The CD44 molecule is known to display extensive size heterogeneity, which has been attributed both to alternative splicing and to differential glycosylation within the exracellular domain. Although the presence of several alternative exons has been partly inferred from cDNA sequencing, the precise intron-exon oration of the CD44 gene has not been described to date to our knowledge. In the present study we describe the structure of the human CD44 gene, which contains at least 19 exons s ning some 50 kiobases of DNA. We have identified 10 alternatively spliced exons within the extracellular domain, including 1 exon that has not been previously reported. In addition to the cluson or excusion of whole exons, more diversity is generated through the uztion of internal splice donor and acceptor sites within 2 of the individual exons. The variation previously reported for the cytoplasmic domain is shown to result from the alternative splicing of 2 exons. The genomic structure of CD44 reveals a remarkable degree of complexity, and we confirm the role of alternative splicing as the basis of the structural and functional diversity seen in the CD44 molecule.The human CD44 glycoprotein [Pgp-1 (1), HCAM (2), Hermes antigen (3), ECMR III (4)] has been proposed to function as a lymph node homing receptor on circulating lymphocytes. Expressed on a wide range of different tissues, the CD44 molecule also binds the extracellular matrix components hyaluronic acid (5), fibronectin (6), and collagen (4) as well as the cytoskeletal protein ankyrin (7). Several antibodies recognizing CD44 have been shown to induce lymphocyte activation (8,9) and to inhibit lymphopoiesis (10). In addition, CD44 can mediate both homotypic and heterotypic cell adhesion (11,12). The many functional roles of this molecule may relate to its considerable size heterogeneity, which cannot be accounted for simply by differences in glycosylation (5,13,14).Recently, we and others have isolated a number of different isoforms of CD44 (15-18). These have been characterized by cDNA sequencing and appear to arise by alternative splicing in two different regions, the membrane proximal extracellular domain and the cytoplasmic tail. Some of this variation has been shown to produce functional changes in the molecule. For example, the presence ofthe 396-base-pair (bp) insert in the epithelial variant of CD44 reduces the affinity for hyaluronic acid (5). Study ofthese cDNA variants has given some insight into the genomic organization of CD44 but has not allowed the precise characterization of the number and boundaries of exons that encode the variant region of the molecule.In the present paper we have cloned the gene for CD44 from a human yeast artificial chromosome (YAC) and characterized its genomic structure.* These studies reveal a remarkable degree of complexity within the structure of the CD44 gene and demonstrate conclusively the role of alternative splicing in generating the structural heterogeneity that is characteristic of the CD44 molecule. MATERIALS AND M...

Background: Hydroxychloroquine and chloroquine have been proposed as treatments for coronavirus disease 2019 (COVID-19) on the basis of in vitro activity, uncontrolled data, and small randomized studies. Methods: The Randomised Evaluation of COVID-19 therapy (RECOVERY) trial is a randomized, controlled, open-label, platform trial comparing a range of possible treatments with usual care in patients hospitalized with COVID-19. We report the preliminary results for the comparison of hydroxychloroquine vs. usual care alone. The primary outcome was 28-day mortality. Results: 1561 patients randomly allocated to receive hydroxychloroquine were compared with 3155 patients concurrently allocated to usual care. Overall, 418 (26.8%) patients allocated hydroxychloroquine and 788 (25.0%) patients allocated usual care died within 28 days (rate ratio 1.09; 95% confidence interval [CI] 0.96 to 1.23; P=0.18). Consistent results were seen in all pre-specified subgroups of patients. Patients allocated to hydroxychloroquine were less likely to be discharged from hospital alive within 28 days (60.3% vs. 62.8%; rate ratio 0.92; 95% CI 0.85-0.99) and those not on invasive mechanical ventilation at baseline were more likely to reach the composite endpoint of invasive mechanical ventilation or death (29.8% vs. 26.5%; risk ratio 1.12; 95% CI 1.01-1.25). There was no excess of new major cardiac arrhythmia. Conclusions: In patients hospitalized with COVID-19, hydroxychloroquine was not associated with reductions in 28-day mortality but was associated with an increased length of hospital stay and increased risk of progressing to invasive mechanical ventilation or death.

BATD and problem-solving interventions represent practical interventions that may improve psychological outcomes and quality of life among depressed breast cancer patients. Study limitations and future research directions are discussed.

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