High-energy neutrino follow-up search of gravitational wave event GW150914 with ANTARES and IceCube

Copyright © 2016 American Physical Society and reproduced in accordance with the publisher copyright policyWe present the high-energy-neutrino follow-up observations of the first gravitational wave transient GW150914 observed by the Advanced LIGO detectors on September 14, 2015. We search for coincident neutrino candidates within the data recorded by the IceCube and Antares neutrino detectors. A possible joint detection could be used in targeted electromagnetic follow-up observations, given the significantly better angular resolution of neutrino events compared to gravitational waves. We find no neutrino candidates in both temporal and spatial coincidence with the gravitational wave event. Within ± 500     s of the gravitational wave event, the number of neutrino candidates detected by IceCube and Antares were three and zero, respectively. This is consistent with the expected atmospheric background, and none of the neutrino candidates were directionally coincident with GW150914. We use this nondetection to constrain neutrino emission from the gravitational-wave event

High-Energy Neutrino Follow-Up Search of Gravitational Wave Event GW150914 with ANTARES and Icecube

We present the high-energy-neutrino follow-up observations of the first gravitational wave transient GW150914 observed by the Advanced LIGO detectors on September 14, 2015. We search for coincident neutrino candidates within the data recorded by the IceCube and Antares neutrino detectors. A possible joint detection could be used in targeted electromagnetic follow-up observations, given the significantly better angular resolution of neutrino events compared to gravitational waves. We find no neutrino candidates in both temporal and spatial coincidence with the gravitational wave event. Within ±500 s of the gravitational wave event, the number of neutrino candidates detected by IceCube and Antares were three and zero, respectively. This is consistent with the expected atmospheric background, and none of the neutrino candidates were directionally coincident with GW150914. We use this nondetection to constrain neutrino emission from the gravitational-wave event

828 kHz retinal imaging with an 840 nm Fourier domain mode locked laser

This paper presents a Fourier domain mode locked (FDML) laser centered around 840 nm. It features a bidirectional sweep repetition rate of 828 kHz and a spectral bandwidth of 40 nm. An axial resolution of ∼9.9 μm in water and a 1.4 cm sensitivity roll-off are achieved. Utilizing a complex master-slave (CMS) recalibration method and due to a sufficiently high sensitivity of 84.6 dB, retinal layers of the human eye in-vivo can be resolved during optical coherence tomography (OCT) examination. The developed FDML laser enables acquisition rates of 3D-volumes with a size of 200 × 100 × 256 voxels in under 100 milliseconds. Detailed information on the FDML implementation, its challenging design tasks, and OCT images obtained with the laser are presented in this paper

Mass hierarchy discrimination with atmospheric neutrinos in large volume ice/water Cherenkov detectors

Large mass ice/water Cherenkov experiments, optimized to detect low energy (1-20 GeV) atmospheric neutrinos, have the potential to discriminate between normal and inverted neutrino mass hierarchies. The sensitivity depends on several model and detector parameters, such as the neutrino flux profile and normalization, the Earth density profile, the oscillation parameter uncertainties, and the detector effective mass and resolution. A proper evaluation of the mass hierarchy discrimination power requires a robust statistical approach. In this work, the Toy Monte Carlo, based on an extended unbinned likelihood ratio test statistic, was used. The effect of each model and detector parameter, as well as the required detector exposure, was then studied. While uncertainties on the Earth density and atmospheric neutrino flux profiles were found to have a minor impact on the mass hierarchy discrimination, the flux normalization, as well as some of the oscillation parameter (\Delta m^2_{31}, \theta_{13}, \theta_{23}, and \delta_{CP}) uncertainties and correlations resulted critical. Finally, the minimum required detector exposure, the optimization of the low energy threshold, and the detector resolutions were also investigated.Comment: 23 pages, 16 figure

Serum short chain fatty acids mediate hippocampal BDNF and correlate with decreasing neuroinflammation following high pectin fiber diet in mice

