PRKN mutations are the most common recessive cause of Parkinson’s disease and are a promising target for gene and cell replacement therapies. Identification of biallelic PRKN patients at the population scale, however, remains a challenge, as roughly half are copy number variants and many single nucleotide polymorphisms are of unclear significance. Additionally, the true prevalence and disease risk associated with heterozygous PRKN mutations is unclear, as a comprehensive assessment of PRKN mutations has not been performed at a population scale. To address these challenges, we evaluated PRKN mutations in two cohorts with near complete genotyping of both single nucleotide polymorphisms and copy number variants: the NIH-PD + AMP-PD cohort, the largest Parkinson’s disease case-control cohort with whole genome sequencing data from 4094 participants, and the UK Biobank, the largest cohort study with whole exome sequencing and genotyping array data from 200 606 participants. Using the NIH-PD participants, who were genotyped using whole genome sequencing, genotyping array, and multi-plex ligation-dependent probe amplification, we validated genotyping array for the detection of copy number variants. Additionally, in the NIH-PD cohort, functional assays of patient fibroblasts resolved variants of unclear significance in biallelic carriers and suggested that cryptic loss of function variants in monoallelic carriers are not a substantial confounder for association studies. In the UK Biobank, we identified 2692 PRKN copy number variants from genotyping array data from nearly half a million participants (the largest collection to date). Deletions or duplications involving exon 2 accounted for roughly half of all copy number variants and the vast majority (88%) involved exons 2, 3, or 4. In the UK Biobank, we found a pathogenic PRKN mutation in 1.8% of participants and two mutations in ∼1/7800 participants. Those with one PRKN pathogenic variant were as likely as non-carriers to have Parkinson’s disease [odds ratio = 0.91 (0.58–1.38), P-value 0.76] or a parent with Parkinson’s disease [odds ratio = 1.12 (0.94–1.31), P-value = 0.19]. Similarly, those in the NIH-PD + AMP + PD cohort with one PRKN pathogenic variant were as likely as non-carriers to have Parkinson’s disease [odds ratio = 1.29 (0.74–2.38), P-value = 0.43]. Together our results demonstrate that heterozygous pathogenic PRKN mutations are common in the population but do not increase the risk of Parkinson’s disease.

Objective To describe and evaluate the utility of a new sonographic microcystic pattern, which is typical of borderline ovarian tumor (BOT) papillary projections, solid component(s) and/or septa, as a new ultrasound marker that is capable of distinguishing BOT from other adnexal masses, and to present/obtain histologic confirmation. Methods In this retrospective study, we identified women with a histologic diagnosis of BOT following surgical resection who had undergone preoperative transvaginal ultrasound (TVS) examination. All images were reviewed for presence or absence of thin-walled, fluid-filled cluster(s) of 1-3-mm cystic formations, associated with solid component(s), papillary projections and/or septa. From the same cases, histopathologic slides of each BOT were examined for presence of any of these microcystic features which had been identified on TVS. To confirm that the microcystic TVS pattern is unique to BOTs, we also selected randomly from our ultrasound and surgical database 20 cases of epithelial ovarian cancer and 20 cases of benign cystadenoma, for review by the same pathologists. To confirm the novelty of our findings, we searched PubMed for literature published in the English language between 2010 and 2018 to determine whether the association between microcystic tissue pattern and BOT has been described previously. Results Included in the final analysis were 62 patients (67 ovaries) with preoperative TVS and surgically confirmed BOT on pathologic examination. The mean patient age at surgery was 39.8 years. The mean BOT size at TVS was 60.7 mm. Of the 67 BOTs, 47 (70.1%) were

