Developing a scoring system for gene curation prioritization in lysosomal diseases.

INTRODUCTION: Diseases caused by lysosomal dysfunction often exhibit multisystemic involvement, resulting in substantial morbidity and mortality. Ensuring accurate diagnoses for individuals with lysosomal diseases (LD) is of great importance, especially with the increasing prominence of genetic testing as a primary diagnostic method. As the list of genes associated with LD continues to expand due to the use of more comprehensive tests such as exome and genome sequencing, it is imperative to understand the clinical validity of the genes, as well as identify appropriate genes for inclusion in multi-gene testing and sequencing panels. The Clinical Genome Resource (ClinGen) works to determine the clinical importance of genes and variants to support precision medicine. As part of this work, ClinGen has developed a semi-quantitative framework to assess the strength of evidence for the role of a gene in a disease. Given the diversity in gene composition across LD panels offered by various laboratories and the evolving comprehension of genetic variants affecting secondary lysosomal functions, we developed a scoring system to define LD (Lysosomal Disease Scoring System - LDSS). This system sought to aid in the prioritization of genes for clinical validity curation and assess their suitability for LD-targeted sequencing panels. METHODS: Through literature review encompassing terms associated with both classically designated LD and LFRD, we identified 14 criteria grouped into "Overall Definition," "Phenotype," and "Pathophysiology." These criteria included concepts such as the "accumulation of undigested or partially digested macromolecules within the lysosome" and being "associated with a wide spectrum of clinical manifestations impacting multiple organs and systems." The criteria, along with their respective weighted values, underwent refinement through expert panel evaluation differentiating them between "major" and "minor" criteria. Subsequently, the LDSS underwent validation on 12 widely acknowledged LD and was later tested by applying these criteria to the Lysosomal Disease Network's (LDN) official Gene List. RESULTS: The final LDSS comprised 4 major criteria and 10 minor criteria, with a cutoff of 2 major or 1 major and 3 minor criteria established to define LD. Interestingly, when applied to both the LDN list and a comprehensive gene list encompassing genes included in clinical panels and published as LFRD genes, we identified four genes (GRN, SLC29A3, CLN7 and VPS33A) absent from the LDN list, that were deemed associated with LD. Conversely, a subset of non-classic genes included in the LDN list, such as MTOR, OCRL, and SLC9A6, received lower LDSS scores for their associated disease entities. While these genes may not be suitable for inclusion in clinical LD multi-gene panels, they could be considered for inclusion on other, non-LD gene panels. DISCUSSION: The LDSS offers a systematic approach to prioritize genes for clinical validity assessment. By identifying genes with high scores on the LDSS, this method enhanced the efficiency of gene curation by the ClinGen LD GCEP. CONCLUSION: The LDSS not only serves as a tool for gene prioritization prior to clinical validity curation, but also contributes to the ongoing discussion on the definition of LD. Moreover, the LDSS provides a flexible framework adaptable to future discoveries, ensuring its relevance in the ever-expanding landscape of LD research.

Assessment of genes involved in lysosomal diseases using the ClinGen Clinical Validity framework.

Lysosomal diseases (LDs) are a heterogeneous group of rare genetic disorders that result in impaired lysosomal function, leading to progressive multiorgan system dysfunction. Accurate diagnosis is paramount to initiating targeted therapies early in the disease process in addition to providing prognostic information and appropriate support for families. In recent years, genomic sequencing technologies have become the first-line approach in the diagnosis of LDs. Understanding the clinical validity of the role of a gene in a disease is critical for the development of genomic technologies, such as which genes to include on next generation sequencing panels, and the interpretation of results from exome and genome sequencing. To this aim, the ClinGen Lysosomal Diseases Gene Curation Expert Panel utilized a semi-quantitative framework incorporating genetic and experimental evidence to assess the clinical validity of the 56 LD-associated genes on the Lysosomal Disease Network's list. Here, we describe the results, and the key themes and challenges encountered.

Expert panel curation of 31 genes in relation to limb girdle muscular dystrophy.

