Publications by authors named "M S Kelly"

4,995 Publications

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Developing a death literacy index.

Death Stud 2021 Jun 21:1-13. Epub 2021 Jun 21.

School of Social Sciences, Western Sydney University, Sydney, Australia.

Performing end-of-life care can be a catalyst for developing a capacity called death literacy. This study aimed to develop a comprehensive and useable measure of death literacy that has the potential to assess interventions with individuals, communities, and societies. Using a mixed methods approach, a Death Literacy Index was developed from personal narratives and input from practitioners and experts. Refined on a sample of 1330 Australians using exploratory and confirmatory factor analysis and structural equation modeling, a 29-item Death Literacy Index was found to be reliable and demonstrated construct validity. Further studies are needed to test predictive validity.
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http://dx.doi.org/10.1080/07481187.2021.1894268DOI Listing
June 2021

Effects of temperature on chaotropic anion-induced shape transitions of star molecular bottlebrushes with heterografted poly(ethylene oxide) and poly(,-dialkylaminoethyl methacrylate) side chains in acidic water.

Soft Matter 2021 Jun 21. Epub 2021 Jun 21.

Department of Chemistry, University of Tennessee, Knoxville, Tennessee 37996, USA.

This article reports a study of the effects of temperature on chaotropic anion (CA)-induced star-globule shape transitions in acidic water of three-arm star bottlebrushes composed of heterografted poly(ethylene oxide) (PEO) and either poly(2-(N,N-dimethylamino)ethyl methacrylate) (PDMAEMA) or poly(2-(N,N-diethylamino)ethyl methacrylate) (PDEAEMA) (the brushes denoted as SMB-11 and -22, respectively). The brush polymers were synthesized by grafting alkyne-end-functionalized PEO and PDMAEMA or PDEAEMA onto an azide-bearing three-arm star backbone polymer using the copper(i)-catalyzed alkyne-azide cycloaddition reaction. Six anions were studied for their effects on the conformations of SMB-11 and -22 in acidic water: super CAs [Fe(CN)6]3- and [Fe(CN)6]4-, moderate CAs PF6- and ClO4-, weak CA I-, and for comparison, kosmotropic anion SO42-. At 25 °C, the addition of super and moderate CAs induced shape transitions of SMB-11 and -22 in pH 4.50 water from a starlike to a collapsed globular state stabilized by PEO side chains, which was driven by the ion pairing of protonated tertiary amine groups with CAs and the chaotropic effect. The shape changes occurred at much lower salt concentrations for super CAs than moderate CAs. Upon heating from near room temperature to 70 °C, the super CA-collapsed brushes remained in the globular state, whereas the moderate CA-collapsed brushes underwent reversible globule-to-star shape transitions. The transition temperature increased with increasing salt concentration and was found to be higher for SMB-22 at the same salt concentration, presumably caused by the chaotropic effect. In contrast, I- and SO42- had small effects on the conformations of SMB-11 and -22 at 25 °C in the studied salt concentration range, and only small and gradual size variations were observed upon heating to 70 °C. The results reported here may have potential uses in the design of stimuli-responsive systems for substance encapsulation and release.
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http://dx.doi.org/10.1039/d1sm00728aDOI Listing
June 2021

Multiparametric Magnetic Resonance Imaging, Autoimmune Hepatitis, and Prediction of Disease Activity.

Hepatol Commun 2021 Jun 23;5(6):1009-1020. Epub 2021 Feb 23.

Centre for Liver and Gastrointestinal Research National Institute for Health Research (NIHR) Birmingham Liver Biomedical Research Centre Birmingham United Kingdom.

