html., (© 2024 The Authors. Journal of Genetic Counseling published by Wiley Periodicals LLC on behalf of National Society of Genetic Counselors.)

Background: Breast cancer (BC) risk prediction models consider cancer family history (FH) and germline pathogenic variants (PVs) in risk genes. It remains elusive to what extent complementation with polygenic risk score (PRS) and non-genetic risk factor (NGRFs) data affects individual intensified breast surveillance (IBS) recommendations according to European guidelines., Methods: For 425 cancer-free women with cancer FH (mean age 40·6 years, range 21-74), recruited in France, Germany and the Netherlands, germline PV status, NGRFs, and a 306 variant-based PRS (PRS 306 ) were assessed to calculate estimated lifetime risks (eLTR) and estimated 10-year risks (e10YR) using CanRisk. The proportions of women changing country-specific European risk categories for IBS recommendations, i.e. ≥20 % and ≥30 % eLTR, or ≥5 % e10YR were determined., Findings: Of the women with non-informative PV status, including PRS 306 and NGRFs changed clinical recommendations for 31·0 %, (57/184, 20 % eLTR), 15·8 % (29/184, 30 % eLTR) and 22·4 % (41/183, 5 % e10YR), respectively whereas of the women tested negative for a PV observed in their family, clinical recommendations changed for 16·7 % (25/150), 1·3 % (2/150) and 9·5 % (14/147). No change was observed for 82 women with PVs in high-risk genes (BRCA1/2, PALB2). Combined consideration of eLTRs and e10YRs identified BRCA1/2 PV carriers benefitting from IBS <30 years, and women tested non-informative/negative for whom IBS may be postponed., Interpretation: For women who tested non-informative/negative, PRS and NGRFs have a considerable impact on IBS recommendations. Combined consideration of eLTRs and e10YRs allows personalizing IBS starting age., Funding: Horizon 2020, German Cancer Aid, Federal Ministry of Education and Research, Köln Fortune., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Tidal wetlands are critical but highly threatened ecosystems that provide vital services. Efficient stewardship of tidal wetlands requires robust comparative assessments of different marshes to understand their resilience to stressors, particularly in the face of relative sea level rise. Existing assessment frameworks aim to address tidal marsh resilience, but many are either too localized or too general, and few directly translate resilience evaluations to recommendations for management strategies. In response to the deficiencies in existing frameworks, we identified a set of metrics that influence overall marsh resilience that can be assessed at any spatial scale. We then developed a new comprehensive assessment framework to rank relative marsh resilience using these metrics, which are nested within three categories. We represent resilience as the sum of results across the three metric categories: current condition, adaptive capacity, and vulnerability. Users of this framework can add scores from each category to generate a total resilience score to compare across marshes or take the score from each category and refer to recommended management actions we developed based on expert elicitation for each combination of category results. We then applied the framework across the contiguous United States using publicly available data, and summarized results at multiple spatial scales, from regions to coastal states to National Estuarine Research Reserves to finer scale marsh units, to demonstrate the framework's value across these scales. Our national analysis allowed for comparison of tidal marsh resilience across geographies, which is valuable for determining where to prioritize management actions for desired future marsh conditions. In combination, the assessment framework and recommended management actions function as a broadly applicable decision-support tool that will enable resource managers to evaluate tidal marshes and select appropriate strategies for conservation, restoration, and other stewardship goals., Competing Interests: The authors have declared that no competing interests exist., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)