A BS TRACT: Background: Cytoplasmic inclusions of α-synuclein (α-syn) in brainstem neurons are characteristic of idiopathic Parkinson's disease (PD). PD also entails α-syn buildup in sympathetic nerves. Among genetic forms of PD, the relative extents of sympathetic intraneuronal accumulation of α-syn have not been reported. Objective: This cross-sectional observational study compared magnitudes of intraneuronal deposition of α-syn in common and rare genetic forms of PD. Methods: α-Syn deposition was quantified by the α-syntyrosine hydroxylase colocalization index in C2 cervical skin biopsies from 65 subjects. These included 30 subjects with pathogenic mutations in SNCA (n = 3), PRKN [biallelic (n = 7) and monoallelic (n = 3)], LRRK2 (n = 7), GBA (n = 7), or PARK7/DJ1 [biallelic (n = 1) and monoallelic (n = 2)]. Twenty-five of the mutation carriers had PD and five did not. Data were also analyzed from 19 patients with idiopathic PD and 16 control participants.Results: α-Syn deposition varied as a function of genotype (F = 16.7, P < 0.0001). It was above the control range in 100% of subjects with SNCA mutations, 100% with LRRK2 mutations, 95% with idiopathic PD, 83% with GBA mutations, and 0% with biallelic PRKN mutations. α-Syn deposition in the biallelic PRKN group was significantly higher than in the control group. In addition, patients with biallelic PRKN mutations had higher α-syn deposition than their unaffected siblings. Conclusions: Individuals with SNCA, DJ-1, LRRK2, or GBA mutations have substantial intraneuronal α-syn deposition in sympathetic noradrenergic nerves in skin biopsies, whereas those with biallelic PRKN mutations do not. Biallelic PRKN patients may have mildly increased α-syn deposition compared with control subjects.

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Objectives Cystadenofibromas (CAFs) are rare benign ovarian tumors without a widely accepted ultrasound (US) pattern. They are usually described by as thin‐walled, unilocular or multilocular, and at times septated cysts with scant blood flow and no solid components. We describe a unique US feature, the “shadow sign,” seen in prospectively diagnosed benign CAFs. We also provide the histopathologic basis for this typical US appearance. Methods Ultrasound (US) examinations were performed in our obstetric and gynecologic US unit. Pathologic examinations were performed by a dedicated gynecologic pathology team. The US and pathology department's database was searched for the diagnosis of a CAF between 2010 and 2017. Results We identified 20 patients who underwent transvaginal US examinations with a sole US diagnosis of a CAF, and the tumors were surgically removed. The common US feature across the 20 cases was the presence of hyperechoic avascular shadowing nodules. The correlating histologic features were unilocular or multilocular cysts with a smooth internal wall surface lined by a simple epithelium and occasional robust polypoid fibrous stroma. Conclusions This US marker helps in differentiating CAFs from borderline ovarian tumors, which do not show this US feature. We hope that recognizing the suggested shadow sign as an additional descriptor of CAFs will lead to minimizing their unnecessary removal and eliminating additional and unnecessary imaging by computed tomography and magnetic resonance imaging.

PRKN mutations are the most common recessive cause of Parkinson′s disease (PD) and are a promising target for gene and cell replacement therapies. Identification of biallelic PRKN patients (PRKN-PD) at the population scale, however, remains a challenge, as roughly half are copy number variants (CNVs) and many single nucleotide polymorphisms (SNPs) are of unclear significance. Additionally, the true prevalence and disease risk associated with heterozygous PRKN mutations is unclear, as a comprehensive assessment of PRKN SNPs and CNVs has not been performed at a population scale. To address these challenges, we evaluated PRKN mutations in 2 cohorts analyzed with both a genotyping array and exome or genome sequencing: the NIH PD cohort, a deeply phenotyped cohort of PD patients, and the UK Biobank, a population scale cohort with nearly half a million participants. Genotyping array identified the majority of PRKN mutations and at least 1 mutation in most biallelic PRKN mutation carriers in both cohorts. Additionally, in the NIH PD cohort, functional assays of patient fibroblasts resolved variants of unclear significance in biallelic carriers and ruled out cryptic loss of function variants in monoallelic carriers. In the UK Biobank, we identified 2,692 PRKN CNVs from genotyping array data from nearly half a million participants (the largest collection to date). Deletions or duplications involving exons 2 accounted for roughly half of all CNVs and the vast majority (88%) involved exons 2, 3, or 4. Combining estimates from whole exome sequencing (from ~200,000 participants) and genotyping array data, we found a pathogenic PRKN mutation in 1.8% of participants and 2 mutations in ~1/7,800 participants. Those with 1 PRKN pathogenic variant were as likely as non-carriers to have PD (OR = 0.91, CI= 0.58 – 1.38, p-value = 0.76) or a parent with PD (OR = 1.12, CI = 0.94 – 1.31, p-value = 0.19). Together our results demonstrate that heterozygous pathogenic PRKN mutations are common in the population but do not increase the risk of PD. Additionally, they suggest a cost-effective framework to screen for biallelic PRKN patients at the population scale for targeted studies.

