Publications by authors named "W D Kelley"

504 Publications

Genome sequencing as a first-line diagnostic test for hospitalized infants.

Genet Med 2021 Nov 27. Epub 2021 Nov 27.

Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL.

Purpose: SouthSeq is a translational research study that undertook genome sequencing (GS) for infants with symptoms suggestive of a genetic disorder. Recruitment targeted racial/ethnic minorities and rural, medically underserved areas in the Southeastern United States, which are historically underrepresented in genomic medicine research.

Methods: GS and analysis were performed for 367 infants to detect disease-causal variation concurrent with standard of care evaluation and testing.

Results: Definitive diagnostic (DD) or likely diagnostic (LD) genetic findings were identified in 30% of infants, and 14% of infants harbored an uncertain result. Only 43% of DD/LD findings were identified via concurrent clinical genetic testing, suggesting that GS testing is better for obtaining early genetic diagnosis. We also identified phenotypes that correlate with the likelihood of receiving a DD/LD finding, such as craniofacial, ophthalmologic, auditory, skin, and hair abnormalities. We did not observe any differences in diagnostic rates between racial/ethnic groups.

Conclusion: We describe one of the largest-to-date GS cohorts of ill infants, enriched for African American and rural patients. Our results show the utility of GS because it provides early-in-life detection of clinically relevant genetic variations not detected by current clinical genetic testing, particularly for infants exhibiting certain phenotypic features.
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http://dx.doi.org/10.1016/j.gim.2021.11.020DOI Listing
November 2021

Selection of Analytical Technology and Development of Analytical Procedures Using the Analytical Target Profile.

Anal Chem 2022 Jan 20;94(2):559-570. Epub 2021 Dec 20.

Analytical Research and Development, GSK, 1330 Rixensart, Belgium.

A structured approach to method development can help to ensure an analytical procedure is robust across the lifecycle of its use. The analytical target profile (ATP), which describes the required quality of the reportable value to be produced by the analytical procedure, enables the analytical scientist to select the best analytical technology on which to develop their procedure(s). Once the technology has been identified, screening of potentially fit for purpose analytical procedures should take place. Analytical procedures that have been demonstrated to meet the ATP should be evaluated against business drivers (e.g., operational constraints) to determine the most suitable analytical procedure. Three case studies are covered from across small molecules, vaccines, and biotherapeutics. The case studies cover different aspects of the analytical procedure selection process, such as the use of platform method development processes and procedures, the development of multiattribute analytical procedures, and the use of analytical technologies to provide product characterization knowledge in order to define or redefine the ATP. Challenges associated with method selection are discussed such as where existing pharmacopoeial monographs link acceptance criteria to specific types of analytical technology.
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http://dx.doi.org/10.1021/acs.analchem.1c03854DOI Listing
January 2022

Polysalicylic Acid Polymer Microparticle Decoys Therapeutically Treat Acute Respiratory Distress Syndrome.

Adv Healthc Mater 2021 Dec 8:e2101534. Epub 2021 Dec 8.

Department of Chemical Engineering, University of Michigan, Ann Arbor, MI, 48109, USA.

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) remain problematic due to high mortality rates and lack of effective treatments. Neutrophilic injury contributes to mortality in ALI/ARDS. Here, technology for rapid ARDS intervention is developed and evaluated, where intravenous salicylic acid-based polymer microparticles, i.e., Poly-Aspirin (Poly-A), interfere with neutrophils in blood, reducing lung neutrophil infiltration and injury in vivo in mouse models of ALI/ARDS. Importantly, Poly-A particles reduce multiple inflammatory cytokines in the airway and bacterial load in the bloodstream in a live bacteria lung infection model of ARDS, drastically improving survival. It is observed that phagocytosis of the Poly-A microparticles, with salicylic acid in the polymer backbone, alters the neutrophil surface expression of adhesion molecules, potentially contributing to their added therapeutic benefits. Given the proven safety profile of the microparticle degradation products-salicylic acid and adipic acid-it is anticipated that the Poly-A particles represent a therapeutic strategy in ARDS with a rare opportunity for rapid clinical translation.
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http://dx.doi.org/10.1002/adhm.202101534DOI Listing
December 2021

Remdesivir and GS-441524 Extraction by Ex Vivo Extracorporeal Life Support Circuits.

ASAIO J 2021 Nov 17. Epub 2021 Nov 17.

From the Department of Pediatrics, University of Utah, Salt Lake City, Utah Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, Utah University of Utah, Center for Human Toxicology, Salt Lake City, Utah Biomedical Department, American Red Cross, Salt Lake City, Utah Department of Pathology, University of Arizona, Tucson, Arizona, USA.

Patients with severe, COVID-related multi-organ failure often require extracorporeal life support (ECLS) such as extracorporeal membrane oxygenation (ECMO) or continuous renal replacement therapy (CRRT). An ECLS can alter drug exposure via multiple mechanisms. Remdesivir (RDV) and its active metabolite GS-441524 are likely to interact with ECLS circuits, resulting in lower than expected exposures. We evaluated circuit-drug interactions in closed loop, ex vivo ECMO and CRRT circuits. We found that mean (standard deviation) recovery of RDV at 6 hours after dosing was low in both the ECMO (33.3% [2.0]) and CRRT (3.5% [0.4]) circuits. This drug loss appears to be due primarily to drug adsorption by the circuit materials and potentially due to metabolism in the blood. GS-441524 recovery at 6 hours was high in the ECMO circuit 75.8% (16.5); however, was not detectable at 6 hours in the CRRT circuit. Loss in the CRRT circuit appears to be due primarily to efficient hemodiafiltration. The extent of loss for both molecules, especially in CRRT, suggests that in patients supported with ECMO and CRRT, RDV dosing adjustments are needed.
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http://dx.doi.org/10.1097/MAT.0000000000001616DOI Listing
November 2021

The Role of ArlRS and VraSR in Regulating Ceftaroline Hypersusceptibility in Methicillin-Resistant .

Antibiotics (Basel) 2021 Jul 6;10(7). Epub 2021 Jul 6.

Department of Microbiology and Molecular Medicine, University Hospital and Medical School of Geneva, 1206 Geneva, Switzerland.

Methicillin-resistant infections are a global health problem. New control strategies, including fifth-generation cephalosporins such as ceftaroline, have been developed, however rare sporadic resistance has been reported. Our study aimed to determine whether disruption of two-component environmental signal systems detectably led to enhanced susceptibility to ceftaroline in CA-MRSA strain MW2 at sub-MIC concentrations where cells normally continue to grow. A collection of sequential mutants in all fifteen non-essential two-component systems (TCS) was first screened for ceftaroline sub-MIC susceptibility, using the spot population analysis profile method. We discovered a role for both ArlRS and VraSR TCS as determinants responsible for MW2 survival in the presence of sub-MIC ceftaroline. Subsequent analysis showed that dual disruption of both and resulted in a very strong ceftaroline hypersensitivity phenotype. Genetic complementation analysis confirmed these results and further revealed that and likely regulate some common pathway(s) yet to be determined. Our study shows that uses particular TCS environmental sensing systems for this type of defense and illustrates the proof of principle that if these TCS were inhibited, the efficacy of certain antibiotics might be considerably enhanced.
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http://dx.doi.org/10.3390/antibiotics10070821DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8300640PMC
July 2021
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