IntroductionDietary components, such as prebiotic fiber, are known to impact brain chemistry via the gut-brain axis. In particular, short chain fatty acids (SCFAs) generated from excessive soluble fiber consumption are thought to impact neuroimmune signaling and brain function through increased production of neurotropic factors. Given reports that high dietary fiber intake is associated with increased mental health and improved quality of life scores, we set out to identify whether changes in SCFA levels as a result of a high soluble fiber diet mediate hippocampal neuroinflammation and brain derived neurotrophic factor (BDNF) in mice.MethodsAdult male and female C57BL/6 mice were fed a 1-month high pectin fiber or cellulose-based control diet. Following 1 month of excessive pectin consumption, serum SCFAs were measured using gas chromatography–mass spectrometry (GC-MS) and hippocampal cytokines and BDNF were assessed via multiplex magnetic bead immunoassay.ResultsPectin-based fiber diet increased circulating acetic acid in both sexes, with no effect on propionic or butyric acid. In the hippocampus, a high fiber diet decreased TNFa, IL-1ß, IL-6, and IFNγ and increased BDNF levels. Furthermore, increased SCFA levels were inversely correlated with neuroinflammation in the hippocampus, with acetic acid revealed as a strong mediator of increased BDNF production.ConclusionCollectively, these findings highlight the beneficial effects of fiber-induced molecular changes in a brain region known to influence mood- and cognition-related behaviors. Dietary composition should be considered when developing mental health management plans for men and women with an emphasis on increasing soluble fiber intake

High-energy neutrino follow-up search of gravitational wave event GW150914 with ANTARES and IceCube

We present the high-energy-neutrino follow-up observations of the first gravitational wave transient GW150914 observed by the Advanced LIGO detectors on September 14, 2015. We search for coincident neutrino candidates within the data recorded by the IceCube and Antares neutrino detectors. A possible joint detection could be used in targeted electromagnetic follow-up observations, given the significantly better angular resolution of neutrino events compared to gravitational waves. We find no neutrino candidates in both temporal and spatial coincidence with the gravitational wave event. Within ±500  s of the gravitational wave event, the number of neutrino candidates detected by IceCube and Antares were three and zero, respectively. This is consistent with the expected atmospheric background, and none of the neutrino candidates were directionally coincident with GW150914. We use this nondetection to constrain neutrino emission from the gravitational-wave event. © 2016 The American Physical Societ

Emulsion and liposome-based adjuvanted R21 vaccine formulations mediate protection against malaria through distinct immune mechanisms

Adjuvanted protein vaccines offer high efficacy, yet most potent adjuvants remain proprietary. Several adjuvant compounds are being developed by the Vaccine Formulation Institute in Switzerland for global open access clinical use. In the context of the R21 malaria vaccine, in a mouse challenge model, we characterize the efficacy and mechanism of action of four Vaccine Formulation Institute adjuvants: two liposomal (LQ and LMQ) and two squalene emulsion-based adjuvants (SQ and SMQ), containing QS-21 saponin (Q) and optionally a synthetic TLR4 agonist (M). Two R21 vaccine formulations, R21/LMQ and R21/SQ, offer the highest protection (81%–100%), yet they trigger different innate sensing mechanisms in macrophages with LMQ, but not SQ, activating the NLRP3 inflammasome. The resulting in vivo adaptive responses have a different TH1/TH2 balance and engage divergent innate pathways while retaining high protective efficacy. We describe how modular changes in vaccine formulation allow for the dissection of the underlying immune pathways, enabling future mechanistically informed vaccine design

Assessment of Multilocus Sequence Analysis (MLSA) for Identification of Candidatus Liberibacter Solanacearum from Different Host Plants in Spain