OBJECTIVE: Limb girdle muscular dystrophies (LGMDs) are a group of genetically heterogeneous autosomal conditions with some degree of phenotypic homogeneity. LGMD is defined as having onset >2 years of age with progressive proximal weakness, elevated serum creatine kinase levels and dystrophic features on muscle biopsy. Advances in massively parallel sequencing have led to a surge in genes linked to LGMD. METHODS: The ClinGen Muscular Dystrophies and Myopathies gene curation expert panel (MDM GCEP, formerly Limb Girdle Muscular Dystrophy GCEP) convened to evaluate the strength of evidence supporting gene-disease relationships (GDR) using the ClinGen gene-disease clinical validity framework to evaluate 31 genes implicated in LGMD. RESULTS: The GDR was exclusively LGMD for 17 genes, whereas an additional 14 genes were related to a broader phenotype encompassing congenital weakness. Four genes (CAPN3, COL6A1, COL6A2, and COL6A3) were split into two separate disease entities, based on each displaying both dominant and recessive inheritance patterns, resulting in curation of 35 GDRs. Of these, 30 (86%) were classified as definitive, 4 (11%) as moderate, and 1 (3%) as limited. Two genes, POMGNT1 and DAG1, though definitively related to myopathy, currently have insufficient evidence to support a relationship specifically with LGMD. INTERPRETATION: The expert-reviewed assertions on the clinical validity of genes implicated in LGMDs form an invaluable resource for clinicians and molecular geneticists. We encourage the global neuromuscular community to publish case-level data that help clarify disputed or novel LGMD associations.

Neighborhood Deprivation and Treatment Challenges in Pediatric Musculoskeletal Infections: A Socioeconomic Analysis.

Introduction Musculoskeletal (MSK) infections are prevalent in the pediatric population, with previous research highlighting the significant impact of socioeconomic status (SES) on treatment outcomes. However, the specific link in pediatric cohorts remains poorly understood. The Area Deprivation Index (ADI), a measure of neighborhood-level disadvantage, serves as a crucial marker for SES. This study aims to investigate how ADI influences disease characteristics, treatment delays, and outcomes in pediatric patients with MSK infections. Methods A single-center retrospective cohort analysis was conducted using patient charts from a large urban pediatric hospital over six years from 2017 to 2022. Patients aged 0-18 years with diagnoses of osteomyelitis, septic arthritis, cellulitis, or pyomyositis were identified using the International Classification of Diseases - 10th Revision (ICD-10) codes. Data collection included demographics, disease characteristics, treatment delay intervals, and complications. Patient zip codes were obtained and entered into the Neighborhood Atlas® mapping website to determine their ADI. Patients were then stratified into four groups based on ADI scores: 1-10, 11-20, 21-40, and 41-100. Statistical analysis included the use of the Mann-Whitney U test for continuous data and the Chi-square/Fisher's exact test for binary and categorical data comparisons among the ADI groups. Results A total of 121 patients were included. Categorization based on ADI revealed 25 (20.7%) patients in the 1-10 ADI percentile group, 36 (29.8%) in the 11-20 group, 38 (31.4%) in the 21-40 group, and 22 (18.2%) in the 41-100 group. There were no significant differences between ADI and patient demographics, disease characteristics, presentation delay interval, treatment received, and complications. Conclusion The study demonstrates that there was no significant difference between ADI groups regarding demographics, disease characteristics, presentation delay interval, treatment received, and complications in pediatric populations. Despite the lack of evidence for differences in MSK infections attributable to ADI, this does not negate the potential existence of such a relationship.

Expert Panel Curation of 31 Genes in Relation to Limb Girdle Muscular Dystrophy.

Introduction: Limb girdle muscular dystrophies (LGMDs) are a group of genetically heterogeneous autosomal conditions with some degree of phenotypic homogeneity. LGMD is defined as having onset >2 years of age with progressive proximal weakness, elevated serum creatine kinase levels and dystrophic features on muscle biopsy. Advances in massively parallel sequencing have led to a surge in genes linked to LGMD. Methods: The ClinGen Muscular Dystrophies and Myopathies gene curation expert panel (MDM GCEP, formerly Limb Girdle Muscular Dystrophy GCEP) convened to evaluate the strength of evidence supporting gene-disease relationships (GDR) using the ClinGen gene-disease clinical validity framework to evaluate 31 genes implicated in LGMD. Results: The GDR was exclusively LGMD for 17 genes, whereas an additional 14 genes were related to a broader phenotype encompassing congenital weakness. Four genes (CAPN3, COL6A1, COL6A2, COL6A3) were split into two separate disease entities, based on each displaying both dominant and recessive inheritance patterns, resulting in curation of 35 GDRs. Of these, 30 (86%) were classified as Definitive, 4 (11%) as Moderate and 1 (3%) as Limited. Two genes, POMGNT1 and DAG1, though definitively related to myopathy, currently have insufficient evidence to support a relationship specifically with LGMD. Conclusions: The expert-reviewed assertions on the clinical validity of genes implicated in LGMDs form an invaluable resource for clinicians and molecular geneticists. We encourage the global neuromuscular community to publish case-level data that help clarify disputed or novel LGMD associations.

