Abstract
SPECC1L mutations have been identified in patients with rare atypical orofacial clefts and with syndromic cleft lip and/or palate (CL/P). These mutations cluster in the second coiled-coil ...and calponin homology domains of SPECC1L and severely affect the ability of SPECC1L to associate with microtubules. We previously showed that gene-trap knockout of Specc1l in mouse results in early embryonic lethality. We now present a truncation mutant mouse allele, Specc1lΔC510, that results in perinatal lethality. Specc1lΔC510/ΔC510 homozygotes showed abnormal palate rugae but did not show cleft palate. However, when crossed with a gene-trap allele, Specc1lcGT/ΔC510 compound heterozygotes showed a palate elevation delay with incompletely penetrant cleft palate. Specc1lcGT/ΔC510 embryos exhibit transient oral epithelial adhesions at E13.5, which may delay shelf elevation. Consistent with oral adhesions, we show periderm layer abnormalities, including ectopic apical expression of adherens junction markers, similar to Irf6 hypomorphic mutants and Arhgap29 heterozygotes. Indeed, SPECC1L expression is drastically reduced in Irf6 mutant palatal shelves. Finally, we wanted to determine if SPECC1L deficiency also contributed to non-syndromic (ns) CL/P. We sequenced 62 Caucasian, 89 Filipino, 90 Ethiopian, 90 Nigerian and 95 Japanese patients with nsCL/P and identified three rare coding variants (p.Ala86Thr, p.Met91Iso and p.Arg546Gln) in six individuals. These variants reside outside of SPECC1L coiled-coil domains and result in milder functional defects than variants associated with syndromic clefting. Together, our data indicate that palate elevation is sensitive to deficiency of SPECC1L dosage and function and that SPECC1L cytoskeletal protein functions downstream of IRF6 in palatogenesis.
Women with epithelial ovarian cancer (EOC) who have a germline mutation, somatic mutation or are found to have homologous recombination deficiency (HRD) have been shown to have an improved survival ...with use of a PARP inhibitor after completion of first-line chemotherapy. A quality improvement project aimed to develop a pathway for somatic/HRD testing in all patients with EOC.
Standard quality improvement methodology was employed to complete a stakeholder analysis, process mapping, an Ishikawa diagram, a pro/con brainstorming session and a provider survey. Additionally, we benchmarked with another academic institution. Patient education material on genetic testing was developed. Plan-Do-Study-Act (PDSA) cycles were employed throughout the quality improvement process. All newly diagnosed patients with EOC who underwent surgery between January - June 2019 (preimplementation) and June-August 2020 (post-implementation) were identified. Data was abstracted from medical records to determine which patients were referred to genetics and which patients were provided with somatic testing recommendations.
Prior to implementation, 42.9% (30/70) patients who completed primary treatment of EOC had somatic testing ordered prior to completing primary adjuvant chemotherapy. Post-implementation, 63% (17/27) of patients had somatic testing recommended. Confining analysis to those patients who returned for a postoperative visit at the surgical institution, 77.8% (14/18) had somatic testing recommended. Germline testing referral and rates (countermeasure) did not change 88.6% (62/70) vs 85.3% (29/34) (pre versus post-implementation).
Development of a structured process for somatic/HRD testing after surgery for EOC results improved rates of somatic testing discussion. A stepwise process ensures that these patients still receive the necessary counseling about germline testing prior to undergoing somatic/HRD testing.
Early diagnosis of persons infected with human immunodeficiency virus (HIV) through diagnostic testing and screening is a critical priority for individual and public health. Emergency departments ...(EDs) have an important role in this effort. As EDs gain experience in HIV testing, it is increasingly apparent that implementing testing is conceptually and operationally complex. A wide variety of HIV testing practice and research models have emerged, each reflecting adaptations to site‐specific factors and the needs of local populations. The diversity and complexity inherent in nascent ED HIV testing practice and research are associated with the risk that findings will not be described according to a common lexicon. This article presents a comprehensive set of terms and definitions that can be used to describe ED‐based HIV testing programs, developed by consensus opinion from the inaugural meeting of the National ED HIV Testing Consortium. These definitions are designed to facilitate discussion, increase comparability of future reports, and potentially accelerate wider implementation of ED HIV testing.
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