Background/objective: To analyze changes in recurrent/refractory osteosarcoma phase II trials over time to inform future trials in this population with poor prognosis., Methods: A systematic review of trials registered on trial registries between 01/01/2017-14/02/2022. Comparison of 98 trials identified between 2003 and 2016. Publication search/analysis for both periods, last update on 01/12/2022., Results: Between 2017 and 2022, 71 phase-II trials met our selection criteria (19 osteosarcoma-specific trials, 14 solid tumor trials with and 38 trials without an osteosarcoma-specific stratum). The trial number increased over time: 13.9 versus 7 trials/year (p = 0.06). Monotherapy remained the predominant treatment (62% vs. 62%, p = 1). Targeted therapies were increasingly evaluated (66% vs. 41%, P = 0.001). Heterogeneity persisted in the trial characteristics. The inclusion criteria were measurable disease (75%), evaluable disease (14%), and surgical remission (11%). 82% of the trials included pediatric or adolescent patients. Biomarker-driven trials accounted for 25% of the total trials. The survival endpoint use (rather than response) slightly increased (40% versus 31%), but the study H 1 /H 0 hypotheses remained heterogeneous. Single-arm designs predominated over multiarm trials (n = 7). Available efficacy data on 1361 osteosarcoma patients in 58 trials remained disappointing, even though 21% of these trials were considered positive, predominantly those evaluating multi-targeted kinase inhibitors., Conclusion: Despite observed changes in trial design and an increased number of trials investigating new therapies, high heterogeneity remained with respect to patient selection, study design, primary endpoints, and statistical hypotheses in recently registered phase II trials for osteosarcoma. Continued optimization of trial design informed by a deeper biological understanding should strengthen the development of new therapies., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [RE declares funding by the Princess Maxima foundation. KB declares honoraria for educational events for Novartis and has received honoraria for participation on advisory boards for glaxosmithkline, Bayer, NEC Oncoimmunity and Incyte. NE declares honoraria for educational events by Merck/MSD. NH declares a grant by the Swedish Childhood Cancer Fund. EP declares honoraria for participation on advisory boards for Deciphera Pharmaceutical, Eusa Pharma, SynOx Therapeutics and Daiichy Sankyo. SS declares consulting fees by Ceridwen Oncology, support for travel by Adaptimmune and has received honoraria for participation of an advisory board for glaxosmithkline. All remaining authors have declared no conflicts of interest.]., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: The growing population of long-term childhood cancer survivors encounter a substantial burden of cardiovascular complications. The highest risk of cardiovascular complications is associated with exposure to anthracyclines and chest radiation. Longitudinal cardiovascular surveillance is recommended for childhood cancer patients; however, the optimal methods and timing are yet to be elucidated., Aims: We aimed to investigate the feasibility of different echocardiographic methods to evaluate left ventricular systolic function in retrospective datasets, including left ventricular ejection fraction (LVEF), fractional shortening (FS), global longitudinal strain (GLS) and longitudinal strain (LS) as well as the incidence and timing of subclinical left ventricular dysfunction detected by these methods., Methods and Results: A retrospective longitudinal study was performed with re-analysis of longitudinal echocardiographic data, acquired during treatment and early follow-up, including 41 pediatric sarcoma patients, aged 2.1-17.8 years at diagnosis, treated at Astrid Lindgren Children's Hospital, Stockholm, Sweden, during the period 2010-2021. All patients had received treatment according to protocols including high cumulative doxorubicin equivalent doses (≥250 mg/m 2 ). In 68% of all 366 echocardiograms, LS analysis was feasible. Impaired LS values (<17%) was demonstrated in >40%, with concomitant impairment of either LVEF or FS in 20% and combined impairment of both LVEF and FS in <10%. Importantly, there were no cases of abnormal LVEF and FS without concomitant LS impairment., Conclusion: Our findings demonstrate feasibility of LS in a majority of echocardiograms and a high incidence of impaired LS during anthracycline treatment for childhood sarcoma. We propose inclusion of LS in pediatric echocardiographic surveillance protocols., (© 2023 The Authors. Cancer Reports published by Wiley Periodicals LLC.)

Langerhans cell histiocytosis (LCH) is a potentially life-threatening inflammatory myeloid neoplasia linked to pediatric neurodegeneration, whereby transformed LCH cells form agglomerated lesions in various organs. Although MAP-kinase pathway mutations have been identified in LCH cells, the functional consequences of these mutations and the mechanisms that cause the pathogenic behavior of LCH cells are not well understood. In our study, we used an in vitro differentiation system and RNA-sequencing to compare monocyte-derived dendritic cells from LCH patients to those derived from healthy controls or patients with Crohn's disease, a non-histiocytic inflammatory disease. We observed that interferon-γ treatment exacerbated intrinsic differences between LCH patient and control cells, including strikingly increased endo- and exocytosis gene activity in LCH patients. We validated these transcriptional patterns in lesions and functionally confirmed that LCH cells exhibited increased endo- and exocytosis. Furthermore, RNA-sequencing of extracellular vesicles revealed the enrichment of pathological transcripts involved in cell adhesion, MAP-kinase pathway, vesicle trafficking and T-cell activation in LCH patients. Thus, we tested the effect of the LCH secretome on lymphocyte activity and found significant activation of NK cells. These findings implicate extracellular vesicles in the pathology of LCH for the first time, in line with their established roles in the formation of various other tumor niches. Thus, we describe novel traits of LCH patient cells and suggest a pathogenic mechanism of potential therapeutic and diagnostic importance.

