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| 4. |
- Bryant, J. M., et al.
(författare)
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Emergence and spread of a human-transmissible multidrug-resistant nontuberculous mycobacterium
- 2016
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 354:6313, s. 751-757
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Tidskriftsartikel (refereegranskat)abstract
- Lung infections with Mycobacterium abscessus, a species of multidrug-resistant nontuberculous mycobacteria, are emerging as an important global threat to individuals with cystic fibrosis (CF), in whom M. abscessus accelerates inflammatory lung damage, leading to increased morbidity and mortality. Previously, M. abscessus was thought to be independently acquired by susceptible individuals from the environment. However, using whole-genome analysis of a global collection of clinical isolates, we show that the majority of M. abscessus infections are acquired through transmission, potentially via fomites and aerosols, of recently emerged dominant circulating clones that have spread globally. We demonstrate that these clones are associated with worse clinical outcomes, show increased virulence in cell-based and mouse infection models, and thus represent an urgent international infection challenge.
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| 5. |
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| 6. |
- Tartaglia, L., et al.
(författare)
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The Early Detection and Follow-up of the Highly Obscured Type II Supernova 2016ija/DLT16am
- 2018
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Ingår i: Astrophysical Journal. - : American Astronomical Society. - 0004-637X .- 1538-4357. ; 853:1
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Tidskriftsartikel (refereegranskat)abstract
- We present our analysis of the Type II supernova DLT16am (SN 2016ija). The object was discovered during the ongoing D < 40 Mpc (DLT40) one-day cadence supernova search at r similar to 20.1 mag in the edge-on nearby (D = 20.0 +/- 4.0 Mpc) galaxy NGC 1532. The subsequent prompt and high-cadenced spectroscopic and photometric follow-up revealed a highly extinguished transient, with E(B - V) = 1.95 +/- 0.15 mag, consistent with a standard extinction law with R-V = 3.1 and a bright (M-V = -18.48 +/- 0.77 mag) absolute peak magnitude. A comparison of the photometric features with those of large samples of SNe II reveals a fast rise for the derived luminosity and a relatively short plateau phase, with a slope of S-50V = 0.84 +/- 0.04 mag/50 days, consistent with the photometric properties typical of those of fast-declining SNe II. Despite the large uncertainties on the distance and the extinction in the direction of DLT16am, the measured photospheric expansion velocity and the derived absolute V-band magnitude at similar to 50 days after the explosion match the existing luminosity-velocity relation for SNe II.
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| 7. |
- Tinyanont, S., et al.
(författare)
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Keck Infrared Transient Survey. I. Survey Description and Data Release 1
- 2024
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Ingår i: Publications of the Astronomical Society of the Pacific. - 0004-6280 .- 1538-3873. ; 136:1
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Tidskriftsartikel (refereegranskat)abstract
- We present the Keck Infrared Transient Survey, a NASA Key Strategic Mission Support program to obtain near-infrared (NIR) spectra of astrophysical transients of all types, and its first data release, consisting of 105 NIR spectra of 50 transients. Such a data set is essential as we enter a new era of IR astronomy with the James Webb Space Telescope (JWST) and the upcoming Nancy Grace Roman Space Telescope (Roman). NIR spectral templates will be essential to search JWST images for stellar explosions of the first stars and to plan an effective Roman SN Ia cosmology survey, both key science objectives for mission success. Between 2022 February and 2023 July, we systematically obtained 274 NIR spectra of 146 astronomical transients, representing a significant increase in the number of available NIR spectra in the literature. Here, we describe the first release of data from the 2022A semester. We systematically observed three samples: a flux-limited sample that includes all transients <17 mag in a red optical band (usually ZTF r or ATLAS o bands); a volume-limited sample including all transients within redshift z < 0.01 (D ≈ 50 Mpc); and an SN Ia sample targeting objects at phases and light-curve parameters that had scant existing NIR data in the literature. The flux-limited sample is 39% complete (60% excluding SNe Ia), while the volume-limited sample is 54% complete and is 79% complete to z = 0.005. Transient classes observed include common Type Ia and core-collapse supernovae, tidal disruption events, luminous red novae, and the newly categorized hydrogen-free/helium-poor interacting Type Icn supernovae. We describe our observing procedures and data reduction using PypeIt, which requires minimal human interaction to ensure reproducibility.