[EN] Liberibacteris a bacterial group causing different diseases and disorders in plants. Among liberibacters,CandidatusLiberibacter solanaceraum (CLso) produces disorders in several species mainly within Apiaceae and Solanaceae families. CLso isolates are usually grouped in defined haplotypes according to single nucleotide polymorphisms in genes associated with ribosomal elements. In order to characterize more precisely isolates of CLso identified in potato in Spain, a Multilocus Sequence Analysis (MLSA) was applied. This methodology was validated by a complete analysis of ten housekeeping genes that showed an absence of positive selection and a nearly neutral mechanism for their evolution. Most of the analysis performed with single housekeeping genes, as well as MLSA, grouped together isolates of CLso detected in potato crops in Spain within the haplotype E, undistinguishable from those infecting carrots, parsnips or celery. Moreover, the information from these housekeeping genes was used to estimate the evolutionary divergence among the different CLso by using the concatenated sequences of the genes assayed. Data obtained on the divergence among CLso haplotypes support the hypothesis of evolutionary events connected with different hosts, in different geographic areas, and possibly associated with different vectors. Our results demonstrate the absence in Spain of CLso isolates molecularly classified as haplotypes A and B, traditionally considered causal agents of zebra chip in potato, as well as the uncertain possibility of the present haplotype to produce major disease outbreaks in potato that may depend on many factors that should be further evaluated in future worksThis research was funded by Instituto Nacional de Investigacion y Tecnologia Agraria y Alimentaria (INIA), grant numbers AT2016-007 and RTA2014-00008-C04-03-E, co-financed by FEDER.Ruiz-Padilla, A.; Redondo, C.; Asensio, A.; Garita-Cambronero, J.; Martinez, C.; Perez-Padilla, V.; Marquinez, R.... (2020). Assessment of Multilocus Sequence Analysis (MLSA) for Identification of Candidatus Liberibacter Solanacearum from Different Host Plants in Spain. Microorganisms. 8(9):1-19. https://doi.org/10.3390/microorganisms8091446S11989Haapalainen, M. (2014). Biology and epidemics ofCandidatusLiberibacter species, psyllid-transmitted plant-pathogenic bacteria. Annals of Applied Biology, 165(2), 172-198. doi:10.1111/aab.12149Raddadi, N., Gonella, E., Camerota, C., Pizzinat, A., Tedeschi, R., Crotti, E., … Alma, A. (2010). ‘Candidatus Liberibacter europaeus’ sp. nov. that is associated with and transmitted by the psyllid Cacopsylla pyri apparently behaves as an endophyte rather than a pathogen. Environmental Microbiology, 13(2), 414-426. doi:10.1111/j.1462-2920.2010.02347.xWang, N., Pierson, E. A., Setubal, J. C., Xu, J., Levy, J. G., Zhang, Y., … Martins, J. (2017). The Candidatus Liberibacter–Host Interface: Insights into Pathogenesis Mechanisms and Disease Control. Annual Review of Phytopathology, 55(1), 451-482. doi:10.1146/annurev-phyto-080516-035513Morris, J., Shiller, J., Mann, R., Smith, G., Yen, A., & Rodoni, B. (2017). Novel ‘Candidatus Liberibacter’ species identified in the Australian eggplant psyllid, Acizzia solanicola. Microbial Biotechnology, 10(4), 833-844. doi:10.1111/1751-7915.12707Alfaro-Fernández, A., Hernández-Llopis, D., & Font, M. I. (2017). Haplotypes of ‘Candidatus Liberibacter solanacearum’ identified in Umbeliferous crops in Spain. European Journal of Plant Pathology, 149(1), 127-131. doi:10.1007/s10658-017-1172-2Haapalainen, M., Wang, J., Latvala, S., Lehtonen, M. T., Pirhonen, M., & Nissinen, A. I. (2018). Genetic Variation of ‘Candidatus Liberibacter solanacearum’ Haplotype C and Identification of a Novel Haplotype from Trioza urticae and Stinging Nettle. Phytopathology®, 108(8), 925-934. doi:10.1094/phyto-12-17-0410-rHaapalainen, M., Latvala, S., Wickström, A., Wang, J., Pirhonen, M., & Nissinen, A. I. (2019). A novel haplotype of ‘Candidatus Liberibacter solanacearum’ found in Apiaceae and Polygonaceae family plants. European Journal of Plant Pathology, 156(2), 413-423. doi:10.1007/s10658-019-01890-0Mauck, K. E., Sun, P., Meduri, V. R., & Hansen, A. K. (2019). New Ca. Liberibacter psyllaurous haplotype