Evaluating the clinical validity of genes related to hemostasis and thrombosis using the Clinical Genome Resource gene curation framework.

BACKGROUND: Inherited bleeding, thrombotic, and platelet disorders (BTPDs) are a heterogeneous set of diseases, many of which are very rare globally. Over the past 5 decades, the genetic basis of some of these disorders has been identified, and recently, high-throughput sequencing has become the primary means of identifying disease-causing genetic variants. OBJECTIVES: Knowledge of the clinical validity of a gene-disease relationship is essential to provide an accurate diagnosis based on results of diagnostic gene panel tests and inform the construction of such panels. The Scientific and Standardization Committee for Genetics in Thrombosis and Hemostasis undertook a curation process for selecting 96 TIER1 genes for BTPDs. The purpose of the process was to evaluate the evidence supporting each gene-disease relationship and provide an expert-reviewed classification for the clinical validity of genes associated with BTPDs. METHODS: The Clinical Genome Resource (ClinGen) Hemostasis/Thrombosis Gene Curation Expert Panel assessed the strength of evidence for TIER1 genes using the semiquantitative ClinGen gene-disease clinical validity framework. ClinGen Lumping and Splitting guidelines were used to determine the appropriate disease entity or entities for each gene, and 101 gene-disease relationships were identified for curation. RESULTS: The final outcome included 68 Definitive (67%), 26 Moderate (26%), and 7 Limited (7%) classifications. The summary of each curation is available on the ClinGen website. CONCLUSION: Expert-reviewed assignment of gene-disease relationships by the ClinGen Hemostasis/Thrombosis Gene Curation Expert Panel facilitates accurate molecular diagnoses of BTPDs by clinicians and diagnostic laboratories. These curation efforts can allow genetic testing to focus on genes with a validated role in disease.

Excitatory and Inhibitory Descending Commissural Interneurons Differentially Integrate Supraspinal and Segmental Sensory Signals.

The limited information about how descending inputs from the brain and sensory inputs from the periphery use spinal cord interneurons (INs) is a major barrier to understanding how these inputs may contribute to motor functions under normal and pathologic conditions. Commissural interneurons (CINs) are a heterogeneous population of spinal INs that has been implicated in crossed motor responses and bilateral motor coordination (ability to use the right and left side of the body in a coordinated manner) and, therefore, are likely involved in many types of movement (e.g., dynamic posture stabilization, jumping, kicking, walking). In this study, we incorporate mouse genetics, anatomy, electrophysiology, and single-cell calcium imaging to investigate how a subset of CINs, those with descending axons called dCINs, are recruited by descending reticulospinal and segmental sensory signals independently and in combination. We focus on two groups of dCINs set apart by their principal neurotransmitter (glutamate and GABA) and identified as VGluT2+ dCINs and GAD2+ dCINs. We show that VGluT2+ and GAD2+ dCINs are both extensively recruited by reticulospinal and sensory input alone but that VGluT2+ and GAD2+ dCINs integrate these inputs differently. Critically, we find that when recruitment depends on the combined action of reticulospinal and sensory inputs (subthreshold inputs), VGluT2+ dCINs, but not GAD2+ dCINs, are recruited. This difference in the integrative capacity of VGluT2+ and GAD2+ dCINs represents a circuit mechanism that the reticulospinal and segmental sensory systems may avail themselves of to regulate motor behaviors both normally and after injury.SIGNIFICANCE STATEMENT The way supraspinal and peripheral sensory inputs use spinal cord interneurons is fundamental to defining how motor functions are supported both in health and disease. This study, which focuses on dCINs, a heterogeneous population of spinal interneurons critical for crossed motor responses and bilateral motor coordination, shows that both glutamatergic (excitatory) and GABAergic (inhibitory) dCINs can be recruited by supraspinal (reticulospinal) or peripheral sensory inputs. Additionally, the study demonstrates that in conditions where the recruitment of dCINs depends on the combined action of reticulospinal and sensory inputs, only excitatory dCINs are recruited. The study uncovers a circuit mechanism that the reticulospinal and segmental sensory systems may avail themselves of to regulate motor behaviors both normally and after injury.

Evaluating the strength of evidence for genes implicated in peroxisomal disorders using the ClinGen clinical validity framework and providing updates to the peroxisomal disease nomenclature.

