Updated variant curation expert panel criteria and pathogenicity classifications for 251 variants for RYR1-related malignant hyperthermia susceptibility.

The ClinGen malignant hyperthermia susceptibility (MHS) variant curation expert panel specified the American College of Medical Genetics and Genomics/Association of Molecular Pathologists (ACMG/AMP) criteria for RYR1-related MHS and a pilot analysis of 84 variants was published. We have now classified an additional 251 variants for RYR1-related MHS according to current ClinGen standards and updated the criteria where necessary. Criterion PS4 was modified such that individuals with multiple RYR1 variants classified as pathogenic (P), likely pathogenic (LP), or variant of uncertain significance (VUS) were not considered as providing evidence for pathogenicity. Criteria PS1 and PM5 were revised to consider LP variants at the same amino-acid residue as providing evidence for pathogenicity at reduced strength. Finally, PM1 was revised such that if PS1 or PM5 are used PM1, if applicable, should be downgraded to supporting. Of the 251 RYR1 variants, 42 were classified as P/LP, 16 as B/LB, and 193 as VUS. The primary driver of 175 VUS classifications was insufficient evidence supporting pathogenicity, rather than evidence against pathogenicity. Functional data supporting PS3/BS3 was identified for only 13 variants. Based on the posterior probabilities of pathogenicity and variant frequencies in gnomAD, we estimated the prevalence of individuals with RYR1-related MHS pathogenic variants to be between 1/300 and 1/1075, considerably higher than current estimates. We have updated ACMG/AMP criteria for RYR1-related MHS and classified 251 variants. We suggest that prioritization of functional studies is needed to resolve the large number of VUS classifications and allow for appropriate risk assessment. RYR1-related MHS pathogenic variants are likely to be more common than currently appreciated.

Comparison of literature mining tools for variant classification: Through the lens of 50 RYR1 variants.

PURPOSE: The American College of Medical Genetics and Genomics and the Association for Molecular Pathology have outlined a schema that allows for systematic classification of variant pathogenicity. Although gnomAD is generally accepted as a reliable source of population frequency data and ClinGen has provided guidance on the utility of specific bioinformatic predictors, there is no consensus source for identifying publications relevant to a variant. Multiple tools are available to aid in the identification of relevant variant literature, including manually curated databases and literature search engines. We set out to determine the utility of 4 literature mining tools used for ascertainment to inform the discussion of the use of these tools. METHODS: Four literature mining tools including the Human Gene Mutation Database, Mastermind, ClinVar, and LitVar 2.0 were used to identify relevant variant literature for 50 RYR1 variants. Sensitivity and precision were determined for each tool. RESULTS: Sensitivity among the 4 tools ranged from 0.332 to 0.687. Precision ranged from 0.389 to 0.906. No single tool retrieved all relevant publications. CONCLUSION: At the current time, the use of multiple tools is necessary to completely identify the literature relevant to curate a variant.

Scoping review on the state of racial disparities literature in the treatment of neurosurgical disease: a call for action.

OBJECTIVE: Racial disparities are ubiquitous across medicine in the US. This study aims to assess the evidence of racial disparities within neurosurgery and across its subspecialties, with a specific goal of quantifying the distribution of articles devoted to either identifying, understanding, or reducing disparities. METHODS: The authors searched the MEDLINE, EMBASE, and Scopus databases by using keywords to represent the concepts of neurosurgery, patients, racial disparities, and specific study types. Two independent reviewers screened the article titles and abstracts for relevance. A third reviewer resolved conflicts. Data were then extracted from the included articles and each article was categorized into one of three phases: identifying, understanding, or reducing disparities. This review was conducted in accordance with the PRISMA Extension for Scoping Reviews (PRISMA-ScR) guidelines. RESULTS: Three hundred seventy-one studies published between 1985 and 2023 were included. The distribution of racial disparities literature was not equally spread among specialties, with spine representing approximately 48.3% of the literature, followed by tumor (22.1%) and general neurosurgery (12.9%). Most studies were dedicated to identifying racial disparities (83.6%). The proportion of literature devoted to understanding and reducing disparities was much lower (15.1% and 1.3%, respectively). Black patients were the most negatively impacted racial/ethnic group in the review (63.3%). The Hispanic or Latino ethnic group was the second most negatively impacted (25.1%). The following categories-other outcomes (28.0%), the offering of treatment (21.6%), complications (18.6%), and survival (16.7%)-represented the most frequently measured outcomes. CONCLUSIONS: Although strides have been taken to identify racial disparities within neurosurgery, fewer studies have focused on understanding and reducing these disparities. The tremendous rise of literature within this domain but the relative paucity of solutions necessitates the study of targeted interventions to provide equitable care for all patients undergoing neurosurgical treatment.

The ACMG SF v3.0 gene list increases returnable variant detection by 22% when compared with v2.0 in the ClinSeq cohort.

