Functional variomics provides the foundation for personalized medicine by linking genetic variation to disease expression, outcome and treatment, yet its utility is dependent on appropriate assays to evaluate mutation impact on protein function. To fully assess the effects of 106 missense and nonsense variants of PTEN associated with autism spectrum disorder, somatic cancer and PTEN hamartoma syndrome (PHTS), we take a deep phenotypic profiling approach using 18 assays in 5 model systems spanning diverse cellular environments ranging from molecular function to neuronal morphogenesis and behavior. Variants inducing instability occur across the protein, resulting in partial-to-complete loss-of-function (LoF), which is well correlated across models. However, assays are selectively sensitive to variants located in substrate binding and catalytic domains, which exhibit complete LoF or dominant negativity independent of effects on stability. Our results indicate that full characterization of variant impact requires assays sensitive to instability and a range of protein functions.

Cervical vertebral AV fistulae are uncommon vascular lesions involving abnormal communication between the extradural vertebral artery and surrounding venous structures. We examine the case of a female evaluated in the emergency department with a vertebral AV fistula presenting classically as pulsatile tinnitus and later successfully treated with standard endovascular techniques. A discussion on the etiology, pathophysiology, and management of vertebral AV fistulae follows.

Purpose Nearly half the cases of thyroid cancer, a malignancy rapidly rising in incidence within the United States, are attributable to small and asymptomatic papillary thyroid cancers that will not increase mortality. A primary driver of thyroid cancer overdiagnosis is ultrasound use. It is therefore valuable to understand how inappropriate use of thyroid ultrasound is defined, analyze the current evidence for its frequency, and identify interventions to lessen misuse. Methods Ovid MEDLINE(R), Ovid EMBASE, and Scopus databases were searched from inception to June 2020 for studies assessing inappropriate use of thyroid ultrasound. Reviewers, working independently and in duplicate, evaluated studies for inclusion, extracted data, and graded risk of bias. We used a random-effects model with a generalized linear mixed approach to calculate the mean overall proportion estimates of inappropriate use. Results Seven studies (total n = 1573) met the inclusion criteria with moderate to high risk of bias. Inappropriate thyroid ultrasound use was described variably, using published practice guidelines, third-party expert reviewers, or author interpretations of the literature. The overall frequency of inappropriate thyroid ultrasound use was 46% (95% CI 15-82%; n = 388) and 34% (95% CI 16-57%; n = 190) among studies using guideline based definitions. The pooled frequency of iUS due to thyroid dysfunction (either hypothyroidism or thyrotoxicosis) was 17% (95% CI 7-37%; n = 191) and the frequency of iUS due to nonspecific symptoms without a palpable mass was 11% (95% CI 5-22%; n = 124). No study examined interventions to address inappropriate use. Conclusions Low quality evidence suggests that inappropriate use of thyroid ultrasound is common. Interventional studies aiming to decrease the inappropriate use of thyroid ultrasound are urgently needed.