Multi-year population-based analysis of Asian patients with acute decompensated heart failure and advanced chronic kidney disease.

BACKGROUND: Data on disparities in outcomes and risk factors in Asian patients with advanced chronic kidney disease admitted for heart failure are scare. METHODS: This was a retrospective cohort study that utilized data from the National Inpatient Sample between January 2016 and December 2019. Patients who had a primary diagnosis of acute decompensated heart failure and a concomitant diagnosis of advanced CKD were included. The primary outcome of interest was in-hospital mortality. Secondary outcomes include hospital cost, length of stay, and other clinical outcomes. Weighted multivariable logistic regression was used to adjust for comorbidities. RESULTS: There were 251,578 cases of ADHF with advanced CKD, out of which 2.6 % were from individuals of Asian ethnicity. Asian patients exhibited a higher burden of comorbidities in comparison to other UREM patients, but a lower burden than White patients. Regardless of differences in comorbidity burden, Asian patients exhibited a higher likelihood of experiencing severe consequences. After adjusting for comorbidies, White (OR:1.11; 95 % CI 1.03-1.20;0.009) patients had higher odds of mortality than Asian patients. However, Blacks (OR: 0.58; 95 % CI 0.53 to 0.63; p < 0.001) and Hispanics (OR: 0.69; 95 % CI 0.62 to 0.78; p < 0.001) had lower odds of mortality. CONCLUSION: This first population-based studies shows that Asian patients with advanced CKD admitted for ADHF have greater comorbidity burden and poorer outcomes Black and Hispanic patients. This data underscores the importance of comprehensive approaches in phenotyping, and ethnic specific interventions.

Large-scale detection of metals with a small set of fluorescent DNA-like chemosensors.

An important advantage of pattern-based chemosensor sets is their potential to detect and differentiate a large number of analytes with only few sensors. Here we test this principle at a conceptual limit by analyzing a large set of metal ion analytes covering essentially the entire periodic table, employing fluorescent DNA-like chemosensors on solid support. A tetrameric "oligodeoxyfluoroside" (ODF) library of 6561 members containing metal-binding monomers was screened for strong responders to 57 metal ions in solution. Our results show that a set of 9 chemosensors could successfully discriminate the 57 species, including alkali, alkaline earth, post-transition, transition, and lanthanide metals. As few as 6 ODF chemosensors could detect and differentiate 50 metals at 100 µM; sensitivity for some metals was achieved at midnanomolar ranges. A blind test with 50 metals further confirmed the discriminating power of the ODFs.

Differentiating between fluorescence-quenching metal ions with polyfluorophore sensors built on a DNA backbone.

A common problem in detecting metal ions with fluorescentchemosensors is the emission-suppressing effects of fluorescence-quenching metal ions. This quenching tendency makes it difficult to design sensors with turn-on signal, and differentiate between several metal ions that may yield a strong quenching response. To address these challenges, we investigate a new sensor design strategy, incorporating fluorophores and metal ligands as DNA base replacements in DNA-like oligomers, for generating a broader range of responses for quenching metal ions. The modular molecular design enabled rapid synthesis and discovery of sensors from libraries on PEG-polystyrene beads. Using this approach, water-soluble sensors 1-5 were identified as strong responders to a set of eight typically quenching metal ions (Co(2+), Ni(2+), Cu(2+), Hg(2+), Pb(2+), Ag(+), Cr(3+), and Fe(3+)). They were synthesized and characterized for sensing responses in solution. Cross-screening with the full set of metal ions showed that they have a wide variety of responses, including emission enhancements and red- and blue-shifts. The diversity of sensor responses allows as few as two sensors (1 and 2) to be used together to successfully differentiate these eight metals. As a test, a set of unknown metal ion solutions in blind studies were also successfully identified based on the response pattern of the sensors. The modular nature of the sensor design strategy suggests a broadly applicable approach to finding sensors for differentiating many different cations by pattern-based recognition, simply by varying the sequence and composition of ligands and fluorophores on a DNA synthesizer.

Selective sensor for silver ions built from polyfluorophores on a DNA backbone.

To explore a new modular metal ion sensor design strategy, fluorophores and ligands were incorporated into short DNA-like oligomers. Compound 1 was found to function as a selective sensor for Ag(+) in aqueous buffer, where low micromolar concentrations of Ag(+) induce a red-shifted, turn-on fluorescence signal. Experiments with HeLa cells show that 1 can penetrate cells and yield a signal for intracellular Ag(+). This suggests a broadly applicable approach to developing sensors for a wide variety of cations.

Probing the interaction of archaeal DNA polymerases with deaminated bases using X-ray crystallography and non-hydrogen bonding isosteric base analogues.

Archaeal family-B DNA polymerases stall replication on encountering the pro-mutagenic bases uracil and hypoxanthine. This publication describes an X-ray crystal structure of Thermococcus gorgonarius polymerase in complex with a DNA containing hypoxanthine in the single-stranded region of the template, two bases ahead of the primer-template junction. Full details of the specific recognition of hypoxanthine are revealed, allowing a comparison with published data that describe uracil binding. The two bases are recognized by the same pocket, in the N-terminal domain, and make very similar protein-DNA interactions. Specificity for hypoxanthine (and uracil) arises from a combination of polymerase-base hydrogen bonds and shape fit between the deaminated bases and the pocket. The structure with hypoxanthine at position 2 explains the stimulation of the polymerase 3'-5' proofreading exonuclease, observed with deaminated bases at this location. A beta-hairpin element, involved in partitioning the primer strand between the polymerase and exonuclease active sites, inserts between the two template bases at the extreme end of the double-stranded DNA. This denatures the two complementary primer bases and directs the resulting 3' single-stranded extension toward the exonuclease active site. Finally, the relative importance of hydrogen bonding and shape fit in determining selectivity for deaminated bases has been examined using nonpolar isosteres. Affinity for both 2,4-difluorobenzene and fluorobenzimidazole, non-hydrogen bonding shape mimics of uracil and hypoxanthine, respectively, is strongly diminished, suggesting polar protein-base contacts are important. However, residual interaction with 2,4-difluorobenzene is seen, confirming a role for shape recognition.