resurrected from a 49-year-old specimen of Solanum umbelliferum: a native host of the psyllid vector. Scientific Reports, 9(1). doi:10.1038/s41598-019-45975-6Teixeira, D. C., Eveillard, S., Sirand-Pugnet, P., Wulff, A., Saillard, C., Ayres, A. J., & Bove, J. M. (2008). The tufB-secE-nusG-rplKAJL-rpoB gene cluster of the liberibacters: sequence comparisons, phylogeny and speciation. INTERNATIONAL JOURNAL OF SYSTEMATIC AND EVOLUTIONARY MICROBIOLOGY, 58(6), 1414-1421. doi:10.1099/ijs.0.65641-0Glaeser, S. P., & Kämpfer, P. (2015). Multilocus sequence analysis (MLSA) in prokaryotic taxonomy. Systematic and Applied Microbiology, 38(4), 237-245. doi:10.1016/j.syapm.2015.03.007Gevers, D., Cohan, F. M., Lawrence, J. G., Spratt, B. G., Coenye, T., Feil, E. J., … Swings, J. (2005). Re-evaluating prokaryotic species. Nature Reviews Microbiology, 3(9), 733-739. doi:10.1038/nrmicro1236Swisher Grimm, K. D., & Garczynski, S. F. (2019). Identification of a New Haplotype of ‘CandidatusLiberibacter solanacearum’ inSolanum tuberosum. Plant Disease, 103(3), 468-474. doi:10.1094/pdis-06-18-0937-reLin, H., Lou, B., Glynn, J. M., Doddapaneni, H., Civerolo, E. L., Chen, C., … Vahling, C. M. (2011). The Complete Genome Sequence of ‘Candidatus Liberibacter solanacearum’, the Bacterium Associated with Potato Zebra Chip Disease. PLoS ONE, 6(4), e19135. doi:10.1371/journal.pone.0019135Thompson, S. M., Johnson, C. P., Lu, A. Y., Frampton, R. A., Sullivan, K. L., Fiers, M. W. E. J., … Smith, G. R. (2015). Genomes of ‘Candidatus Liberibacter solanacearum’ Haplotype A from New Zealand and the United States Suggest Significant Genome Plasticity in the Species. Phytopathology®, 105(7), 863-871. doi:10.1094/phyto-12-14-0363-fiLin, H., Pietersen, G., Han, C., Read, D. A., Lou, B., Gupta, G., & Civerolo, E. L. (2015). Complete Genome Sequence of « Candidatus Liberibacter africanus,» a Bacterium Associated with Citrus Huanglongbing. Genome Announcements, 3(4). doi:10.1128/genomea.00733-15Wulff, N. A., Zhang, S., Setubal, J. C., Almeida, N. F., Martins, E. C., Harakava, R., … Gabriel, D. W. (2014). The Complete Genome Sequence of ‘Candidatus Liberibacter americanus’, Associated with Citrus Huanglongbing. Molecular Plant-Microbe Interactions®, 27(2), 163-176. doi:10.1094/mpmi-09-13-0292-rDuan, Y., Zhou, L., Hall, D. G., Li, W., Doddapaneni, H., Lin, H., … Gottwald, T. (2009). Complete Genome Sequence of Citrus Huanglongbing Bacterium, ‘CandidatusLiberibacter asiaticus’ Obtained Through Metagenomics. Molecular Plant-Microbe Interactions®, 22(8), 1011-1020. doi:10.1094/mpmi-22-8-1011Katoh, H., Miyata, S., Inoue, H., & Iwanami, T. (2014). Unique Features of a Japanese ‘Candidatus Liberibacter asiaticus’ Strain Revealed by Whole Genome Sequencing. PLoS ONE, 9(9), e106109. doi:10.1371/journal.pone.0106109Leonard, M. T., Fagen, J. R., Davis-Richardson, A. G., Davis, M. J., & Triplett, E. W. (2012). Complete genome sequence of Liberibacter crescens BT-1. Standards in Genomic Sciences, 7(2), 271-283. doi:10.4056/sigs.3326772Teresani, G. R., Bertolini, E., Alfaro-Fernández, A., Martínez, C., Tanaka, F. A. O., Kitajima, E. W., … Font, M. I. (2014). Association of ‘Candidatus Liberibacter solanacearum’ with a Vegetative Disorder of Celery in Spain and Development of a Real-Time PCR Method for Its Detection. Phytopathology®, 104(8), 804-811. doi:10.1094/phyto-07-13-0182-rLi, W., Hartung, J. S., & Levy, L. (2006). Quantitative real-time PCR for detection and identification of Candidatus Liberibacter species associated with citrus huanglongbing. Journal of Microbiological Methods, 66(1), 104-115. doi:10.1016/j.mimet.2005.10.018Munyaneza, J. E., Sengoda, V. G., Crosslin, J. M., De la Rosa-Lozano, G., & Sanchez, A. (2009). First Report of ‘Candidatus Liberibacter psyllaurous’ in Potato Tubers with Zebra Chip Disease in Mexico. Plant Disease, 93(5), 552-552. doi:10.1094/pdis-93-5-0552aPhillips, J. L., & Gnanakaran, S. (2014). A data-driven approach to modeling the tripartite structure of multidrug resistance efflux pumps. Proteins: Structure, Function, and Bioinformatics, 83(1), 46-65. doi:10.1002/prot.24632Kumar, S., Stecher, G., Li, M., Knyaz, C., & Tamura, K. (2018). MEGA X: Molecular Evolutionary Genetics Analysis across Computing Platforms. Molecular