Peroxisomal disorders are heterogeneous in nature, with phenotypic overlap that is indistinguishable without molecular testing. Newborn screening and gene sequencing for a panel of genes implicated in peroxisomal diseases are critical tools for the early and accurate detection of these disorders. It is therefore essential to evaluate the clinical validity of the genes included in sequencing panels for peroxisomal disorders. The Peroxisomal Gene Curation Expert Panel (GCEP) assessed genes frequently included on clinical peroxisomal testing panels using the Clinical Genome Resource (ClinGen) gene-disease validity curation framework and classified gene-disease relationships as Definitive, Strong, Moderate, Limited, Disputed, Refuted, or No Known Disease Relationship. Subsequent to gene curation, the GCEP made recommendations to update the disease nomenclature and ontology in the Monarch Disease Ontology (Mondo) database. Thirty-six genes were assessed for the strength of evidence supporting their role in peroxisomal disease, leading to 36 gene-disease relationships, after two genes were removed for their lack of a role in peroxisomal disease and two genes were curated for two different disease entities each. Of these, 23 were classified as Definitive (64%), one as Strong (3%), eight as Moderate (23%), two as Limited (5%), and two as No known disease relationship (5%). No contradictory evidence was found to classify any relationships as Disputed or Refuted. The gene-disease relationship curations are publicly available on the ClinGen website (https://clinicalgenome.org/affiliation/40049/). The changes to peroxisomal disease nomenclature are displayed on the Mondo website (http://purl.obolibrary.org/obo/MONDO_0019053). The Peroxisomal GCEP-curated gene-disease relationships will inform clinical and laboratory diagnostics and enhance molecular testing and reporting. As new data will emerge, the gene-disease classifications asserted by the Peroxisomal GCEP will be re-evaluated periodically.

A prospective cohort study of assisted bladder emptying following primary cloacal repair: The Children's National experience.

INTRODUCTION/BACKGROUND: Although the combination of bladder dysfunction and upper tract anomalies puts patient with cloaca at risk for renal disease, the rarity of this condition makes it difficult to study empirically. As a high-volume center, we uniquely capture bladder function outcomes following our growing number of cloacal repairs. OBJECTIVE: 1) Describe the rates of incomplete bladder emptying following primary cloacal repair (at 2-3 months after repair and last follow up), and 2) identify clinical factors associated with assisted bladder emptying. STUDY DESIGN: We performed a prospective cohort study of patients undergoing primary cloaca repair by our Children's National Colorectal Center team between 2020 and 2021. The primary outcome was assisted bladder emptying at 2-3 months postoperatively and last visit. Covariables included preoperative characteristics (cloacagram measurements), ARM complexity (moderate = common channel [CC] <3-cm, severe = CC ≥ 3-cm), vesicoureteral reflux (VUR) status, sacral ratio (good ≥0.7, intermediate 0.7-0.4, poor ≤0.4), spinal cord status, means of preoperative bladder emptying, and operative details (age at repair, repair type, & concomitant laparotomy). RESULTS: Eighteen participants were eligible. A majority had moderate cloaca (78%), VUR (67%), spinal cord abnormalities (89%), and good sacral ratios (56%). Preoperatively, 10 patients were diapered for urine and 8 had assisted bladder emptying. Surgical repairs were performed at a median age of 8 months (range 4-46). Nine (50%) patients underwent urogenital separation (UGS), eight (44%) total urogenital mobilization, and 1 (6%) perineal sparing posterior sagittal anorectoplasty with introitoplasty. Exploratory laparotomy was performed in 7 (39%) patients. At 2-3 months, 7 patients were voiding and 11 required assisted bladder emptying. Median length of long-term follow up was 12 months (range 5-25), and 8 patients were voiding and 10 required assisted bladder emptying. Postoperative need for assisted bladder emptying was significantly associated with assisted bladder emptying preoperatively, a shorter urethra and increasing common channel length, UGS and exploratory laparotomy. Spinal cord imaging findings were not associated. DISCUSSION: Bladder emptying following cloaca repair is likely a result of congenital function and surgical effects. Indeed, increasingly cloaca complexity requiring UGS and laparotomy was associated with both pre- and post-operative assisted bladder emptying. The lack of association with spinal cord imaging may reflect a divergence between anatomy and function. CONCLUSION: Approximately half of patients required assisted bladder emptying in this study. Associated factors included urethral and common channel length, the need for assisted bladder emptying preoperatively, the type of surgical approach and additional laparotomy. Being diapered with seemingly normal voiding prior to surgery did not guarantee normal bladder function postoperatively.

Validation of Neck Disability Index Severity among Patients Receiving One or Two-Level Anterior Cervical Surgery.