Background: Treatment of newly diagnosed acute myeloid leukaemia (AML) is based on combination chemotherapy with cytarabine (ara-C) and anthracyclines. Five-year overall survival is below 30%, which has partly been attributed to cytarabine resistance. Preclinical data suggest that the addition of hydroxyurea potentiates cytarabine efficacy by increasing ara-C triphosphate (ara-CTP) levels through targeted inhibition of SAMHD1., Objectives: In this phase 1 trial, we evaluated the feasibility, safety and efficacy of the addition of hydroxyurea to standard chemotherapy with cytarabine/daunorubicin in newly diagnosed AML patients., Methods: Nine patients were enrolled and received at least two courses of ara-C (1 g/m 2 /2 h b.i.d. d1-5, i.e., a total of 10 g/m 2 per course), hydroxyurea (1-2 g d1-5) and daunorubicin (60 mg/m 2 d1-3). The primary endpoint was safety; secondary endpoints were complete remission rate and measurable residual disease (MRD). Additionally, pharmacokinetic studies of ara-CTP and ex vivo drug sensitivity assays were performed., Results: The most common grade 3-4 toxicity was febrile neutropenia (100%). No unexpected toxicities were observed. Pharmacokinetic analyses showed a significant increase in median ara-CTP levels (1.5-fold; p = 0.04) in patients receiving doses of 1 g hydroxyurea. Ex vivo, diagnostic leukaemic bone marrow blasts from study patients were significantly sensitised to ara-C by a median factor of 2.1 (p = 0.0047). All nine patients (100%) achieved complete remission, and all eight (100%) with validated MRD measurements (flow cytometry or real-time quantitative polymerase chain reaction [RT-qPCR]) had an MRD level <0.1% after two cycles of chemotherapy. Treatment was well-tolerated, and median time to neutrophil recovery >1.0 × 10 9 /L and to platelet recovery >50 × 10 9 /L after the start of cycle 1 was 19 days and 22 days, respectively. Six of nine patients underwent allogeneic haematopoietic stem-cell transplantation (allo-HSCT). With a median follow-up of 18.0 (range 14.9-20.5) months, one patient with adverse risk not fit for HSCT experienced a relapse after 11.9 months but is now in second complete remission., Conclusion: Targeted inhibition of SAMHD1 by the addition of hydroxyurea to conventional AML therapy is safe and appears efficacious within the limitations of the small phase 1 patient cohort. These results need to be corroborated in a larger study., (© 2022 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.)

The contribution of germline copy number variants (CNVs) to risk of developing cancer in individuals with pathogenic BRCA1 or BRCA2 variants remains relatively unknown. We conducted the largest genome-wide analysis of CNVs in 15,342 BRCA1 and 10,740 BRCA2 pathogenic variant carriers. We used these results to prioritise a candidate breast cancer risk-modifier gene for laboratory analysis and biological validation. Notably, the HR for deletions in BRCA1 suggested an elevated breast cancer risk estimate (hazard ratio (HR) = 1.21), 95% confidence interval (95% CI = 1.09-1.35) compared with non-CNV pathogenic variants. In contrast, deletions overlapping SULT1A1 suggested a decreased breast cancer risk (HR = 0.73, 95% CI 0.59-0.91) in BRCA1 pathogenic variant carriers. Functional analyses of SULT1A1 showed that reduced mRNA expression in pathogenic BRCA1 variant cells was associated with reduced cellular proliferation and reduced DNA damage after treatment with DNA damaging agents. These data provide evidence that deleterious variants in BRCA1 plus SULT1A1 deletions contribute to variable breast cancer risk in BRCA1 carriers., (© 2022. The Author(s).)