Biology and Evolution, 35(6), 1547-1549. doi:10.1093/molbev/msy096Estimation of the number of nucleotide substitutions in the control region of mitochondrial DNA in humans and chimpanzees. (1993). Molecular Biology and Evolution. doi:10.1093/oxfordjournals.molbev.a040023Rozas, J., Ferrer-Mata, A., Sánchez-DelBarrio, J. C., Guirao-Rico, S., Librado, P., Ramos-Onsins, S. E., & Sánchez-Gracia, A. (2017). DnaSP 6: DNA Sequence Polymorphism Analysis of Large Data Sets. Molecular Biology and Evolution, 34(12), 3299-3302. doi:10.1093/molbev/msx248Liao, J., Wiedmann, M., & Kovac, J. (2017). Genetic Stability and Evolution of the sigB Allele, Used for Listeria Sensu Stricto Subtyping and Phylogenetic Inference. Applied and Environmental Microbiology, 83(12). doi:10.1128/aem.00306-17Tamura, K., Battistuzzi, F. U., Billing-Ross, P., Murillo, O., Filipski, A., & Kumar, S. (2012). Estimating divergence times in large molecular phylogenies. Proceedings of the National Academy of Sciences, 109(47), 19333-19338. doi:10.1073/pnas.1213199109Tamura, K., Tao, Q., & Kumar, S. (2018). Theoretical Foundation of the RelTime Method for Estimating Divergence Times from Variable Evolutionary Rates. Molecular Biology and Evolution, 35(7), 1770-1782. doi:10.1093/molbev/msy044López-Hermoso, C., de la Haba, R. R., Sánchez-Porro, C., Papke, R. T., & Ventosa, A. (2017). Assessment of MultiLocus Sequence Analysis As a Valuable Tool for the Classification of the Genus Salinivibrio. Frontiers in Microbiology, 8. doi:10.3389/fmicb.2017.01107Hajri, A., Loiseau, M., Cousseau-Suhard, P., Renaudin, I., & Gentit, P. (2017). Genetic Characterization of ‘Candidatus Liberibacter solanacearum’ Haplotypes Associated with Apiaceous Crops in France. Plant Disease, 101(8), 1383-1390. doi:10.1094/pdis-11-16-1686-reFang, Y., Wang, Y., Liu, Z., Dai, H., Cai, H., Li, Z., … Wang, D. (2019). Multilocus Sequence Analysis, a Rapid and Accurate Tool for Taxonomic Classification, Evolutionary Relationship Determination, and Population Biology Studies of the Genus Shewanella. Applied and Environmental Microbiology, 85(11). doi:10.1128/aem.03126-18Konstantinidis, K. T., Ramette, A., & Tiedje, J. M. (2006). Toward a More Robust Assessment of IntraspeciesDiversity, Using Fewer GeneticMarkers. Applied and Environmental Microbiology, 72(11), 7286-7293. doi:10.1128/aem.01398-06Ajene, I. J., Khamis, F., Ballo, S., Pietersen, G., van Asch, B., Seid, N., … Mohamed, S. (2020). Detection of Asian Citrus Psyllid (Hemiptera: Psyllidae) in Ethiopia: A New Haplotype and its Implication to the Proliferation of Huanglongbing. Journal of Economic Entomology, 113(4), 1640-1647. doi:10.1093/jee/toaa113Thapa, S. P., De Francesco, A., Trinh, J., Gurung, F. B., Pang, Z., Vidalakis, G., … Coaker, G. (2020). Genome‐wide analyses of Liberibacter species provides insights into evolution, phylogenetic relationships, and virulence factors. Molecular Plant Pathology, 21(5), 716-731. doi:10.1111/mpp.12925Antolinez, C. A., Fereres, A., & Moreno, A. (2017). Risk assessment of ‘Candidatus Liberibacter solanacearum’ transmission by the psyllids Bactericera trigonica and B. tremblayi from Apiaceae crops to potato. Scientific Reports, 7(1). doi:10.1038/srep45534Antolínez, Moreno, Ontiveros, Pla, Plaza, Sanjuan, … Fereres. (2019). Seasonal Abundance of Psyllid Species on Carrots and Potato Crops in Spain. Insects, 10(9), 287. doi:10.3390/insects10090287Wang, J., Haapalainen, M., Schott, T., Thompson, S. M., Smith, G. R., Nissinen, A. I., & Pirhonen, M. (2017). Genomic sequence of «Candidatus Liberibacter solanacearum» haplotype C and its comparison with haplotype A and B genomes. PLOS ONE, 12(2), e0171531. doi:10.1371/journal.pone.0171531Katsir, L., Zhepu, R., Santos Garcia, D., Piasezky, A., Jiang, J., Sela, N., … Bahar, O. (2018). Genome Analysis of Haplotype D of Candidatus Liberibacter Solanacearum. Frontiers in Microbiology, 9. doi:10.3389/fmicb.2018.02933Quintana-González de Chaves, M., Teresani, G. R., Hernández-Suárez, E., Bertolini, E., Moreno, A., Fereres, A., … Siverio, F. (2020). ‘Candidatus Liberibacter Solanacearum’ Is Unlikely to Be Transmitted Spontaneously from Infected Carrot Plants to Citrus Plants by Trioza Erytreae. Insects, 11(8), 514. doi:10.3390/insects1108051

