Publications

Prevention can help older adults avoid illness by identifying and addressing conditions before they cause symptoms, but prevention can also harm older adults if conditions that are unlikely to cause symptoms in the individual's lifetime are identified and treated. To identify older adults who preventive interventions are most likely to benefit (and most likely to harm), we propose a framework that compares an individual's life expectancy (LE) with the time to benefit (TTB) for an intervention. If LE is less than the TTB, the individual is unlikely to benefit but is exposed to the risks of the intervention, and the intervention should generally NOT be recommended. If LE is longer than the TTB, the individual could benefit, and the intervention should generally be recommended. If LE is similar to the TTB, the individual's values and preferences should be the major determinant of the decision. To facilitate the use of this framework in routine clinical care, we explored ways to estimate LE, identified the TTB for common preventive interventions, and developed strategies for communicating with individuals. We have synthesized these strategies and demonstrate how they can be used to individualize prevention for a hypothetical beneficiary in the setting of a Medicare annual wellness visit. Finally, we place prevention in the context of curative and symptom-oriented care and outline how prevention should be focused on healthier older adults, whereas symptom-oriented care should predominate in sicker older adults.

Epidemiological observations have linked increased host iron with malaria susceptibility, and perturbed iron handling has been hypothesized to contribute to the potentially life-threatening anemia that may accompany blood-stage malaria infection. To improve our understanding of these relationships, we examined the pathways involved in regulation of the master controller of iron metabolism, the hormone hepcidin, in malaria infection. We show that hepcidin upregulation in murine malaria infection was accompanied by changes in expression of bone morphogenetic protein (BMP)/sons of mothers against decapentaplegic (SMAD) pathway target genes, a key pathway involved in hepcidin regulation. We therefore investigated known agonists of the BMP/SMAD pathway and found that gene expression was not increased in infection. In contrast, activin B, which can signal through the BMP/SMAD pathway and has been associated with increased hepcidin during inflammation, was upregulated in the livers of -infected mice; hepatic activin B was also upregulated at peak parasitemia during infection with Concentrations of the closely related protein activin A increased in parallel with hepcidin in serum from malaria-naive volunteers infected in controlled human malaria infection (CHMI) clinical trials. However, antibody-mediated neutralization of activin activity during murine malaria infection did not affect hepcidin expression, suggesting that these proteins do not stimulate hepcidin upregulation directly. In conclusion, we present evidence that the BMP/SMAD signaling pathway is perturbed in malaria infection but that activins, although raised in malaria infection, may not have a critical role in hepcidin upregulation in this setting.

There exists compelling evidence that some genetic variants are associated with the risk of multiple cancer sites (i.e., pleiotropy). However, the biological mechanisms through which the pleiotropic variants operate are unclear. We obtained all cancer risk associations from the National Human Genome Research Institute-European Bioinformatics Institute GWAS Catalog, and correlated cancer risk variants were clustered into groups. Pleiotropic variant groups and genes were functionally annotated. Associations of pleiotropic cancer risk variants with noncancer traits were also obtained. We identified 1,431 associations between variants and cancer risk, comprised of 989 unique variants associated with 27 unique cancer sites. We found 20 pleiotropic variant groups (2.1%) composed of 33 variants (3.3%), including novel pleiotropic variants rs3777204 and rs56219066 located in the gene. Relative to single-cancer risk variants, pleiotropic variants were more likely to be in genes (89.0% vs. 65.3%, = 2.2 × 10), and to have somewhat larger risk allele frequencies (median RAF = 0.49 versus 0.39, = 0.046). The 27 genes to which the pleiotropic variants mapped were suggestive for enrichment in response to radiation and hypoxia, alpha-linolenic acid metabolism, cell cycle, and extension of telomeres. In addition, we observed that 8 of 33 pleiotropic cancer risk variants were associated with 16 traits other than cancer. This study identified and functionally characterized genetic variants showing pleiotropy for cancer risk. Our findings suggest biological pathways common to different cancers and other diseases, and provide a basis for the study of genetic testing for multiple cancers and repurposing cancer treatments. .