Using Esterase Selectivity to Determine the in Vivo Duration of Systemic Availability and Abolish Systemic Side Effects of Topical β-Blockers

© 2020 American Chemical Society. For disorders of the skin, eyes, ears, and respiratory tract, topical drugs, delivered directly to the target organ, are a therapeutic option. Compared with systemic oral therapy, the benefits of topical treatments include a faster onset of action, circumventing the liver first pass drug metabolism, and reducing systemic side effects. Nevertheless, some systemic absorption still occurs for many topical agents resulting in systemic side effects. One way to prevent these would be to develop drugs that are instantly degraded upon entry into the bloodstream by serum esterases. Because topical β-blockers are used in glaucoma and infantile hemeangioma and cause systemic side effects, the β-adrenoceptor system was used to test this hypothesis. Purified liver esterase reduced the apparent affinity of esmolol, an ester-containing β-blocker used in clinical emergencies, for the human β-adrenoceptors in a concentration and time-dependent manner. However, purified serum esterase had no effect on esmolol. Novel ester-containing β-blockers were synthesized and several were sensitive to both liver and serum esterases. Despite good in vitro affinity, one such compound, methyl 2-(3-chloro-4-(3-((2-(3-(3-chlorophenyl)ureido)ethyl)amino)-2-hydroxypropoxy)phenyl)acetate, had no effect on heart rate when injected intravenously into rats, even at 10 times the equipotent dose of esmolol and betaxolol that caused short and sustained reductions in heart rate, respectively. Thus, ester-based drugs, sensitive to serum esterases, offer a mechanism for developing topical agents that are truly devoid of systemic side effects. Furthermore, differential susceptibility to liver and serum esterases degradation may also allow the duration of systemic availability for other drugs to be fine-tuned

Profiling of molecular interactions in real time using acoustic detection

Acoustic sensors that exploit resonating quartz crystals to directly detect the binding of an analyte to a receptor are finding increasing utility in the quantification of clinically-relevant analytes. We have developed a novel acoustic detection technology, which we term Resonant Acoustic Profiling (RAP™). This technology builds on the fundamental basics of the “quartz crystal microbalance” or “QCM” with several key additional features including two- or four-channel automated sample delivery, in-line referencing and microfluidic sensor ‘cassettes’ that are pre-coated with easy-to-use surface chemistries. Example applications are described for the quantification of myoglobin concentration and its interaction kinetics, and for the ranking of enzyme-cofactor specificities. © 2006 Elsevier B.V. All rights reserved

Immunocompromised patients with acute respiratory distress syndrome : Secondary analysis of the LUNG SAFE database

The aim of this study was to describe data on epidemiology, ventilatory management, and outcome of acute respiratory distress syndrome (ARDS) in immunocompromised patients. Methods: We performed a post hoc analysis on the cohort of immunocompromised patients enrolled in the Large Observational Study to Understand the Global Impact of Severe Acute Respiratory Failure (LUNG SAFE) study. The LUNG SAFE study was an international, prospective study including hypoxemic patients in 459 ICUs from 50 countries across 5 continents. Results: Of 2813 patients with ARDS, 584 (20.8%) were immunocompromised, 38.9% of whom had an unspecified cause. Pneumonia, nonpulmonary sepsis, and noncardiogenic shock were their most common risk factors for ARDS. Hospital mortality was higher in immunocompromised than in immunocompetent patients (52.4% vs 36.2%; p < 0.0001), despite similar severity of ARDS. Decisions regarding limiting life-sustaining measures were significantly more frequent in immunocompromised patients (27.1% vs 18.6%; p < 0.0001). Use of noninvasive ventilation (NIV) as first-line treatment was higher in immunocompromised patients (20.9% vs 15.9%; p = 0.0048), and immunodeficiency remained independently associated with the use of NIV after adjustment for confounders. Forty-eight percent of the patients treated with NIV were intubated, and their mortality was not different from that of the patients invasively ventilated ab initio. Conclusions: Immunosuppression is frequent in patients with ARDS, and infections are the main risk factors for ARDS in these immunocompromised patients. Their management differs from that of immunocompetent patients, particularly the greater use of NIV as first-line ventilation strategy. Compared with immunocompetent subjects, they have higher mortality regardless of ARDS severity as well as a higher frequency of limitation of life-sustaining measures. Nonetheless, nearly half of these patients survive to hospital discharge. Trial registration: ClinicalTrials.gov, NCT02010073. Registered on 12 December 2013