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| 8. |
- Edlmann, E, et al.
(författare)
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Dex-CSDH randomised, placebo-controlled trial of dexamethasone for chronic subdural haematoma: report of the internal pilot phase
- 2019
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 9:1, s. 5885-
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Tidskriftsartikel (refereegranskat)abstract
- The Dex-CSDH trial is a randomised, double-blind, placebo-controlled trial of dexamethasone for patients with a symptomatic chronic subdural haematoma. The trial commenced with an internal pilot, whose primary objective was to assess the feasibility of multi-centre recruitment. Primary outcome data collection and safety were also assessed, whilst maintaining blinding. We aimed to recruit 100 patients from United Kingdom Neurosurgical Units within 12 months. Trial participants were randomised to a 2-week course of dexamethasone or placebo in addition to receiving standard care (which could include surgery). The primary outcome measure of the trial is the modified Rankin Scale at 6 months. This pilot recruited ahead of target; 100 patients were recruited within nine months of commencement. 47% of screened patients consented to recruitment. The primary outcome measure was collected in 98% of patients. No safety concerns were raised by the independent data monitoring and ethics committee and only five patients were withdrawn from drug treatment. Pilot trial data can inform on the design and resource provision for substantive trials. This internal pilot was successful in determining recruitment feasibility. Excellent follow-up rates were achieved and exploratory outcome measures were added to increase the scientific value of the trial.
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| 10. |
- Davitt, C. J. H., et al.
(författare)
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A novel adjuvanted capsule based strategy for oral vaccination against infectious diarrhoeal pathogens
- 2016
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Ingår i: Journal of Controlled Release. - : Elsevier BV. - 0168-3659. ; 233, s. 162-173
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Tidskriftsartikel (refereegranskat)abstract
- Diarrhoeal infections are a major cause of morbidity and mortality with enterotoxigenic Escherichia coli (ETEC) and cholera imposing a significant global burden. There is currently no licensed vaccine for ETEC. Development of new nonliving oral vaccines has proven difficult due to the physicochemical and immunological challenges associated with the oral route. This demands innovative delivery solutions to protect antigens, control their release and build in immune-stimulatory activity. We describe the Single Multiple Pill (R) (SmPill (R)) vaccine formulation which combines the benefits of enteric polymer coating to protect against low gastric pH, a dispersed phase to control release and aid the solubility of non-polar components and an optimized combination of adjuvant and antigen to promote mucosal immunity. We demonstrate the effectiveness of this system with whole cell killed E. coli overexpressing colonization factor antigen I (CFA/I), JT-49. Alpha-galactosylceramide was identified as a potent adjuvant within SmPill (R) that enhanced the immunogenicity of JT-49. The bacteria associated with the dispersed phase were retained within the capsules at gastric pH but released at intestinal pH. Vaccination with an optimized SmPill (R) formulation promoted CFA/I-specific immunoglobulin A (IgA) responses in the intestinal mucosa in addition to serum IgG and a solubilized adjuvant was indispensable for efficacy.
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| 11. |
- Davitt, C. J. H., et al.
(författare)
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Alpha-galactosylceramide enhances mucosal immunity to oral whole-cell cholera vaccines
- 2019
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Ingår i: Mucosal Immunology. - : Elsevier BV. - 1933-0219. ; 12, s. 1055-1064
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Tidskriftsartikel (refereegranskat)abstract
- Cholera is a severe diarrheal disease caused by the bacterium Vibrio cholerae (V. cholerae) that results in 3–4 million cases globally with 100,000–150,000 deaths reported annually. Mostly confined to developing nations, current strategies to control the spread of cholera include the provision of safe drinking water and improved sanitation and hygiene, ideally in conjunction with oral vaccination. However, difficulties associated with the costs and logistics of these strategies have hampered their widespread implementation. Specific challenges pertaining to oral cholera vaccines (OCVs) include a lack of safe and effective adjuvants to further enhance gut immune responses, the complex and costly multicomponent vaccine manufacturing, limitations of conventional liquid formulation and the lack of an integrated delivery platform. Herein we describe the use of the orally active adjuvant α-Galactosylceramide (α-GalCer) to strongly enhance intestinal bacterium- and toxin-specific IgA responses to the OCV, Dukoral ® in C57BL/6 and BALB/c mice. We further demonstrate the mucosal immunogenicity of a novel multi-antigen, single-component whole-cell killed V. cholerae strain and the enhancement of its immunogenicity by adding α-GalCer. Finally, we report that combining these components and recombinant cholera toxin B subunit in the SmPill ® minisphere delivery system induced strong intestinal and systemic antigen-specific antibody responses. © 2019, The Author(s).