Objectives: To evaluate the influence of congestive heart failure (CHF) on safety and efficacy of left atrial appendage closure (LAAC) in non-valvular atrial fibrillation (NVAF) patients., Methods: A total of 401 patients who consecutively underwent LAAC with Watchman and LAmbre devices were divided into CHF (85 cases) and non-CHF (316 cases) groups. Comparisons between groups were performed against data., Results: No significant differences were found in implantation success and periprocedural complication rates between the two groups. During a mean 2.2 years of follow-up, the incidence rate of thromboembolism, major bleeding, device-related thrombus, and non-cardiovascular death was comparable. However, patients with CHF had significantly increased risk of all-cause death ( P = 0.015), cardiovascular death ( P = 0.014), and combined efficacy endpoints ( P = 0.02). After performing propensity score matching, the risk of all-cause death ( P = 0.01), cardiovascular death ( P = 0.01), and combined efficacy endpoints ( P = 0.006) was still higher. The logistic regression analyses identified CHF (OR: 3.642, 95% CI: 1.296-10.232, P = 0.014) as an independent predictor of cardiovascular death., Conclusions: Implantation of atrial appendage occluder is effective and safe in NVAF patients with CHF. The increased risk of mortality and combined efficacy endpoints in patients with CHF versus non-CHF after LAAC may be associated with the high risk of CHF itself.

Risk-reducing mastectomy (RRM) is the most efficient form of breast cancer (BC) risk reduction in BRCA1/2 pathogenic variant (pV) carriers. However, this intervention in physical integrity is associated with significant morbidity. We assessed long-term perception of satisfaction and health-related quality of life (QoL) after bilateral RRM and reconstruction using the validated BREAST-Q. We searched the prospective database of the Center for Hereditary Breast and Ovarian Cancer Cologne for previvors and survivors who underwent bilateral RRM from 1994 to 2015 and evaluated the results of their BREAST-Q scores. The study enrolled 43 previvors and 90 survivors after a mean follow-up of 46.3 ± 45.3 months after RRM. Satisfaction and QoL were independent of the technique of RRM or type of reconstruction but depended on the time of RRM. Compared to survivors, previvors had significantly higher mean satisfaction scores in their psychosocial, sexual, and physical well-being (chest) in both modules. Among previvors and survivors, higher psychological well-being correlated with a higher satisfaction with information and higher satisfaction with outcome. As psychological well-being correlated with satisfaction with information and outcome, we developed decision aids to improve shared decision making and long-term satisfaction with the decision and the postoperative outcome.

Background: Higher CHA 2 DS 2 -VASc score is associated with an increased risk of adverse cardio-cerebrovascular events in patients with non-valvular atrial fibrillation (NVAF), regardless of oral anticoagulation (OAC) status. However, whether this association still exists in patients undergoing left atrial appendage closure (LAAC) is unknown. We evaluated the impact of CHA 2 DS 2 -VASc score on LAAC efficacy and outcomes., Methods: A total of 401 consecutive patients undergoing LAAC were included and divided into 3 groups based on CHA 2 DS 2 -VASc score (0-2, 3-4, and ≥5). Baseline characteristics, periprocedural complications, and long-term outcomes were collected and compared across all groups., Results: There were no significant differences in implantation success, periprocedural complications, and long-term outcomes across all score groups. Kaplan-Meier estimation showed that the cumulative ratio of freedom from all-cause mortality ( P = 0.146), cardiovascular mortality ( P = 0.519), and non-cardiovascular mortality ( P = 0.168) did not differ significantly by CHA 2 DS 2 -VASc score group. LAAC decreased the risks of thromboembolism and major bleeding, resulting in a relative risk reduction (RRR) of 82.4% ( P < 0.001) and 66.7% ( P < 0.001) compared with expected risks in the overall cohort, respectively. Subgroup analysis indicated that observed risks of thromboembolism and major bleeding were significantly lower than the expected risks in score 3-4 and score ≥5 groups, respectively. The level of RRR increased with CHA 2 DS 2 -VASc score ( P < 0.001 for trend) for thromboembolism but not for major bleeding ( P = 0.2729 for trend)., Conclusion: Patients with higher CHA 2 DS 2 -VASc score did not experience worse outcomes, which may be partly attributed to more benefits provided by LAAC intervention in such patients compared to those with a low score., (Copyright © 2022 Zhao, Zhao, Hou, Post, Herold, Walsleben, Yuan, Meng and Yu.)

