GPNMB Biomarker Levels in GBA1 Carriers with Lewy Body Disorders.

BACKGROUND: The GPNMB single-nucleotide polymorphism rs199347 and GBA1 variants both associate with Lewy body disorder (LBD) risk. GPNMB encodes glycoprotein nonmetastatic melanoma protein B (GPNMB), a biomarker for GBA1-associated Gaucher's disease. OBJECTIVE: The aim of this study was to determine whether GPNMB levels (1) differ in LBD with and without GBA1 variants and (2) associate with rs199347 genotype. METHODS: We quantified GPNMB levels in plasma and cerebrospinal fluid (CSF) from 124 individuals with LBD with one GBA1 variant (121 plasma, 14 CSF), 631 individuals with LBD without GBA1 variants (626 plasma, 41 CSF), 9 neurologically normal individuals with one GBA1 variant (plasma), and 2 individuals with two GBA1 variants (plasma). We tested for associations between GPNMB levels and rs199347 or GBA1 status. RESULTS: GPNMB levels associate with rs199347 genotype in plasma (P = 0.022) and CSF (P = 0.007), but not with GBA1 status. CONCLUSIONS: rs199347 is a protein quantitative trait locus for GPNMB. GPNMB levels are unaltered in individuals carrying one GBA1 variant. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Plasma MIA, CRP, and Albumin Predict Cognitive Decline in Parkinson's Disease.

OBJECTIVE: Using a multi-cohort, discovery-replication-validation design, we sought new plasma biomarkers that predict which individuals with Parkinson's disease (PD) will experience cognitive decline. METHODS: In 108 discovery cohort PD individuals and 83 replication cohort PD individuals, we measured 940 plasma proteins on an aptamer-based platform. Using proteins associated with subsequent cognitive decline in both cohorts, we trained a logistic regression model to predict which patients with PD showed fast (> = 1 point drop/year on Montreal Cognitive Assessment [MoCA]) versus slow (< 1 point drop/year on MoCA) cognitive decline in the discovery cohort, testing it in the replication cohort. We developed alternate assays for the top 3 proteins and confirmed their ability to predict cognitive decline - defined by change in MoCA or development of incident mild cognitive impairment (MCI) or dementia - in a validation cohort of 118 individuals with PD. We investigated the top plasma biomarker for causal influence by Mendelian randomization (MR). RESULTS: A model with only 3 proteins (melanoma inhibitory activity protein [MIA], C-reactive protein [CRP], and albumin) separated fast versus slow cognitive decline subgroups with an area under the curve (AUC) of 0.80 in the validation cohort. The individuals with PD in the validation cohort in the top quartile of risk for cognitive decline based on this model were 4.4 times more likely to develop incident MCI or dementia than those in the lowest quartile. Genotypes at MIA single nucleotide polymorphism (SNP) rs2233154 associated with MIA levels and cognitive decline, providing evidence for MIA's causal influence. CONCLUSIONS: An easily obtained plasma-based predictor identifies individuals with PD at risk for cognitive decline. MIA may participate causally in development of cognitive decline. ANN NEUROL 2022;92:255-269.

Genetic and phenotypic characterization of Parkinson's disease at the clinic-wide level.

Observational studies in Parkinson's disease (PD) deeply characterize relatively small numbers of participants. The Molecular Integration in Neurological Diagnosis Initiative seeks to characterize molecular and clinical features of every PD patient at the University of Pennsylvania (UPenn). The objectives of this study are to determine the feasibility of genetic characterization in PD and assess clinical features by sex and GBA1/LRRK2 status on a clinic-wide scale. All PD patients with clinical visits at the UPenn PD Center between 9/2018 and 12/2022 were eligible. Blood or saliva were collected, and a clinical questionnaire administered. Genotyping at 14 GBA1 and 8 LRRK2 variants was performed. PD symptoms were compared by sex and gene groups. 2063 patients were approached and 1,689 (82%) were enrolled, with 374 (18%) declining to participate. 608 (36%) females were enrolled, 159 (9%) carried a GBA1 variant, and 44 (3%) carried a LRRK2 variant. Compared with males, females across gene groups more frequently reported dystonia (53% vs 46%, p = 0.01) and anxiety (64% vs 55%, p < 0.01), but less frequently reported cognitive impairment (10% vs 49%, p < 0.01) and vivid dreaming (53% vs 60%, p = 0.01). GBA1 variant carriers more frequently reported anxiety (67% vs 57%, p = 0.04) and depression (62% vs 46%, p < 0.01) than non-carriers; LRRK2 variant carriers did not differ from non-carriers. We report feasibility for near-clinic-wide enrollment and characterization of individuals with PD during clinical visits at a high-volume academic center. Clinical symptoms differ by sex and GBA1, but not LRRK2, status.