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| 12. |
- Longet, S., et al.
(författare)
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An oral alpha-galactosylceramide adjuvanted Helicobacter pylori vaccine induces protective IL-1R-and IL-17R-dependent Th1 responses
- 2019
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Ingår i: Npj Vaccines. - : Springer Science and Business Media LLC. - 2059-0105. ; 4
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Tidskriftsartikel (refereegranskat)abstract
- Helicobacter pylori causes chronic gastric infection that can lead to peptic ulcers and is an identified risk factor for gastric cancer development. Although much effort has been put into the development of a Helicobacter pylori vaccine over the last three decades, none has yet reached clinical application. Specific challenges pertaining to effective H. pylori vaccine development include the lack of proven vaccine-effective antigens and safe mucosal adjuvants to enhance local immune responses as well as the lack of accepted correlates of protection. Herein, we demonstrate that prophylactic intragastric immunisation with a whole-cell killed H. pylori antigen administered together with the non-toxic oral adjuvant alpha-galactosylceramide (alpha-GalCer) induced effective immune protection against H. pylori infection in mice, which was of similar magnitude as when using the "gold standard" cholera toxin as adjuvant. We further describe that this alpha-GalCer-adjuvanted vaccine formulation elicited strong intestinal and systemic Th1 responses as well as significant antigen-specific mucosal and systemic antibody responses. Finally, we report that the protective intestinal Th1 responses induced by alpha-GalCer are dependent on CD1d, IL-1R as well as IL-17R signalling. In summary, our results show that alpha-GalCer is a promising adjuvant for inclusion in an oral vaccine against H. pylori infection.
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| 13. |
- Longet, S., et al.
(författare)
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Thermostability of the coating, antigen and immunostimulator in an adjuvanted oral capsule vaccine formulation
- 2017
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Ingår i: International Journal of Pharmaceutics. - : Elsevier BV. - 0378-5173. ; 534:1-2, s. 60-70
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Tidskriftsartikel (refereegranskat)abstract
- Oral vaccines present an attractive alternative to injectable vaccines for enteric diseases due to ease of delivery and the induction of intestinal immunity at the site of infection. However, susceptibility to gastrointestinal proteolysis, limited transepithelial uptake and a lack of clinically acceptable adjuvants present significant challenges. A further challenge to mass vaccination in developing countries is the very expensive requirement to maintain the cold chain. We recently described the effectiveness of a Single Multiple Pill® (SmPill®) adjuvanted capsule approach to enhance the effectiveness of a candidate enterotoxigenic Escherichia coli (ETEC) oral vaccine. Here it was demonstrated that this delivery system maintains the antigenicity of ETEC colonisation factor antigen I (CFA/I) and the immunostimulatory activity of the orally active α-Galactosylceramide (α-GalCer) adjuvant after storage of SmPill® minispheres under room temperature and extreme storage conditions for several months. In addition, the internal structure of the cores of SmPill® minispheres and antigen release features at intestinal pH were found to be preserved under all these conditions. However, changes in the surface morphology of SmPill® minispheres leading to the antigen release at gastric pH were observed after a few weeks of storage under extreme conditions. Those modifications were prevented by the introduction of an Opadry® White film coating layer between the core of SmPill® minispheres and the enteric coating. Under these conditions, protection against antigen release at gastric pH was maintained even under high temperature and humidity conditions. These results support the potential of the SmPill® minisphere approach to maintain the stability of an adjuvanted whole cell killed oral vaccine formulation. © 2017 Elsevier B.V.
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| 15. |
- Coughlin, M. W., et al.