Coastal wetlands are not only among the world's most valued ecosystems but also among the most threatened by high greenhouse gas emissions that lead to accelerated sea level rise. There is intense debate regarding the extent to which landward migration of wetlands might compensate for seaward wetland losses. By integrating data from 166 estuaries across the conterminous United States, we show that landward migration of coastal wetlands will transform coastlines but not counter seaward losses. Two-thirds of potential migration is expected to occur at the expense of coastal freshwater wetlands, while the remaining one-third is expected to occur at the expense of valuable uplands, including croplands, forests, pastures, and grasslands. Our analyses underscore the need to better prepare for coastal transformations and net wetland loss due to rising seas.

Sea level rise threatens the coastal landscape, including coastal wetlands, which provide a unique natural habitat to a variety of animal and plant species as well as an array of ecosystem service flows of value to people. The economic valuation of potential changes in coastal wetland areas, while challenging, allows for a comparison with other types of economic impacts from climate change and enhances our understanding of the potential benefits of greenhouse gas mitigation. In this study, we estimate an ensemble of future changes in coastal wetland areas considering both sea level rise, future greenhouse gas emissions, and accretion rate uncertainty, using outputs from the National Ocean and Atmospheric (NOAA) marsh migration model. By the end of the century, total wetland losses range from 2.0 to 10.7 million acres across sea level rise scenarios. For Representative Concentration Pathway (RCP) 4.5 and RCP8.5, respectively, cummulative net wetland area loss is 1.8 and 2.4 million acres by 2050 and 3.5 and 5.2 million acres by 2100. We then estimate economic impacts with two distinct approaches: restoration cost and ecosystem services. The ecosystem services considered are limited by what can be reliably quantified-namely, coastal property protection from coastal flooding and carbon sequestration, the latter using a social cost of carbon approach. By the end of the century, annual restoration costs reach $1.5 and $3.1 billion for RCP 4.5 and RCP8.5, respectively. The lost ecosystem services, together, reach annual economic impacts that are much higher, reaching $2.5 billion for RCP4.5 and $6.1 billion for RCP8.5., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Conformational change of the β2 integrin lymphocyte function-associated antigen 1 (LFA-1) is an early marker of T cell activation. A protocol using the mAb clone m24 recognizing the active, extended high-affinity conformation has been previously described for the assessment of functional CD4 + and CD8 + T cells in response to MHC-peptide stimulation. We investigated the applicability of the m24 mAb to detect the activation of γδ T cells in response to different soluble and immobilized stimuli. m24 mAb staining was associated with the expression of cytokines and was detectable as early as 10 min after stimulation, but with different kinetics depending on the nature of the stimulus. Hence, we conclude that this assay is suitable for the detection of functional γδ T cells and allows the assessment of activation more rapidly than alternative methods such as cytokine detection. Intracellular staining, protein trafficking inhibitors, or prior knowledge of the stimulating moiety recognized are no longer required for monitoring γδ T cell activation., (© 2022 The Authors. European Journal of Immunology published by Wiley-VCH GmbH.)

The first International Workshop of the ATM and Cancer Risk group focusing on the role of Ataxia-Telangiectasia Mutated (ATM) gene in cancer was held on December 4 and 5, 2019 at Institut Curie in Paris, France. It was motivated by the fact that germline ATM pathogenic variants have been found to be associated with different cancer types. However, due to the lack of precise age-, sex-, and site-specific risk estimates, no consensus on management guidelines for variant carriers exists, and the clinical utility of ATM variant testing is uncertain. The meeting brought together epidemiologists, geneticists, biologists and clinicians to review current knowledge and on-going challenges related to ATM and cancer risk. This report summarizes the meeting sessions content that covered the latest results in family-based and population-based studies, the importance of accurate variant classification, the effect of radiation exposures for ATM variant carriers, and the characteristics of ATM-deficient tumors. The report concludes that ATM variant carriers outside of the context of Ataxia-Telangiectasia may benefit from effective cancer risk management and therapeutic strategies and that efforts to set up large-scale studies in the international framework to achieve this goal are necessary., (© 2021. The Author(s), under exclusive licence to Springer Nature B.V.)