GPNMB confers risk for Parkinson's disease through interaction with α-synuclein.

Many risk loci for Parkinson's disease (PD) have been identified by genome-wide association studies (GWASs), but target genes and mechanisms remain largely unknown. We linked the GWAS-derived chromosome 7 locus (sentinel single-nucleotide polymorphism rs199347) to GPNMB through colocalization analyses of expression quantitative trait locus and PD risk signals, confirmed by allele-specific expression studies in the human brain. In cells, glycoprotein nonmetastatic melanoma protein B (GPNMB) coimmunoprecipitated and colocalized with α-synuclein (aSyn). In induced pluripotent stem cell-derived neurons, loss of GPNMB resulted in loss of ability to internalize aSyn fibrils and develop aSyn pathology. In 731 PD and 59 control biosamples, GPNMB was elevated in PD plasma, associating with disease severity. Thus, GPNMB represents a PD risk gene with potential for biomarker development and therapeutic targeting.

The Resident-Run Minor Surgery Clinic: A Four-Year Analysis of Patient Outcomes, Satisfaction, and Resident Education.

OBJECTIVE: A resident-run minor surgery clinic was developed to increase resident procedural autonomy. We evaluated whether 1) there was a significant difference between complications and patient satisfaction when procedures were independently performed by surgical residents vs. a surgical attending and 2) if participation was associated with an increase in resident procedural confidence. DESIGN: Third year general surgery residents participated in a weekly procedure clinic from 2014-2018. Post-procedure complications and patient satisfaction were compared between patients operated on by residents vs. the staff surgeon. Residents were surveyed regarding their confidence in independently performing a variety of clinic-based patient care tasks. SETTING: Massachusetts General Hospital General in Boston, MA; an academic tertiary care general surgery residency program. PARTICIPANTS: Post-graduate year three general surgery residents that ran the clinic as part of a general surgery rotation. RESULTS: 1230 patients underwent 1592 procedures (612 in resident clinic, 980 in attending clinic). There was no significant difference in the 30-day complication rate between patients operated on by the resident vs. attending (2.5% vs. 1.9%, p = 0.49). 459 patient satisfaction surveys were administered with a 79.1% response rate. There was no significant difference in the overall quality of care rating between residents and the attending surgeon (87.5% top-box rating vs. 93.1%, p = 0.15). Twenty-one residents completed both a pre- and post-rotation survey (77.8% response rate). The proportion of residents indicating that they could independently perform a variety of patient care tasks significantly increased across the rotation (all p < 0.05). CONCLUSION: Mid-level general surgery residents can independently perform office-based procedures without detriment to safety or patient satisfaction. The resident-run procedure clinic serves as an environment for residents to grow in confidence in both technical and non-technical skills. Given the high rate at which patients provide resident feedback, future work may investigate how to best incorporate patient derived evaluations into resident assessment.

Whole Clinic Research Enrollment in Parkinson's Disease: The Molecular Integration in Neurological Diagnosis (MIND) Study.

BACKGROUND: Observational studies in Parkinson's disease (PD) have focused on relatively small numbers of research participants who are studied extensively. The Molecular Integration in Neurological Diagnosis Initiative at the University of Pennsylvania aims to characterize molecular and clinical features of PD in every patient in a large academic center. OBJECTIVE: To determine the feasibility and interest in a global-capture biomarker research protocol. Additionally, to describe the clinical characteristics and GBA and LRRK2 variant carrier status among participants. METHODS: All patients at UPenn with a clinical diagnosis of PD were eligible. Informed consent included options for access to the medical record, future recontact, and use of biosamples for additional studies. A blood sample and a completed questionnaire were obtained from participants. Targeted genotyping for four GBA and eight LRRK2 variants was performed, with plasma and DNA banked for future research. RESULTS: Between September 2018 and December 2019, 704 PD patients were approached for enrollment; 652 (92.6%) enrolled, 28 (3.97%) declined, and 24 (3.41%) did not meet eligibility criteria. Median age was 69 (IQR 63_75) years, disease duration was 5.41 (IQR 2.49_9.95) years, and 11.10%of the cohort was non-white. Disease risk-associated variants in GBA were identified in 39 participants (5.98%) and in LRRK2 in 16 participants (2.45%). CONCLUSIONS: We report the clinical and genetic characteristics of PD patients in an all-comers, global capture protocol from an academic center. Patient interest in participation and yield for identification of GBA and LRRK2 mutation carriers is high, demonstrating feasibility of PD clinic-wide molecular characterization.

A comparison of patient satisfaction when office-based procedures are performed by general surgery residents versus an attending surgeon.