STUDY DESIGN: Retrospective cohort. PURPOSE: To evaluate the validity of established severity thresholds for Neck Disability Index (NDI) among patients undergoing anterior cervical discectomy and fusion (ACDF) or cervical disc arthroplasty (CDA). OVERVIEW OF LITERATURE: Few studies have examined the validity of established NDI threshold values among patients undergoing ACDF or CDA. METHODS: A surgical database was reviewed to identify patients undergoing cervical spine procedures. Demographics, operative characteristics, comorbidities, NDI, Visual Analog Scale (VAS), and 12-item Short Form (SF-12) physical and mental composite scores (PCS and MCS) were recorded. NDI severity was categorized using previously established threshold values. Improvement from preoperative scores at each postoperative timepoint and convergent validity of NDI was evaluated. Discriminant validity of NDI was evaluated against VAS neck and arm and SF-12 PCS and MCS. RESULTS: All 290 patients included in the study demonstrated significant improvements from baseline values for all patient-reported outcome measures (PROMs) at all postoperative timepoints (p<0.001) except SF-12 MCS at 2 years (p =0.393). NDI showed a moderate- to-strong correlation (r≥0.419) at most timepoints for VAS neck, VAS arm, SF-12 PCS, and SF-12 MCS (p<0.001, all). NDI severity categories demonstrated significant differences in mean VAS neck, VAS arm, SF-12 PCS, and SF-12 MCS at all timepoints (p<0.001, all). Differences between NDI severity groups were not uniform for all PROMs. VAS neck values demonstrated significant intergroup differences at most timepoints, whereas SF-12 MCS showed significantly different values between most severity groups. CONCLUSIONS: Neck disability is strongly correlated with neck and arm pain, physical function, and mental health and demonstrates worse outcomes with increasing severity. Previously established severity categories may be more applicable to pain than physical function or mental health and may be more uniformly applied preoperatively for cervical spine patients.

Acute kidney injury and early fluid load in a retrospective cohort of neonatal sepsis.

BACKGROUND: Sepsis and acute kidney injury (AKI) are associated with mortality in the newborn intensive care unit (NICU). There is a paucity of studies that describe AKI and fluid overload in neonatal sepsis and their association with mortality. METHODS: Retrospective study of neonates with culture positive sepsis admitted to the NICU between June 2020 and June 2021 was conducted. Primary outcome was in-hospital mortality according to AKI as defined by the neonatal modified Kidney Diseases Improving Outcomes criteria. Secondary outcomes were early fluid overload and vasopressor use. RESULTS: Thirty-three percent of neonates had AKI with sepsis, and 57% of cases were severe AKI. AKI was associated with mortality after adjusting for variables that were different between survivors and non-survivors (aOR 5.7 [95% CI 1.1-36], p = 0.04). Early fluid overload occurred in 27% of neonates who were at higher risk of having AKI with sepsis (OR 7.4 [95% CI 1.6-26.0], p = 0.01) and higher risk of mortality (aOR 17.8 [95% CI 2-7545], p = 0.02). CONCLUSIONS: AKI and early fluid overload are associated with mortality in sepsis in our retrospective cohort. Mitigating AKI and early fluid overload in sepsis might be a fruitful strategy in reducing mortality with sepsis. A higher resolution version of the Graphical abstract is available as Supplementary information.

Anterior Cervical Discectomy and Fusion Results in Clinically Significant Improvements in Patients With Preoperative Sleep Difficulties.

BACKGROUND: Individual items within the Patient Health Questionnaire-9 (PHQ-9) have not been assessed as predictors of postoperative outcomes. Our objective is to study the relationship between responses to individual PHQ-9 items and achievement of a minimum clinically important difference (MCID) following anterior cervical discectomy and fusion (ACDF). METHODS: A prospective surgical database was reviewed for primary, single-level ACDF procedures performed for degenerative spinal pathology. Patient demographics, preoperative spinal pathology, and perioperative characteristics were recorded. Patient-reported outcome measures (PROMs) including PHQ-9, visual analog scale (VAS) neck and arm, Neck Disability Index, 12-item Short Form physical component score (SF-12 PCS), and Patient-Reported Outcomes Measurement Information System Physical Function were administered at preoperative and 6-week, 12-week, 6-month, 1-year, and 2-year postoperative timepoints. MCID achievement was determined by comparing postoperative PROM improvement from baseline to previously established values. Logistic regression assessed responses to each individual question of the preoperative PHQ-9 as predictors of MCID achievement in each other PROMs. RESULTS: Sixty-six ACDF patients were included with a mean age of 47.2 years. Herniated nucleus pulposus was the most common preoperative spinal diagnosis (95.6%). The mean operative duration was 50.3 minutes, the mean estimated blood loss was 27.5 mL, and most patients were discharged on postoperative day 0 (81.8%). A majority of patients achieved MCID for all measures except SF-12 PCS. PHQ-9 question 3 significantly predicted MCID achievement for VAS neck (P = 0.045), VAS arm (P = 0.049), and SF-12 PCS (P = 0.037). No other PHQ-9 items or overall PHQ-9 scores significantly predicted MCID achievement. CONCLUSION: Question 3 of the PHQ-9 regarding "trouble falling asleep, staying asleep, or sleeping too much" significantly predicted clinically meaningful improvement in neck pain, arm pain, and physical function following ACDF, although overall PHQ-9 scores did not. Providers should inform patients experiencing significant sleep-related difficulties that they may be especially likely to benefit from ACDF surgery. CLINICAL RELEVANCE: Evaluation of sleep from the PHQ-9 predicts clinically relevant improvement in neck pain, arm pain, and physical function in patients undergoing ACDF.