PURPOSE: The American College of Medical Genetics and Genomics (ACMG) recommends the return of pathogenic and likely pathogenic (P/LP) secondary findings from exome and genome sequencing. The latest version (ACMG secondary finding [SF] v3.0) includes 14 additional genes. We interrogated the ClinSeq cohort for variants in these genes to determine the additional yield in unselected individuals. METHODS: Exome data from 1473 individuals (60% White, 34% African American or Black, 6% other) were analyzed. We restricted our analyses to coding variants; +1,+2,-1, and -2 splice site variants; and the pathogenic GAA variant, NM_000152.5:c.-32-13T>G. Variants were assessed with slightly modified ACMG/Association of Molecular Pathology guidelines. RESULTS: A total of 25 P/LP variants were identified. In total, 7 individuals had P/LP variants in genes recommended for return of heterozygous variants, namely HNF1A (1), PALB2 (3), TMEM127 (1), and TTN (2). In total, 4 individuals had a homozygous variant in a gene recommended for biallelic variant return, namely HFE, NM_000410.3(HFE):c.845G>A p.Cys282Tyr. A total of 17 P/LP variants were identified in the heterozygous state in genes recommended only for biallelic variant reporting and were not returned. The frequency of returnable P/LP variants did not significantly differ by race. CONCLUSION: Using the ACMG SF v3.0, the returnable P/LP variant frequency increased in the ClinSeq cohort by 22%, from 3.4% (n = 50, ACMG SF v2.0) to 4.1% (n = 61, ACMG SF v3.0).

Positive Psychological Predictors of Psychological Health in Individuals with Parkinson's Disease.

Parkinson's Disease is associated with depression, anxiety, and stress; however, minimal research has examined positive psychological variables in this population. The present study investigated the relationship between positive psychological variables and psychological health in individuals with Parkinson's Disease. The sample included 140 adults with Parkinson's Disease who completed online surveys on self-compassion, optimism, posttraumatic growth, and psychological health outcomes. Participants reported moderate levels of self-compassion, optimism, and posttraumatic growth. Approximately 50% of participants reported depression and anxiety. Higher self-compassion was a significant predictor of lower depression, anxiety, and stress. Higher optimism was a significant predictor of lower depression and higher life satisfaction. Posttraumatic growth was not a predictor of psychological health. This research suggests that the psychological health of individuals with Parkinson's Disease can be improved, and self-compassion appears to be an important area of focus.

Patient values and preferences regarding prognostic counseling in isolated REM sleep behavior disorder.

STUDY OBJECTIVES: Isolated REM sleep behavior disorder (iRBD) carries a high lifetime risk for phenoconversion to a defined neurodegenerative disease (NDD) including Parkinson disease, dementia with Lewy bodies, and multiple system atrophy. We aimed to examine iRBD patient values and preferences regarding prognostic counseling. METHODS: One hundred thirteen iRBD patient participants enrolled in the Mayo Clinic iRBD Patient Registry were sent an email survey concerning their values and preferences concerning NDD prognostic counseling and their experiences following diagnosis with iRBD. RESULTS: Of 81 respondents (71.7% response rate), the majority were men (74.0%) with an average age of 65.7 (±9.7) years. Responses indicated a strong preference toward receiving prognostic information about possible future NDD development. 92.5% of respondents felt knowledge concerning personal NDD risk was important, while 87.6% indicated prognostic discussions were important to maintaining trust in their physician. 95.7% indicated a desire for more information, while only 4.3% desired less information regarding their NDD prognostic risk. Most respondents strongly agreed that prognostic information was important to discuss with their family and friends and inform future life planning, and most expressed interest in learning more about future neuroprotective therapies and symptomatic treatments for parkinsonism and dementia. CONCLUSIONS: Most iRBD patients indicated strong preferences for disclosure of NDD prognostic risk and indicated that prognostic information was important for family discussions and future life planning. Future broader surveys and qualitative studies of clinic-based and ultimately community dwelling iRBD patients' values and preferences are needed to guide appropriately tailored and individualized prognostic counseling approaches following iRBD diagnosis.

Interactions Between Opioids and Dextroamphetamine on Locomotor Activity: Influence of an Opioid's Relative Efficacy at the Mu Receptor.

Opioids and stimulants are often used in combination for both recreational and non-recreational purposes. High-efficacy mu opioid agonists generally increase the behavioral effects of stimulants, whereas opioid receptor antagonists generally attenuate the behavioral effects of stimulants; however, less is known regarding the interactions between stimulants and opioids possessing low to intermediate efficacy at the mu receptor. The purpose of this study was to examine the role of an opioid's relative efficacy at the mu receptor in altering the behavioral effects of dextro(d-)amphetamine. To this end, opioids possessing a range of relative efficacy at the mu receptor were examined alone and in combination with cumulative doses of d-amphetamine on a test of open-field, locomotor activity in male rats. Levorphanol, buprenorphine, butorphanol, nalbuphine, (-)-pentazocine, (-)-metazocine, (-)-cyclazocine, (-)-NANM, and nalorphine increased the locomotor effects of d-amphetamine in either an additive or greater-than-additive manner according to an effect-additive model. Only the selective, high-efficacy kappa agonist, spiradoline, and the non-selective opioid receptor antagonist, naloxone, failed to increase the effects of d-amphetamine under the conditions examined. These data indicate that opioids possessing a large range of relative efficacy at the mu receptor, including those possessing very low relative efficacy, significantly increase the locomotor effects of d-amphetamine.