Background Deep brain stimulation (DBS) is a well-established treatment option for select patients with Parkinson’s Disease (PD). However, response to DBS varies, therefore, the ability to predict who will have better outcomes can aid patient selection. Some PD-related monogenic mutations have been reported among factors that influence response to DBS. However, monogenic disease accounts for only a minority of patients with PD. The polygenic risk score (PRS) is an indication of cumulative genetic risk for disease. The PRS in PD has also been correlated with age of onset and symptom progression, but it is unknown whether correlations exist between PRS and DBS response. Here, we performed a pilot study to look for any such correlation. Methods We performed a retrospective analysis of 33 PD patients from the NIH PD Clinic and 13 patients from the Parkinson’s Progression Markers Initiative database who had genetic testing and underwent bilateral subthalamic nucleus DBS surgery and clinical follow-up. A PD-specific PRS was calculated for all 46 patients based on the 90 susceptibility variants identified in the latest PD genome-wide association study. We tested associations between PRS and pre- and post-surgery motor and cognitive measures using multiple regression analysis for up to two years after surgery. Results Changes in scores on the Beck Depression Inventory (BDI) were not correlated with PRS when derived from all susceptibility variants, however, when removing pathogenic and high-risk carriers from the calculation, higher PRS was significantly associated with greater reduction in BDI score at 3 months and with similar trend 24 months after DBS. PRS was not a significant predictor of Unified Parkinson’s Disease Rating Scale, Dementia Rating Scale, or phenomic and semantic fluency outcomes at 3- and 24-months after DBS surgery. Conclusions This exploratory study suggests that PRS may predict degree of improvement in depressive symptoms after DBS, though was not predictive of motor and other cognitive outcomes after DBS. Additionally, PRS may be most relevant in predicting DBS outcomes in patients lacking pathogenic or high-risk PD variants. However, this was a small preliminary study and response to DBS treatment is multifactorial, therefore, more standardized high-powered studies are needed.

Dual-degree MD-PhD programs have historically lacked diversity of race, ethnicity, gender, sexual orientation, and other facets of identity. Like MD- and PhD-granting programs, MD-PhD program training environments are also marked by structural barriers that negatively impact measurable academic outcomes of underrepresented and/or marginalized students in academic medicine (racial and ethnic minority groups considered underrepresented by the National Institute of Health, sexual and gender minorities, individuals with disabilities, and individuals of low socioeconomic status). In this article, we review the existing literature on MD-PhD program disparities affecting students from these groups and provide recommendations grounded on the reviewed evidence. Our literature review identified four generalizable barriers that can impact the training outcomes of students from these marginalized and/or underrepresented groups: 1) discrimination and bias, 2) impostor syndrome and stereotype threat, 3) lack of identity-similar mentors, and 4) suboptimal institutional policies and procedures. We propose goal-oriented interventions that may begin to ameliorate the disparities present in MD-PhD program training environments that affect students from marginalized and/or underrepresented groups in academic medicine.