Efficacy of Dapagliflozin According to Geographic Location of Patients With Heart Failure

Background: Because clinical characteristics and prognosis vary by geographic region in patients with heart failure (HF), the response to treatment may also vary. A previous report suggested that the efficacy of sodium-glucose cotransporter-2 inhibitor efficacy in heart failure with reduced ejection fraction (HFrEF) may be modified by region. Objectives: The goal of this study was to examine the efficacy and safety of dapagliflozin in patients with HF according to geographic region. Methods: We conducted a patient-level pooled analysis of the DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) and DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure) trials, which evaluated the effects of dapagliflozin in HFrEF and heart failure with mildly reduced ejection fraction (HFmrEF)/heart failure with preserved ejection fraction (HFpEF), respectively. The primary outcome was the composite of worsening HF or cardiovascular death. Results: Among 11,007 patients, 5,159 (46.9%) were enrolled in Europe, 1,528 (13.9%) in North America, 1,998 (18.2%) in South America, and 2,322 (21.1%) in Asia. The rate of the primary outcome (per 100 person-years) was higher in North America (13.9 [95% CI: 12.5-15.4]) than in other regions: Europe 10.8 (95% CI: 10.1-11.5), South America 10.0 (95% CI: 9.0-11.1), and Asia 10.5 (95% CI: 9.5-11.5). The benefit of dapagliflozin on the primary outcome was not modified by region: dapagliflozin vs placebo HR: Europe, 0.85 (95% CI: 0.75-0.96); North America, 0.75 (95% CI: 0.61-0.93); South America, 0.72 (95% CI: 0.58-0.89); and Asia, 0.74 (95% CI: 0.61-0.91) (P interaction = 0.40). This was the same when evaluated separately for HFrEF (P interaction = 0.39) and HFmrEF/HFpEF (P interaction = 0.84). Patients in North America discontinued randomized treatment more frequently than did those elsewhere (placebo discontinuation: 21.8% in North America vs 6.4% in South America), but discontinuation rates did not differ between placebo and dapagliflozin by region. Conclusions: The efficacy and safety of dapagliflozin were consistent across global regions despite geographic differences in patient characteristics, background treatment, and event rates.</p