Search for solar bosonic dark matter annual modulation with COSINE-100

We present results from a search for solar bosonic dark matter using the annual modulation method with the COSINE-100 experiment. The results were interpreted considering three dark sector bosons models: solar dark photons, Dine-Fischler-Srednicki-Zhitnisky (DFSZ) and Kim-Shifman-Vainshtein-Zakharov (KSVZ) solar axions, and Kaluza-Klein solar axions. No modulation signal compatible with the expected from the models was found from a dataset of 2.82 yr, using 61.3 kg of NaI(Tl) crystals. Therefore, we set a 90% confidence level upper limits for each of the three models studied. For the solar dark photon model, the most stringent mixing parameter upper limit is 1.61×10-14 for dark photons with a mass of 215 eV. For the DFSZ and KSVZ solar axion, and the Kaluza-Klein axion models, the upper limits exclude axion-electron couplings, gae, above 1.61×10-11 for axion mass below 0.2 keV; and axion-photon couplings, gaγγ, above 1.83×10-11 GeV-1 for an axion number density of 4.07×1013 cm-3. This is the first experimental search for solar dark photons and DFSZ and KSVZ solar axions using the annual modulation method. The lower background, higher light yield and reduced threshold of NaI(Tl) crystals of the future COSINE-200 experiment are expected to enhance the sensitivity of the analysis shown in this paper. We show the sensitivities for the three models studied, considering the same search method with COSINE-200. © 2023 authors. Published by the American Physical Society. Published by the American Physical Society under the terms of the https://creativecommons.org/licenses/by/4.0/Creative Commons Attribution 4.0 International license. Further distribution of this work must maintain attribution to the author(s) and the published article&apos;s title, journal citation, and DOI. Funded by SCOAP3.11Nsciescopu

Genome-wide and fine-resolution association analysis of malaria in West Africa

We report a genome-wide association (GWA) study of severe malaria in The Gambia. The initial GWA scan included 2,500 children genotyped on the Affymetrix 500K GeneChip, and a replication study included 3,400 children. We used this to examine the performance of GWA methods in Africa. We found considerable population stratification, and also that signals of association at known malaria resistance loci were greatly attenuated owing to weak linkage disequilibrium (LD). To investigate possible solutions to the problem of low LD, we focused on the HbS locus, sequencing this region of the genome in 62 Gambian individuals and then using these data to conduct multipoint imputation in the GWA samples. This increased the signal of association, from P = 4 × 10(-7) to P = 4 × 10(-14), with the peak of the signal located precisely at the HbS causal variant. Our findings provide proof of principle that fine-resolution multipoint imputation, based on population-specific sequencing data, can substantially boost authentic GWA signals and enable fine mapping of causal variants in African populations

Scintillation light detection in the 6-m drift-length ProtoDUNE Dual Phase liquid argon TPC

DUNE is a dual-site experiment for long-baseline neutrino oscillation studies, neutrino astrophysics and nucleon decay searches. ProtoDUNE Dual Phase (DP) is a 6 $\times$ 6 $\times$ 6 m$^3$ liquid argon time-projection-chamber (LArTPC) that recorded cosmic-muon data at the CERN Neutrino Platform in 2019–2020 as a prototype of the DUNE Far Detector. Charged particles propagating through the LArTPC produce ionization and scintillation light. The scintillation light signal in these detectors can provide the trigger for non-beam events. In addition, it adds precise timing capabilities and improves the calorimetry measurements. In ProtoDUNE-DP, scintillation and electroluminescence light produced by cosmic muons in the LArTPC is collected by photomultiplier tubes placed up to 7 m away from the ionizing track. In this paper, the ProtoDUNE-DP photon detection system performance is evaluated with a particular focus on the different wavelength shifters, such as PEN and TPB, and the use of Xe-doped LAr, considering its future use in giant LArTPCs. The scintillation light production and propagation processes are analyzed and a comparison of simulation to data is performed, improving understanding of the liquid argon properties.DUNE is a dual-site experiment for long-baseline neutrino oscillation studies, neutrino astrophysics and nucleon decay searches. ProtoDUNE Dual Phase (DP) is a 6x6x6m3 liquid argon time-projection-chamber (LArTPC) that recorded cosmic-muon data at the CERN Neutrino Platform in 2019-2020 as a prototype of the DUNE Far Detector. Charged particles propagating through the LArTPC produce ionization and scintillation light. The scintillation light signal in these detectors can provide the trigger for non-beam events. In addition, it adds precise timing capabilities and improves the calorimetry measurements. In ProtoDUNE-DP, scintillation and electroluminescence light produced by cosmic muons in the LArTPC is collected by photomultiplier tubes placed up to 7 m away from the ionizing track. In this paper, the ProtoDUNE-DP photon detection system performance is evaluated with a particular focus on the different wavelength shifters, such as PEN and TPB, and the use of Xe-doped LAr, considering its future use in giant LArTPCs. The scintillation light production and propagation processes are analyzed and a comparison of simulation to data is performed, improving understanding of the liquid argon properties