Noninvasive monitoring of disease activity in autoimmune hepatitis (AIH) has potential advantages for patients for whom liver biopsy is invasive and with risk. We sought to understand the association of multiparametric magnetic resonance imaging (mpMRI) with clinical course of patients with AIH. We prospectively recruited 62 patients (median age, 55 years; 82% women) with clinically confirmed AIH. At recruitment, patients underwent mpMRI with Liver alongside clinical investigations, which were repeated after 12-18 months. Associations between iron-corrected T1 (cT1) and other markers of disease were investigated at baseline and at follow-up. Discriminative performance of cT1, liver stiffness, and enhanced liver fibrosis (ELF) to identify those who failed to maintain remission over follow-up was investigated using the areas under the receiver operating characteristic curves (AUCs). Baseline cT1 correlated with alanine aminotransferase (Spearman's correlation coefficient [] = 0.28,  = 0.028), aspartate aminotransferase ( = 0.26,  = 0.038), international normalized ratio ( = 0.35  = 0.005), Model for End-Stage Liver Disease ( = 0.32,  = 0.020), ELF ( = 0.29,  = 0.022), and liver stiffness  = 0.51,  < 0.001). After excluding those not in remission at baseline (n = 12), 32% of the remainder failed to maintain remission during follow-up. Failure to maintain remission was associated with significant increases in cT1 over follow-up (AUC, 0.71; 95% confidence interval [CI], 0.52-0.90;  = 0.035) but not with changes in liver stiffness (AUC, 0.68; 95% CI, 0.49-0.87;  = 0.067) or ELF (AUC, 0.57; 95% CI, 0.37-0.78;  = 0.502). cT1 measured at baseline was a significant predictor of future loss of biochemical remission (AUC, 0.68; 95% CI, 0.53-0.83;  = 0.042); neither liver stiffness (AUC, 0.53; 95% CI, 0.34-0.71;  = 0.749) nor ELF (AUC, 0.52; 95% CI, 0.33-0.70;  = 0.843) were significant predictors of loss of biochemical remission. Noninvasive mpMRI has potential to contribute to risk stratification in patients with AIH.
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http://dx.doi.org/10.1002/hep4.1687DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8183180PMC
June 2021

Discovery of Arylsulfonamide Na1.7 Inhibitors: IVIVC, MPO Methods, and Optimization of Selectivity Profile.

ACS Med Chem Lett 2021 Jun 1;12(6):1038-1049. Epub 2021 Jun 1.

Discovery Chemistry, Merck & Co., Inc., West Point, Pennsylvania 19486, United States.

The voltage-gated sodium channel Na1.7 continues to be a high-profile target for the treatment of various pain afflictions due to its strong human genetic validation. While isoform selective molecules have been discovered and advanced into the clinic, to date, this target has yet to bear fruit in the form of marketed therapeutics for the treatment of pain. Lead optimization efforts over the past decade have focused on selectivity over Na1.5 due to its link to cardiac side effects as well as the translation of preclinical efficacy to man. Inhibition of Na1.6 was recently reported to yield potential respiratory side effects preclinically, and this finding necessitated a modified target selectivity profile. Herein, we report the continued optimization of a novel series of arylsulfonamide Na1.7 inhibitors to afford improved selectivity over Na1.6 while maintaining rodent oral bioavailability through the use of a novel multiparameter optimization (MPO) paradigm. We also report - correlations from Na1.7 electrophysiology protocols to preclinical models of efficacy to assist in projecting clinical doses. These efforts produced inhibitors such as compound with potency against Na1.7, selectivity over Na1.5 and Na1.6, and efficacy in behavioral models of pain in rodents as well as inhibition of rhesus olfactory response indicative of target modulation.
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http://dx.doi.org/10.1021/acsmedchemlett.1c00218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8201757PMC
June 2021

Discovery of Arylsulfonamide Na1.7 Inhibitors: IVIVC, MPO Methods, and Optimization of Selectivity Profile.

ACS Med Chem Lett 2021 Jun 1;12(6):1038-1049. Epub 2021 Jun 1.

Discovery Chemistry, Merck & Co., Inc., West Point, Pennsylvania 19486, United States.

The voltage-gated sodium channel Na1.7 continues to be a high-profile target for the treatment of various pain afflictions due to its strong human genetic validation. While isoform selective molecules have been discovered and advanced into the clinic, to date, this target has yet to bear fruit in the form of marketed therapeutics for the treatment of pain. Lead optimization efforts over the past decade have focused on selectivity over Na1.5 due to its link to cardiac side effects as well as the translation of preclinical efficacy to man. Inhibition of Na1.6 was recently reported to yield potential respiratory side effects preclinically, and this finding necessitated a modified target selectivity profile. Herein, we report the continued optimization of a novel series of arylsulfonamide Na1.7 inhibitors to afford improved selectivity over Na1.6 while maintaining rodent oral bioavailability through the use of a novel multiparameter optimization (MPO) paradigm. We also report - correlations from Na1.7 electrophysiology protocols to preclinical models of efficacy to assist in projecting clinical doses. These efforts produced inhibitors such as compound with potency against Na1.7, selectivity over Na1.5 and Na1.6, and efficacy in behavioral models of pain in rodents as well as inhibition of rhesus olfactory response indicative of target modulation.
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http://dx.doi.org/10.1021/acsmedchemlett.1c00218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8201757PMC
June 2021