Predicting Acute Changes in Depressive Symptoms Following Lumbar Decompression.

BACKGROUND: While depressive symptoms improve for most patients following minimally invasive lumbar decompression (MIS LD), for some, symptoms may worsen. This study aimed to investigate predictors of change in depressive symptoms in the short-term postoperative period following MIS LD. METHODS: We retrospectively analyzed a prospective surgical database for patients undergoing primary MIS LD procedures from 2016 to 2020. Preoperative pain (visual analog scale back and leg) scores were recorded, and the 9-Item Patient Health Questionnaire (PHQ-9) was administered at the preoperative and postoperative (6 weeks, 12 weeks, 6 months, and 1 year) timepoints. Patients were grouped into 1 of 3 categories of depression severity based on preoperative PHQ-9 scores: minimal (0-4), mild (5-9), and moderate to severe (10-27). Postoperative change in depressive symptoms was calculated by determining differences from baseline scores to scores at 6 weeks, 12 weeks, and 6 months. Analysis of demographics, perioperative characteristics, and spinal pathologies was conducted using χ 2 test. Significant factors contributing to postoperative changes in depression were analyzed using multiple linear regression analysis. Significance was set at P = 0.05. RESULTS: The 216 patients included had a mean age of 48 years, and a majority were men (70.4%). Most patients had a preoperative diagnosis of spinal stenosis (90.3%) or herniated nucleus pulposus (69.9%). Univariate analysis identified age, ethnicity, insurance, and diabetes as significant variables among depression severity groups. Patients demonstrated significant improvements in depressive symptoms at all postoperative timepoints (P < 0.001). Multivariate analysis identified several significant predictors of postoperative change in PHQ-9, which included moderate to severe preoperative depression for all postoperative timepoints (all P ≤ 0.038), mild preoperative depression for 6 weeks and 12 weeks (both P ≤ 0.029), and private insurance (P = 0.002) and smoking status (P = 0.047) at 12 weeks. CONCLUSION: Depression improved at all postoperative timepoints following LD. Insurance type, smoking status, and preoperative depression severity were all identified as significant predictors of postoperative changes in depressive symptoms. CLINICAL RELEVANCE: This study explores predictors of changes in depressive symptoms following LD.

Impact of Lower Extremity Arthroplasty on Improvement of Quality-of-Life Outcomes Following Lumbar Fusion.

BACKGROUND: Both hip-spine and knee-spine syndromes can significantly impact a patient's quality of life; however, few studies have investigated their effect on postoperative outcomes following lumbar fusion. OBJECTIVE: Our study aimed to evaluate the impact of a prior lower extremity arthroplasty on the improvement of patient-reported outcome measures (PROMs) following lumbar fusion surgery. METHODS: Patients undergoing primary, single, or multilevel lumbar interbody fusion were retrospectively reviewed. Patients missing preoperative PROMs were excluded. PROMs were collected preoperatively and postoperatively and included the Oswestry Disability Index (ODI), 12-Item Short Form Physical Component Summary, Patient-Reported Outcomes Measurement Information System Physical Function, and visual analog scale (VAS). A minimum clinically important difference (MCID) was calculated. Patients were categorized based on a history of hip/knee arthroplasty and propensity score matched. Intragroup improvement of PROM scores and intergroup differences in mean scores were evaluated using a paired t test and linear regression. MCID achievement differences were evaluated using logistic regression. RESULTS: A total of 335 patients were included, with 25 having a history of hip/knee arthroplasty. Arthroplasty patients were significantly older (P = 0.001) and typically had a higher Charlson Comorbidity Index (P ≤ 0.003, both). Patients differed in spinal pathology of degenerative spondylolisthesis (P = 0.049). Nonarthroplasty patients demonstrated significant improvements in all PROMs by 2 years (P < 0.001, all). The arthroplasty group demonstrated significant improvements in all PROMs by 1 year (P < 0.031, all). Preoperative VAS back was significantly worse for nonarthroplasty patients (P = 0.035). MCID achievement did not significantly differ between groups except at 6 months for ODI (P = 0.035). CONCLUSION: Following lumbar fusion, patients with a past surgical history did not demonstrate differences in outcome measures or MCID from those without. These results suggest that comorbid orthopedic conditions requiring surgery do not negatively impact the ability of patients to improve following lumbar fusion. CLINICAL RELEVANCE: Prior surgical history of lower extremity arthroplasty should not discourage the use of lumbar fusion when properly indicated, as patients reported clinical improvement regardless of history of hip or knee arthroplasty.