Background: Half the children with high-risk neuroblastoma die with widespread metastases. Molecular radiotherapy is an attractive systemic treatment for this relatively radiosensitive tumor. 131 I-mIBG is the most widely used form in current use, but is not universally effective. Clinical trials of 177 Lutetium DOTATATE have so far had disappointing results, possibly because the administered activity was too low, and the courses were spread over too long a period of time, for a rapidly proliferating tumor. We have devised an alternative administration schedule to overcome these limitations. This involves two high-activity administrations of single agent 177 Lu-DOTATATE given 2 weeks apart, prescribed as a personalized whole body radiation absorbed dose, rather than a fixed administered activity. "A phase II trial of 177 Lutetium-DOTATATE in children with primary refractory or relapsed high-risk neuroblastoma - LuDO-N" (EudraCT No: 2020-004445-36, ClinicalTrials.gov Identifier: NCT04903899) evaluates this new dosing schedule., Methods: The LuDO-N trial is a phase II, open label, multi-center, single arm, two stage design clinical trial. Children aged 18 months to 18 years are eligible. The trial is conducted by the Nordic Society for Pediatric Hematology and Oncology (NOPHO) and it has been endorsed by SIOPEN (https://www.siopen.net). The Karolinska University Hospital, is the sponsor of the LuDO-N trial, which is conducted in collaboration with Advanced Accelerator Applications, a Novartis company. All Scandinavian countries, Lithuania and the Netherlands participate in the trial and the UK has voiced an interest in joining in 2022., Results: The pediatric use of the Investigational Medicinal Product (IMP) 177 Lu-DOTATATE, as well as non-IMPs SomaKit TOC® ( 68 Ga-DOTATOC) and LysaKare® amino acid solution for renal protection, have been approved for pediatric use, within the LuDO-N Trial by the European Medicines Agency (EMA). The trial is currently recruiting. Recruitment is estimated to be finalized within 3-5 years., Discussion: In this paper we present the protocol of the LuDO-N Trial. The rationale and design of the trial are discussed in relation to other ongoing, or planned trials with similar objectives. Further, we discuss the rapid development of targeted radiopharmaceutical therapy and the future perspectives for developing novel therapies for high-risk neuroblastoma and other pediatric solid tumors., Competing Interests: This study received funding from Applied Accelerator Applications, a Novartis company. The funder had the following involvement with the study: Advice on trial design, provision of all investigational and non-investigational products, free of charge for the LuDO-N trial and review of the final manuscript. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Sundquist, Georgantzi, Jarvis, Brok, Koskenvuo, Rascon, van Noesel, Grybäck, Nilsson, Braat, Sundin, Wessman, Herold, Hjorth, Kogner, Granberg, Gaze and Stenman.)

SAMHD1 is a deoxynucleoside triphosphate triphosphohydrolase (dNTPase) that restricts viral replication in infected cells and limits the sensitivity to cytarabine by hydrolysing its active metabolite, as recently shown in acute myeloid leukemia. Cytarabine is an essential component in the Nordic mantle cell lymphoma protocols (MCL2 and MCL3) for induction and high-dose chemotherapy treatment before autologous stem cell transplantation for younger patients with mantle cell lymphoma (MCL). We here investigated the expression of SAMHD1 in a population-based cohort of MCL (N = 150). SAMHD1 was highly variably expressed in MCL (range, 0.4% to 100% of positive tumor cells). Cases with blastoid/pleomorphic morphology had higher SAMHD1 expression (P = 0.028) and SAMHD1 was also correlated to tumor cell proliferation (P = 0.016). SAMHD1 expression showed moderate correlation to the expression of the transcriptional regulator SOX11 (P = 0.036) but genetic silencing of SOX11 and SAMHD1 by siRNA in MCL cell lines did not suggest mutual regulation. We hypothesized that expression of SAMHD1 could predict short time to progression in patients treated with Cytarabine as part of high-dose chemotherapy. Despite the correlation with known biological adverse prognostic factors, neither low or high SAMHD1 expression correlated to PFS or OS in patients treated according to the Nordic MCL2 or MCL3 protocols (N = 158)., (© 2021. The Author(s).)

