Citations

AbstractBackgroundTransient receptor potential cation channel subfamily V member 4 (TRPV4) is an ion channel permeable to Ca2+ that is sensitive to physical, hormonal, and chemical stimuli. This protein is expressed in many cell types, including osteoclasts, chondrocytes, and sensory neurons. As such, pathogenic variants of this gene are associated with skeletal dysplasias and neuromuscular disorders. Pathogenesis of these phenotypes is not yet completely understood, but it is known that genotype–phenotype correlations for TRPV4 pathogenic variants often are not present.MethodsNewly characterized, suspected pathogenic variant in TRPV4 was analyzed using protein informatics and personalized protein‐level molecular studies, genomic exome analysis, and clinical study.ResultsThis statement is demonstrated in the family of our proband, a 47‐year‐old female having the novel c.2401A>G (p.K801E) variant of TRPV4. We discuss the common symptoms between the proband, her father, and her daughter, and compare her phenotype to known TRPV4‐associated skeletal dysplasias.ConclusionsProtein informatics and molecular modeling are used to confirm the pathogenicity of the unique TRPV4 variant found in this family. Multiple data were combined in a comprehensive manner to give complete overall perspective on the patient disease and prognosis.

Abstract Introduction Sexual dysfunction is a common problem in women and the nature of its association with alcohol use remains unclear. Aim To explore the association between alcohol use and female sexual dysfunction (FSD). Methods Associations between self-reported drinking and sexual function were evaluated in 2,253 women presenting for consultation to a women’s health specialty clinic. A short version of the Alcohol Use Disorders Identification Test (AUDIT-C) was used to evaluate alcohol use. Women with an AUDIT-C ≥3 were considered at risk for hazardous drinking. Multivariable regression, controlling for depression, anxiety, and abuse (childhood and recent), was used to assess the association between alcohol consumption and FSD (defined as a Female Sexual Function Index [FSFI] ≤26.55 and Female Sexual Distress Scale [FSDS] ≥11) in sexually active women. Main Outcome Measure The main study outcome measure was the presence of FSD as defined by a score ≤26.55 on the FSFI and ≥11 on the FSDS. Results 57% of the 1,649 sexually active women were classified as having FSD; 80% reported any alcohol use and 38% reported drinking patterns with the potential to be hazardous. The women at risk for hazardous drinking had significantly higher FSFI domain scores indicating better sexual function (P ≤ .001). However, in multivariable analyses, there was no significant difference in the rates of FSD across alcohol use categories in women. Conclusion In women presenting for consultation to a women’s health specialty clinic, an association between alcohol use and FSFI scores was seen, in which greater risk of hazardous drinking was associated with better sexual function scores. However, when sexual distress was included to define sexual dysfunction, those with FSD were not at higher risk of hazardous drinking. Given the complex nature of FSD, additional study is needed to further clarify these relationships.

ObjectiveVoice outcomes following medialization laryngoplasty (ML) for unilateral vocal fold paralysis (UVFP) were compared to those who underwent ML plus arytenoid adduction (AA) (ML+AA).MethodsSingle institution retrospective review of patients with UVFP undergoing ML and ML+AA (2009–2017). Demographic information and history of laryngeal procedures were collected. Preoperative and postoperative Voice Handicap Index‐10 (VHI‐10) and Consensus Perceptual Auditory Evaluation of Voice (CAPE‐V) were assessed.ResultsOf 236 patients, 119 met study criteria. Of those, 70 (59%) underwent ML and 49 (41%) underwent ML+AA. Significant differences between groups at baseline were found for age at time of thyroplasty (P = 0.046), VHI‐10 scores (P < 0.001), and CAPE‐V scores (P = 0.007). Baseline VHI‐10 scores for ML+AA (28 ± 7) were greater than those for ML alone (24 ± 7). At 12 months, overall VHI‐10 scores improved compared to baseline for both groups (ML+AA = 9 ± 7, ML = 16 ± 9); however, there was greater improvement for the ML+AA group compared to ML group (P = 0.001). CAPE‐V scores at 3 or 12 months improved, but differences between the groups were not statistically significant once controlled for covariates.ConclusionBased on current findings, patients who undergo ML+AA likely have greater voice handicap at baseline compared to those undergoing ML alone. Patients selected for ML+AA improve as much or more than those who underwent ML alone. This highlights the importance of appropriate selection of candidates for AA.Level of Evidence4Laryngoscope, 129:1876–1881, 2019

The prevalence, clinicopathologic correlates, and outcomes of previously untreated chronic lymphocytic leukemia (CLL) patients with IGH‐BCL2 and IGH‐BCL3 translocations are not well known. Using the Mayo Clinic CLL database, we identified patients seen between March 1, 2002 and September 30, 2016 who had FISH testing performed within 3 years of CLL diagnosis. The prognostic profile, time to first therapy (TTT), and overall survival (OS) of patients with IGH‐BCL2 and IGH‐BCL3 translocation were compared to patients without these abnormalities (non‐IGH group). Of 1684 patients who met the inclusion criteria, 38 (2.2%) had IGH‐BCL2, and 16 (0.9%) had IGH‐BCL3 translocation at diagnosis. Patients with IGH‐BCL3 translocation were more likely to have high and very‐high CLL‐International Prognostic Index, compared to patients with IGH‐BCL2 translocation and the non‐IGH group. The 5‐year probability of requiring therapy was significantly higher for IGH‐BCL3 compared to IGH‐BCL2 and non‐IGH groups (84% vs 33% vs 29%, respectively, P < 0.0001). The 5‐year OS was significantly shorter for IGH‐BCL3 compared to IGH‐BCL2 and non‐IGH groups (45% vs 89% vs 86%, respectively, P < 0.0001). On multivariable analyses, IGH‐BCL3 translocation was associated with a shorter TTT (hazard ratio [HR] = 2.7; P = 0.005) and shorter OS (HR = 5.5; P < 0.0001); IGH‐BCL2 translocation did not impact TTT and OS. In conclusion, approximately 3% of all newly diagnosed CLL patients have either an IGH‐BCL2 or IGH‐BCL3 translocation. Patients with IGH‐BCL3 translocations have a distinct prognostic profile and outcome. These results support the inclusion of an IGH probe during the routine evaluation of FISH abnormalities in newly diagnosed CLL.

Abstract The CHEK2 gene and its encoded protein Chk2 have a well-known role in cancers, especially those related to breast cancer mediated through the BRCA1 gene. Additionally Chk2 has a crucial role in DNA repair, apoptosis and the cell cycle, which is why classification of variants of uncertain significance (VUS) is an area highly sought for a better elucidation of the “genomic effect” that results. Because it can often take years before enough clinical data is accumulated, and the costly and expensive functional analysis for individual variants presents a significant hurdle, it is important to identify other tools to help aid in clarifying the impact of specific variants on a protein's function and eventually the patient's health outcome. Here we describe a newly identified CHEK2 variant and analyze with an integrated approach combining genomics (whole exome analysis), clinical study, radiographic imaging, and protein informatics to identify and predict the functional impact of the VUS on the protein's behavior and predicted impact on the related pathways. The observed and analyzed defects in the protein were consistent with the expected clinical effect. Here, we support the use of personalized protein modeling and informatics and further our goal of developing a large-scale protein deposition archive for all protein-level VUS.