(författare)
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Standardizing kilonovae and their use as standard candles to measure the Hubble constant
- 2020
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Ingår i: Physical Review Research. - : American Physical Society (APS). - 2643-1564. ; 2:2
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Tidskriftsartikel (refereegranskat)abstract
- The detection of GW170817 is revolutionizing many areas of astrophysics with the joint observation of gravitational waves and electromagnetic emissions. These multimessenger events provide a new approach to determine the Hubble constant, thus, they are a promising candidate for mitigating the tension between measurements of type-Ia supernovae via the local distance ladder and the cosmic microwave background. In addition to the "standard siren"provided by the gravitational-wave measurement, the kilonova itself has characteristics that allow one to improve existing measurements or to perform yet another, independent measurement of the Hubble constant without gravitational-wave information. Here, we employ standardization techniques borrowed from the type-Ia community and apply them to kilonovae, not using any information from the gravitational-wave signal. We use two versions of this technique, one derived from direct observables measured from the light curve, and the other based on inferred ejecta parameters, e.g., mass, velocity, and composition, for two different models. These lead to Hubble constant measurements of H0=109-35+49 km s-1 Mpc-1 for the measured analysis, and H0=85-17+22 km s-1 Mpc-1 and H0=79-15+23 km s-1 Mpc-1 for the inferred analyses. This measurement has error bars within ∼2 to the gravitational-wave measurements (H0=74-8+16 km s-1 Mpc-1), showing its promise as an independent constraint on H0.
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| 16. |
- Heinzel, J., et al.
(författare)
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Comparing inclination-dependent analyses of kilonova transients
- 2021
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Ingår i: Monthly notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 502:2, s. 3057-3065
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Tidskriftsartikel (refereegranskat)abstract
- The detection of the optical transient AT2017gfo proved that binary neutron star mergers are progenitors of kilonovae (KNe). Using a combination of numerical-relativity and radiative-transfer simulations, the community has developed sophisticated models for these transients for a wide portion of the expected parameter space. Using these simulations and surrogate models made from them, it has been possible to perform Bayesian inference of the observed signals to infer properties of the ejected matter. It has been pointed out that combining inclination constraints derived from the KN with gravitational-wave measurements increases the accuracy with which binary parameters can be estimated, in particular breaking the distance-inclination degeneracy from gravitational wave inference. To avoid bias from the unknown ejecta geometry, constraints on the inclination angle for AT2017gfo should be insensitive to the employed models. In this work, we compare different assumptions about the ejecta and radiative reprocesses used by the community and we investigate their impact on the parameter inference. While most inferred parameters agree, we find disagreement between posteriors for the inclination angle for different geometries that have been used in the current literature. According to our study, the inclusion of reprocessing of the photons between different ejecta types improves the modeling fits to AT2017gfo and, in some cases, affects the inferred constraints. Our study motivates the inclusion of large similar to 1-mag uncertainties in the KN models employed for Bayesian analysis to capture yet unknown systematics, especially when inferring inclination angles, although smaller uncertainties seem appropriate to capture model systematics for other intrinsic parameters. We can use this method to impose soft constraints on the ejecta geometry of the KN AT2017gfo.
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| 19. |
- Maccari, Maria Elena, et al.
(författare)
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Activated phosphoinositide 3-kinase δ syndrome: Update from the ESID Registry and comparison with other autoimmune-lymphoproliferative inborn errors of immunity.