The expression patterns of stimulator of interferon genes (STING) were investigated in a cohort of 158 T- and natural killer (NK)-cell and 265 B-cell non-Hodgkin lymphomas (NHLs), as well as in control reactive lymph nodes and tonsils. STING expression was assessed by immunohistochemical methods using diagnostic biopsy specimens obtained prior to treatment. Using an arbitrary 10% cutoff, STING was differentially expressed among T/NK-cell NHLs; positive in 36 out of 38 (95%) cases of ALK+ anaplastic large cell lymphoma (ALCL), 23 out of 37 (62%) ALK-ALCLs, 1 out of 13 (7.7%) angioimmunoblastic T-cell lymphomas, 15 out of 19 (79%) peripheral T-cell lymphomas, not otherwise specified, 20 out of 36 (56%) extranodal NK/T-cell lymphomas of nasal type, 6 out of 7 (86%) T-cell lymphoblastic lymphomas, and 3 out of 4 (75%) mycosis fungoides. STING expression did not correlate with clinicopathological parameters or outcome in these patients with T/NK-cell lymphoma. By contrast, all 265 B-cell NHLs of various types were STING-negative. In addition, STING mRNA levels were very high in 6 out of 7 T-cell NHL cell lines, namely, ALK+ and ALK-ALCL cell lines, and very low or undetectable in 7 B-cell NHL cell lines, suggesting transcriptional downregulation of STING in neoplastic B-cells. At the protein level, using Western blot analysis and immunohistochemistry performed on cell blocks, STING expression was found to be restricted to T-cell NHL cell lines. Taken together, STING expression represents a novel biomarker and therapeutic target in T- and NK-cell lymphomas with direct immunotherapeutic implications since modulators of cGAS-STING activity are already available for clinical use.

Introduction: Patients with non-valvular atrial fibrillation (NVAF) and previous stroke are at significantly higher risk of stroke recurrence. Data on the efficacy of left atrial appendage closure (LAAC) on these patients is limited. The aim of this study was to investigate the differences of LAAC efficacy on long-term cardio- and cerebrovascular outcomes in NVAF patients with vs. without prior stroke. Methods: Three hundred and seventy consecutive NVAF patients who underwent LAAC were enrolled and divided into stroke and non-stroke groups based on history of previous stroke. Endpoints, such as thromboembolism, major bleeding, and mortality post-LAAC, were followed up among groups. Results: Patients in the stroke group had higher mean CHA 2 DS 2 -VASc and HAS-BLED scores compared to the non-stroke group (5.1 vs. 3.6 and 4.1 vs. 3.4, both P < 0.001, respectively). Over a median follow-up of 2.2 years, there were no significant differences in incidence rates of thromboembolism, device-related thrombus (DRT), major bleeding, and combined efficacy endpoints between the two groups. In both stroke and non-stroke groups, LAAC decreased the risk of thromboembolism [relative risk reduction (RRR) 87.5%, P = 0.034, and 74.6%, P = 0.004, respectively] and major bleeding (RRR 68.8%, P = 0.034, and 68.6%, P = 0.007, respectively) compared with predicted risk. The RRR in thromboembolism was greater in patients with vs. without prior stroke (OR 2.45, 95% CI: 1.20-5.12, P = 0.016). The incidence rates of all-cause mortality and non-cardiovascular death were similar between the two groups, but the risks of cardiovascular death post-LAAC both before (1.4% vs. 8.1%, respectively, P = 0.038) and after adjustment for confounding factors (P = 0.048) were significantly decreased in the stroke group. Conclusions: Patients with vs. without prior stroke did not exhibit a worse clinical prognosis after LAAC. LAAC may provide an increased benefit in cardio-cerebrovascular outcomes in patients with previous stroke compared to those without previous stroke. Further research is necessary to evaluate the efficacy of LAAC in this field., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zhao, Zhao, Hou, Post, Herold, Walsleben, Meng and Yu.)