Cardio-Renal-Metabolic Overlap, Outcomes, and Dapagliflozin in Heart Failure With Mildly Reduced or Preserved Ejection Fraction

Background: Cardio-renal-metabolic (CRM) conditions are individually common among patients with heart failure (HF), but the prevalence and influence of overlapping CRM conditions in this population have not been well-studied. Objectives: This study aims to evaluate the impact of overlapping CRM conditions on clinical outcomes and treatment effects of dapagliflozin in HF. Methods: In this post hoc analysis of DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure), we evaluated the prevalence of comorbid CRM conditions (atherosclerotic cardiovascular disease, chronic kidney disease, and type 2 diabetes), their impact on the primary outcome (cardiovascular death or worsening HF), and treatment effects of dapagliflozin by CRM status. Results: Among 6,263 participants, 1,952 (31%), 2,245 (36%), and 1,236 (20%) had 1, 2, and 3 additional CRM conditions, respectively. HF alone was uncommon (13%). Greater CRM multimorbidity was associated with older age, higher body mass index, longer-duration HF, worse health status, and lower left ventricular ejection fraction. Risk of the primary outcome increased with higher CRM overlap, with 3 CRM conditions independently associated with highest risk of primary events (adjusted HR: 2.16 [95% CI: 1.72-2.72]; P &lt; 0.001) compared with HF alone. Relative benefits of dapagliflozin on the primary outcome were consistent irrespective of the type of CRM overlap (Pinteraction = 0.773) and by the number of CRM conditions (Pinteraction = 0.734), with greatest absolute benefits among those with highest CRM multimorbidity. Estimated 2-year numbers needed to treat with dapagliflozin to prevent 1 primary event were approximately 52, 39, 33, and 24 for participants with 0, 1, 2, and 3 additional CRM conditions at baseline, respectively. Adverse events between treatment arms were similar across the CRM spectrum. Conclusions: CRM multimorbidity was common and associated with adverse outcomes among patients with HF and left ventricular ejection fraction &gt;40% in DELIVER. Dapagliflozin was safe and effective across the CRM spectrum, with greater absolute benefits among those with highest CRM overlap (Dapagliflozin Evaluation to Improve the LIVEs of Patients With Preserved Ejection Fraction Heart Failure [DELIVER]; NCT03619213).</p