BACKGROUND: Patient satisfaction is an increasingly important quality metric nationwide. The impact that surgical trainees have on patient-reported satisfaction when they perform operations independently, however, has not been studied. METHODS: We conducted a prospective study at a single academic institution from October 2016 to June 2017. An office-based, postprocedure survey was developed by adapting questions from the validated Consumer Assessment of Healthcare Providers and Systems Surgical Care Survey. Top-box scoring was used to determine satisfaction for categorical questions and a comparison of the means was used for overall quality ratings (scale 0-10). Patients indicated whether their operation was completed by an attending surgeon or a postgraduate year 3 general surgery resident. The primary outcome measured was patient satisfaction with overall quality of care. Individual questions were grouped by phase of care and composite scores were measured as a secondary outcome. RESULTS: The survey response rate was 87.4% (n = 195). There were no differences in patient demographics or the types of procedures performed by residents or an attending surgeon. Excision of a soft tissue mass (ie, lipoma) accounted for 89.2% of all procedures performed (n = 174). There were no differences between preprocedure (resident = 92.5% vs attending = 94.2%) or postprocedure (resident = 95.3% vs attending = 97.7%) composite scores. There was, however, a significant difference in periprocedure satisfaction (resident = 78.7% vs attending = 90.7%, P = .02). There was no difference in overall ratings of quality of care given by patients who had their procedure performed by residents (9.8 ± 0.5) versus an attending surgeon (9.9 ± 0.3, P = .15). Finally, on adjusted analysis, resident care did not independently impact the likelihood of a "best possible care" rating for overall quality of care (odds ratio 0.84 ± 0.27, confidence interval 0.45-1.57, P = .58). CONCLUSION: Patient satisfaction was very high when residents independently performed minor surgery operations in an office-based setting. Of note, there was no difference in satisfaction with overall quality of care compared with an attending surgeon. This study demonstrates that high resident operative autonomy and patient satisfaction are not mutually exclusive goals when postgraduate year 3 residents perform office-based outpatient procedures.

Do Not Blame the Resident: the Impact of Surgeon and Surgical Trainee Experience on the Occurrence of Intraoperative Adverse Events (iAEs) in Abdominal Surgery.

OBJECTIVE: Intraoperative adverse events (iAEs) are defined as inadvertent injuries that occur during an operation and are associated with increased mortality, morbidity, and health care costs. We sought to study the impact of attending surgeon experience as well as resident training level on the occurrence of iAEs. DESIGN: The institutional American College of Surgeons-National Surgical Quality Improvement Program and administrative databases for abdominal surgeries were linked and screened for iAEs using the International Classification of Diseases, Ninth Revision, Clinical Modification-based Patient Safety Indicator "accidental puncture/laceration." Each flagged record was systematically reviewed to confirm iAE occurrence and determine the number of years of independent practice of the attending surgeon and the postgraduate year (PGY) of the assisting resident at the time of the operation. The attending surgeon experience was divided into quartiles (<6 years, 6-13 years, 13-20 years, >20 years). The resident experience level was defined as Junior (PGY-1 to PGY-3) or Senior (PGY-4 or PGY-5). Univariate/bivariate then multivariable logistic regression analyses adjusting for patient demographics, comorbidities, and operation type and/or complexity (using RVUs as a proxy) were performed to assess the independent impact of resident and attending surgeon experience on the occurrence of iAEs. SETTING: A large tertiary care teaching hospital. PARTICIPANTS: Patients included in the 2007-2012 ACS-NSQIP that had an abdominal surgery performed by both an attending surgeon and a resident. RESULTS: A total of 7685 operations were included and iAEs were detected in 159 of them (2.1%). Junior residents participated in 1680 cases (21.9%), while senior residents were involved in 6005 (78.1%). The iAE rates for attending surgeons with <6, 6-13, 13-20, and >20 years of experience were 2.7%, 1.7%, 2.4%, and 1.4%, respectively. In multivariable analyses, the risk of occurrence of an iAE was significantly decreased for surgeons with >20 years of experience compared to those with <6 years of experience (odds ratio=0.52, 95% confidence interval 0.32-0.86, p = 0.011). On bivariate analyses, iAEs occurred in 1.2% of junior resident cases, while senior residents had an iAE rate of 2.3%. However, after risk adjustment on multivariable analyses, the resident experience level did not significantly impact the rate of iAEs. CONCLUSIONS: The surgeon's level of experience, but not the resident's, is associated with the occurrence of iAEs in abdominal surgery. Efforts to improve patient safety in surgery should explore the value of pairing junior surgeons with the more experienced ones thru formalized coaching programs, rather than focus on curbing resident operative autonomy.