The precisionFDA Truth Challenge V2 aimed to assess the state of the art of variant calling in challenging genomic regions. Starting with FASTQs, 20 challenge participants applied their ...variant-calling pipelines and submitted 64 variant call sets for one or more sequencing technologies (Illumina, PacBio HiFi, and Oxford Nanopore Technologies). Submissions were evaluated following best practices for benchmarking small variants with updated Genome in a Bottle benchmark sets and genome stratifications. Challenge submissions included numerous innovative methods, with graph-based and machine learning methods scoring best for short-read and long-read datasets, respectively. With machine learning approaches, combining multiple sequencing technologies performed particularly well. Recent developments in sequencing and variant calling have enabled benchmarking variants in challenging genomic regions, paving the way for the identification of previously unknown clinically relevant variants.
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•Sixty-four submissions employing innovative variant-calling methods for three technologies•Submissions evaluated with new GIAB benchmark sets and new genome stratifications•Submissions differ in performance overall and in challenging genomic regions•Challenge data are available at https://doi.org/10.18434/mds2-2336
Olson et al. report on the results of precisionFDA Truth Challenge V2 for variant-calling pipelines. The challenge focused on small-variant accuracy of innovative deep learning and graph-based methods, utilizing a new benchmark and with new stratifications to demonstrate strengths and weaknesses of different methods.
Huntington’s disease (HD) is an autosomal dominant disease caused by the expansion of cytosine-adenine-guanine (CAG) repeats in one copy of the HTT gene (mutant HTT, mHTT). The unaffected HTT gene ...encodes wild-type HTT (wtHTT) protein, which supports processes important for the health and function of the central nervous system. Selective lowering of mHTT for the treatment of HD may provide a benefit over nonselective HTT-lowering approaches, as it aims to preserve the beneficial activities of wtHTT. Targeting a heterozygous single-nucleotide polymorphism (SNP) where the targeted variant is on the mHTT gene is one strategy for achieving allele-selective activity. Herein, we investigated whether stereopure phosphorothioate (PS)- and phosphoryl guanidine (PN)-containing oligonucleotides can direct allele-selective mHTT lowering by targeting rs362273 (SNP3). We demonstrate that our SNP3-targeting molecules are potent, durable, and selective for mHTT in vitro and in vivo in mouse models. Through comparisons with a surrogate for the nonselective investigational compound tominersen, we also demonstrate that allele-selective molecules display equivalent potency toward mHTT with improved durability while sparing wtHTT. Our preclinical findings support the advancement of WVE-003, an investigational allele-selective compound currently in clinical testing (NCT05032196) for the treatment of patients with HD.
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Iwamoto and colleagues develop chemically modified oligonucleotides that selectively lower mutant huntingtin (mHTT) expression by targeting a heterozygous SNP in the transcript. In preclinical models, the molecules are potent, durable, and selective for mHTT. These findings support the advancement of WVE-003, an investigational oligonucleotide for the treatment of Huntington’s disease.
Ricin toxin may be used as a biological warfare agent and no medical countermeasures are currently available. Here, a well‐characterized lot of ricin was aerosolized to determine the delivered dose ...for future pre‐clinical efficacy studies. Mouse intraperitoneal (IP) median lethal dose (LD50) bioassay measured potency at 5.62 and 7.35 μg/kg on Days 0 and 365, respectively. Additional analyses included total protein, sodium dodecyl sulfate polyacrylamide gel electrophoresis, Western blotting, and rabbit reticulocyte lysate activity assay. The nebulizer aerosol produced consistent concentrations (2.5 × 103, 5.0 × 103, 1.0 × 104, and 1.5 × 104 μg/mL) and spray factor values. The aerosol particle size distribution was of sufficient size to deposit in lung alveoli (1.12–1.43 μm). Ricinus communis Agglutinin II (RCA 60), prepared at 19 mg/mL in phosphate‐buffered saline, pH 7.8, and stored at −70°C, maintained attributes for toxicity following 1‐year storage and aerosolized consistently.
The authors obtained older adults' self-rated judgments about the quality of their activity engagement considered as a whole (global activity evaluation) and, using cross-sectional survey data, ...tested the ability of such judgments to predict well-being. Participants were 460 community-dwelling older adults who responded to (1) global activity evaluations, (2) activity participation frequency scales, and (3) indices of life satisfaction, depression, and physical and mental health-related quality of life. Regression analyses indicated that global activity evaluations had a stronger relationship to psychosocial outcome indices than did participation frequency ratings, although both measurement approaches were associated with statistically significant predictions. However, global evaluations and participation frequency ratings were approximately equal in their ability to predict physical health-related quality of life. These relationships were fairly consistent across ethnic groups. Overall, the results suggest that ideally the two strategies for assessing activity should be incorporated in future research on activity and occupational therapy practice.
Small synthetic molecules termed growth hormone secretagogues (GHSs) act on the pituitary gland and the hypothalamus to stimulate and amplify pulsatile growth hormone (GH) release. A heterotrimeric ...GTP-binding protein (G protein)-coupled receptor (GPC-R) of the pituitary and arcuate ventro-medial and infundibular hypothalamus of swine and humans was cloned and was shown to be the target of the GHSs. On the basis of its pharmacological and molecular characterization, this GPC-R defines a neuroendocrine pathway for the control of pulsatile GH release and supports the notion that the GHSs mimic an undiscovered hormone.
Background Community-dwelling older adults are at risk for declines in physical health, cognition, and psychosocial well-being. However, their enactment of active and health-promoting lifestyles can ...reduce such declines.
Purpose The purpose of this article is to describe the USC Well Elderly II study, a randomized clinical trial designed to test the effectiveness of a healthy lifestyle program for elders, and document how various methodological challenges were addressed during the course of the trial.
Methods In the study, 460 ethnically diverse elders recruited from a variety of sites in the urban Los Angeles area were enrolled in a randomized experiment involving a crossover design component. Within either the first or second 6-month phase of their study involvement, each elder received a lifestyle intervention designed to improve a variety of aging outcomes. At 4—5 time points over an 18—24 month interval, the research participants were assessed on measures of healthy activity, coping, social support, perceived control, stress-related biomarkers, perceived physical health, psychosocial well-being, and cognitive functioning to test the effectiveness of the intervention and document the process mechanisms responsible for its effects.
Results The study protocol was successfully implemented, including the enrollment of study sites, the recruitment of 460 older adults, administration of the intervention, adherence to the plan for assessment, and establishment of a large computerized data base.
Limitations: Methodological challenges were encountered in the areas of site recruitment, participant recruitment, testing, and intervention delivery.
Conclusions The completion of clinical trials involving elders from numerous local sites requires careful oversight and anticipation of threats to the study design that stem from: (a) social situations that are particular to specific study sites; and (b) physical, functional, and social challenges pertaining to the elder population. Clinical Trials 2009; 6: 90—101. http://ctj.sagepub.com
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