100,000 Genomes Pilot on Rare-Disease Diagnosis in Health Care — Preliminary Report

BACKGROUND: The U.K. 100,000 Genomes Project is in the process of investigating the role of genome sequencing in patients with undiagnosed rare diseases after usual care and the alignment of this research with health care implementation in the U.K. National Health Service. Other parts of this project focus on patients with cancer and infection. METHODS: We conducted a pilot study involving 4660 participants from 2183 families, among whom 161 disorders covering a broad spectrum of rare diseases were present. We collected data on clinical features with the use of Human Phenotype Ontology terms, undertook genome sequencing, applied automated variant prioritization on the basis of applied virtual gene panels and phenotypes, and identified novel pathogenic variants through research analysis. RESULTS: Diagnostic yields varied among family structures and were highest in family trios (both parents and a proband) and families with larger pedigrees. Diagnostic yields were much higher for disorders likely to have a monogenic cause (35%) than for disorders likely to have a complex cause (11%). Diagnostic yields for intellectual disability, hearing disorders, and vision disorders ranged from 40 to 55%. We made genetic diagnoses in 25% of the probands. A total of 14% of the diagnoses were made by means of the combination of research and automated approaches, which was critical for cases in which we found etiologic noncoding, structural, and mitochondrial genome variants and coding variants poorly covered by exome sequencing. Cohortwide burden testing across 57,000 genomes enabled the discovery of three new disease genes and 19 new associations. Of the genetic diagnoses that we made, 25% had immediate ramifications for clinical decision making for the patients or their relatives. CONCLUSIONS: Our pilot study of genome sequencing in a national health care system showed an increase in diagnostic yield across a range of rare diseases. (Funded by the National Institute for Health Research and others.)

Design and In Vitro Evaluation of Novel Sustained-Release Double-Layer Tablets of Lornoxicam: Utility of Cyclodextrin and Xanthan Gum Combination

The objective of the present study was to develop new directly compressed, double-layer tablets (DLTs) of lornoxicam, a highly potent nonsteroidal anti-inflammatory drug with short half-life, that are characterized by initial burst drug release in the stomach and comply with the release requirements of sustained-release products. Each of the proposed DLTs is composed of a fast-release layer and a sustained-release layer, anticipating rapid drug release that starts in the stomach to rapidly alleviate the symptoms and continues in the intestine to maintain protracted analgesic effect. An amorphous, freeze-dried inclusion complex of lornoxicam with hydroxypropyl-β-cyclodextrin, present in 1:2 (drug/cyclodextrin) molar ratio, was employed in the fast-release layer to enhance the dissolution of lornoxicam in the stomach and assure rapid onset of its analgesic effect. Xanthan gum (XG), a hydrophilic matrix-forming agent, was integrated in the sustained-release layer to provide appropriate sustainment of drug release. The weight ratios between the sustained-release layer and fast-release layer present in DLTs were adjusted to reach optimal formulations. DLTs composed of sustained-release layer (40% XG) to fast-release layer in 2:1 weight ratio and those composed of sustained-release layer (50% XG) to fast-release layer in 1:1 weight ratio showed the desired release profile. The drug contained in the fast-release layer showed an initial burst drug release of more than 30% of its drug content during the first 30 min of the release study followed by gradual release of the drug for a period of 8 h