History of Prior Lumbar Surgery Does Not Impact Mental Health Outcomes Following Anterior Cervical Discectomy and Fusion.

STUDY DESIGN: This was a retrospective cohort study. OBJECTIVE: The objective of this study was to evaluate the impact of undergoing a prior lumbar procedure on mental health outcomes following anterior cervical discectomy and fusion. SUMMARY OF BACKGROUND DATA: Revision and reoperations are perceived as risk factors for worse mental health outcomes. METHODS: A retrospective review of a surgical database was performed for cervical and lumbar procedures. The mental health measures used were: Short Form 12-Item Mental Composite Score (SF-12 MCS) and Patient Health Questionnaire 9 (PHQ-9). Secondary outcomes of interest were Visual Analogue Scale for neck and arm pain, Neck Disability Index, and Short Form 12-Item Physical Composite Score (SF-12 PCS). All outcomes were collected preoperatively and at 6 weeks, 12 weeks, 6 months, and 1 year postoperatively. Minimum clinically important difference (MCID) was calculated using established values. Patients were grouped based on the surgical history of an elective lumbar spine procedure and propensity-matched. Differences in postoperative outcome scores and MCID achievement were evaluated using linear and logistic regression respectively. RESULTS: A total of 74 patients were included in this study. Mental health outcomes did not demonstrate significant differences between groups for SF-12 MCS and PHQ-9 for all time points except at 6 weeks for PHQ-9 ( P =0.038). MCID achievement was not significantly impacted by surgical history for all outcome measures at all postoperative time points (all P >0.050). The majority of patients achieved an MCID by the 1-year time point for all outcomes for patients without a prior lumbar surgery except for Visual Analogue Scale arm and SF-12 PCS, while those with a surgical history achieved an MCID for all outcomes except SF-12 PCS and PHQ-9. CONCLUSIONS: Anterior cervical discectomy and fusion patients with a past history of lumbar surgery demonstrated significant improvements in depression, neck and arm pain, disability, and physical function as those without a past lumbar surgical history. Prior surgery also did not impact MCID achievement for all outcomes.

Validation of Veterans RAND 12-Item Physical Function Survey in Minimally Invasive Transforaminal Lumbar Interbody Fusion.

BACKGROUND: Veterans RAND 12-item (VR-12) physical component score (PCS) has been validated in both veteran and US citizen populations; however, its use for spine surgery populations has not been evaluated. This study aims to correlate the VR-12 PCS survey with legacy patient-reported outcome measures (PROMs) in patients undergoing minimally invasive transforaminal lumbar interbody fusion (MIS TLIF). METHODS: A prospective surgical database was retrospectively assessed for MIS TLIFs performed at 1 level from March 2015 to June 2019. Inclusion criteria were elective procedures for degenerative spinal pathology. Patients were excluded if they had surgery for metastatic, traumatic, or infectious etiologies or had incomplete preoperative 12-item Short Form (SF-12) PCS or Patient-Reported Outcomes Measurement Information System physical function (PROMIS-PF) survey. Additionally, patients with any incomplete VR-12 PCS surveys through 1 year were excluded. Demographics and perioperative characteristics were recorded. Mean postoperative PROM scores and score difference from preoperative baseline were calculated at each postoperative timepoint through 1 year. The relationship of VR-12-PCS with SF-12-PCS and PROMIS PF was evaluated with a Pearson's correlation coefficient and time-independent partial correlation. RESULTS: A total of 59 patients underwent single-level MIS TLIFs. The cohort was 44.1% women with an average age of 53.8 years, and 52.5% were obese (body mass index ≥30 kg/m2). The VR-12 PCS, SF-12 PCS, and PROMIS PF surveys had significant improvements from baseline to the 6 month through 1 year postoperative timepoints (P ≤ 0.001, all). All timepoints revealed strong VR-12-PCS correlations with SF-12-PCS and PROMIS PF (all P ≤ 0.001). CONCLUSION: VR-12 PCS, SF-12 PCS, and PROMIS PF scores all indicate statistically significant improvements in physical function for patients following MIS TLIF. VR-12 PCS was strongly correlated with the historically validated SF-12 PCS system as well as with the more recent PROMIS PF survey. Our observations give weight to utilizing the VR-12 PCS survey as a valid measure of physical function among patients undergoing MIS TLIF. CLINICAL RELEVANCE: This study validates VR-12 PCS to measure physical function for TLIF patients.

