Hereditary hearing loss is a clinically and genetically heterogeneous disorder. More than 80 genes have been implicated to date, and with the advent of targeted genomic enrichment and massively parallel sequencing (TGE+MPS) the rate of novel deafness-gene identification has accelerated. Here we report a family segregating post-lingual progressive autosomal dominant non-syndromic hearing loss (ADNSHL). After first excluding plausible variants in known deafness-causing genes using TGE+MPS, we completed whole exome sequencing in three hearing-impaired family members. Only a single variant, p.Arg185Pro in HOMER2, segregated with the hearing-loss phenotype in the extended family. This amino acid change alters a highly conserved residue in the coiled-coil domain of HOMER2 that is essential for protein multimerization and the HOMER2-CDC42 interaction. As a scaffolding protein, HOMER2 is involved in intracellular calcium homeostasis and cytoskeletal organization. Consistent with this function, we found robust expression in stereocilia of hair cells in the murine inner ear and observed that over-expression of mutant p.Pro185 HOMER2 mRNA causes anatomical changes of the inner ear and neuromasts in zebrafish embryos. Furthermore, mouse mutants homozygous for the targeted deletion of Homer2 present with early-onset rapidly progressive hearing loss. These data provide compelling evidence that HOMER2 is required for normal hearing and that its sequence alteration in humans leads to ADNSHL through a dominant-negative mode of action.
Background Fecal testing can only reduce colorectal cancer mortality if patients with an abnormal test result receive a follow-up colonoscopy. As part of the Strategies and Opportunities to STOP Colon Cancer in Priority Populations (STOP CRC) project, we examined factors associated with adherence to follow-up colonoscopy among patients with abnormal fecal test results. Methods As part of STOP CRC outreach, Virginia Garcia Memorial Health Center staff distributed 1,753 fecal immunochemical tests (FIT), of which 677 (39%) were completed, and 56 had an abnormal result (8%). Project staff used logistic regression analyses to examine factors associated with colonoscopy referral and completion. Results Of the 56 patients with abnormal FIT results; 45 (80%) had evidence of a referral for colonoscopy, 32 (57%) had evidence of a completed colonoscopy within 18 months, and 14 (25%) within 60 days of an abnormal fecal test result. In adjusted analysis, Hispanics had lower odds of completing follow-up colonoscopy within 60 days than non-Hispanic whites (adjusted OR = 0.20; 95% CI: 0.04, 0.92). Colonoscopy within 60 days trended lower for women than for men (adjusted OR = 0.25; 95% CI 0.06 – 1.04). Among the 24 patients lacking medical record evidence of a colonoscopy, 19 (79%) had a documented reason, including clinician did not pursue, patient refused, and colonoscopy not indicated. No reason was found for 21%. Conclusion Improvements are needed to increase rates of follow-up colonoscopy completion, especially among female and Hispanic patients.
BackgroundColorectal-cancer is a leading cause of cancer death in the United States, and Latinos have particularly low rates of screening. Strategies and Opportunities to STOP Colon Cancer in Priority Populations (STOP CRC) is a partnership among two research institutions and a network of safety net clinics to promote colorectal cancer screening among populations served by these clinics. This paper reports on results of a pilot study conducted in a safety net organization that serves primarily Latinos.MethodsThe study assessed two clinic-based approaches to raise rates of colorectal-cancer screening among selected age-eligible patients not up-to-date with colorectal-cancer screening guidelines. One clinic each was assigned to: (1) an automated data-driven Electronic Health Record (EHR)-embedded program for mailing Fecal Immunochemical Test (FIT) kits (Auto Intervention); or (2) a higher-intensity program consisting of a mailed FIT kit plus linguistically and culturally tailored interventions delivered at the clinic level (Auto Plus Intervention). A third clinic within the safety-net organization was selected to serve as a passive control (Usual Care). Two simple measurements of feasibility were: 1) ability to use real-time EHR data to identify patients eligible for each intervention step, and 2) ability to offer affordable testing and follow-up care for uninsured patients.ResultsThe study was successful at both measurements of feasibility. A total of 112 patients in the Auto clinic and 101 in the Auto Plus clinic met study inclusion criteria and were mailed an introductory letter. Reach was high for the mailed component (92.5% of kits were successfully mailed), and moderate for the telephone component (53% of calls were successful completed). After exclusions for invalid address and other factors, 206 (109 in the Auto clinic and 97 in the Auto Plus clinic) were mailed a FIT kit. At 6 months, fecal test completion rates were higher in the Auto (39.3%) and Auto Plus (36.6%) clinics compared to the usual-care clinic (1.1%).ConclusionsFindings showed that the trial interventions delivered in a safety-net setting were both feasible and raised rates of colorectal-cancer screening, compared to usual care. Findings from this pilot will inform a larger pragmatic study involving multiple clinics.Trial registrationClinicalTrial.gov: NCT01742065
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