- 2023
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Ingår i: The Journal of allergy and clinical immunology. - 1097-6825. ; 152:4
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Tidskriftsartikel (refereegranskat)abstract
- Activated phosphoinositide-3-kinase δ syndrome (APDS) is an inborn error of immunity (IEI) with infection susceptibility and immune dysregulation, clinically overlapping with other conditions. Management depends on disease evolution, but predictors of severe disease are lacking.This study sought to report the extended spectrum of disease manifestations in APDS1 versus APDS2; compare these to CTLA4 deficiency, NFKB1 deficiency, and STAT3 gain-of-function (GOF) disease; and identify predictors of severity in APDS.Data was collected from the ESID (European Society for Immunodeficiencies)-APDS registry and was compared with published cohorts of the other IEIs.The analysis of 170 patients with APDS outlines high penetrance and early onset of APDS compared to the other IEIs. The large clinical heterogeneity even in individuals with the same PIK3CD variant E1021K illustrates how poorly the genotype predicts the disease phenotype and course. The high clinical overlap between APDS and the other investigated IEIs suggests relevant pathophysiological convergence of the affected pathways. Preferentially affected organ systems indicate specific pathophysiology: bronchiectasis is typical of APDS1; interstitial lung disease and enteropathy are more common in STAT3 GOF and CTLA4 deficiency. Endocrinopathies are most frequent in STAT3 GOF, but growth impairment is also common, particularly in APDS2. Early clinical presentation is a risk factor for severe disease in APDS.APDS illustrates how a single genetic variant can result in a diverse autoimmune-lymphoproliferative phenotype. Overlap with other IEIs is substantial. Some specific features distinguish APDS1 from APDS2. Early onset is a risk factor for severe disease course calling for specific treatment studies in younger patients.
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| 20. |
- van Zuydam, Natalie R., et al.
(författare)
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Genetic Predisposition to Coronary Artery Disease in Type 2 Diabetes Mellitus
- 2020
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Ingår i: Circulation. - : Lippincott Williams & Wilkins. - 2574-8300. ; 13:6, s. 640-648
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Coronary artery disease (CAD) is accelerated in subjects with type 2 diabetes mellitus (T2D).METHODS: To test whether this reflects differential genetic influences on CAD risk in subjects with T2D, we performed a systematic assessment of genetic overlap between CAD and T2D in 66 643 subjects (27 708 with CAD and 24 259 with T2D). Variants showing apparent association with CAD in stratified analyses or evidence of interaction were evaluated in a further 117 787 subjects (16 694 with CAD and 11 537 with T2D).RESULTS: None of the previously characterized CAD loci was found to have specific effects on CAD in T2D individuals, and a genome-wide interaction analysis found no new variants for CAD that could be considered T2D specific. When we considered the overall genetic correlations between CAD and its risk factors, we found no substantial differences in these relationships by T2D background.CONCLUSIONS: This study found no evidence that the genetic architecture of CAD differs in those with T2D compared with those without T2D.
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| 21. |
- Ward, Sam M., et al.
(författare)
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Relative Intrinsic Scatter in Hierarchical Type Ia Supernova Sibling Analyses : Application to SNe 2021hpr, 1997bq, and 2008fv in NGC 3147
- 2023
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Ingår i: Astrophysical Journal. - 0004-637X .- 1538-4357. ; 956:2
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Tidskriftsartikel (refereegranskat)abstract
- We present Young Supernova Experiment grizy photometry of SN 2021hpr, the third Type Ia supernova sibling to explode in the Cepheid calibrator galaxy, NGC 3147. Siblings are useful for improving SN-host distance estimates and investigating their contributions toward the SN Ia intrinsic scatter (post-standardization residual scatter in distance estimates). We thus develop a principled Bayesian framework for analyzing SN Ia siblings. At its core is the cosmology-independent relative intrinsic scatter parameter, σRel: the dispersion of siblings distance estimates relative to one another within a galaxy. It quantifies the contribution toward the total intrinsic scatter, σ0, from within-galaxy variations about the siblings' common properties. It also affects the combined distance uncertainty. We present analytic formulae for computing a σRel posterior from individual siblings distances (estimated using any SN model). Applying a newly trained BAYESN model, we fit the light curves of each sibling in NGC 3147 individually, to yield consistent distance estimates. However, the wide σRel posterior means σRel ≈ σ0 is not ruled out. We thus combine the distances by marginalizing over σRel with an informative prior: σRel ∼ U(0, σ0). Simultaneously fitting the trio's light curves improves constraints on distance and each sibling's individual dust parameters, compared to individual fits. Higher correlation also tightens dust parameter constraints. Therefore, σRel marginalization yields robust estimates of siblings distances for cosmology, as well as dust parameters for sibling–host correlation studies. Incorporating NGC 3147's Cepheid distance yields H0 = 78.4 ± 6.5 km s−1 Mpc−1. Our work motivates analyses of homogeneous siblings samples, to constrain σRel and its SN-model dependence.
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