Clinical validity assessment of genes frequently tested on intellectual disability/autism sequencing panels.

PURPOSE: Neurodevelopmental disorders (NDDs), such as intellectual disability (ID) and autism spectrum disorder (ASD), exhibit genetic and phenotypic heterogeneity, making them difficult to differentiate without a molecular diagnosis. The Clinical Genome Resource Intellectual Disability/Autism Gene Curation Expert Panel (GCEP) uses systematic curation to distinguish ID/ASD genes that are appropriate for clinical testing (ie, with substantial evidence supporting their relationship to disease) from those that are not. METHODS: Using the Clinical Genome Resource gene-disease validity curation framework, the ID/Autism GCEP classified genes frequently included on clinical ID/ASD testing panels as Definitive, Strong, Moderate, Limited, Disputed, Refuted, or No Known Disease Relationship. RESULTS: As of September 2021, 156 gene-disease pairs have been evaluated. Although most (75%) were determined to have definitive roles in NDDs, 22 (14%) genes evaluated had either Limited or Disputed evidence. Such genes are currently not recommended for use in clinical testing owing to the limited ability to assess the effect of identified variants. CONCLUSION: Our understanding of gene-disease relationships evolves over time; new relationships are discovered and previously-held conclusions may be questioned. Without periodic re-examination, inaccurate gene-disease claims may be perpetuated. The ID/Autism GCEP will continue to evaluate these claims to improve diagnosis and clinical care for NDDs.

Influence of Preoperative Depressive Burden on Achieving a Minimal Clinically Important Difference Following Lumbar Decompression.

STUDY DESIGN: This was a retrospective cohort study. OBJECTIVE: This study evaluates the association of preoperative mental health with the rate of achieving minimal clinically important difference (MCID) in patient-reported outcomes following lumbar decompression (LD). SUMMARY OF BACKGROUND DATA: Research is scarce regarding the influence of preoperative depression on the rate of achieving MCID for mental health, physical function, and pain among LD patients. METHODS: A surgical registry was retrospectively reviewed for primary LD surgeries. Patients were grouped by depressive symptom severity according to the preoperative Patient Health Questionnaire 9 score. The association of Patient Health Questionnaire 9 subgroups with demographic and surgical variables was analyzed, and differences among subgroups were assessed. Achievement rates of MCID for physical function, pain, disability, and mental health were compared among groups at each time point using previously established MCID thresholds. RESULTS: Of the 321 subjects, 69.8% were male, and 170 subjects had minimal preoperative depressive symptoms, 86 had moderate, and 65 had severe. Patients in moderate and severe groups demonstrated a significantly greater rate of MCID achievement for disability at 6 weeks and 3 months postoperatively. The severe group demonstrated a significantly higher rate of achieving MCID for mental health at the 1-year time point. CONCLUSIONS: Patients with any range of preoperative depressive symptom severity had a similar rate of achieving MCID for pain and physical function throughout 1 year following LD. The severe depressive symptom group had a higher rate of MCID achievement with disability at 6 weeks and with mental health at 1 year. This study demonstrates that patients with any preoperative depressive symptom severity have an indistinguishable ability to attain MCID by 1 year following LD. LEVEL OF EVIDENCE: Level III.

The Worldwide Influence of Social Media on Cervical Spine Literature.

BACKGROUND: The Altmetric (Digital Science, Holtzbrinck Publishing) Attention Score (AAS) is an automatically calculated score that accounts for other literary influences, which include academic sources as well as nonacademically focused social media outlets such as Twitter, Facebook, and news articles. This study compares the most popular cervical surgery articles on social media to the most cited articles within peer-reviewed literature and identifies journals that contribute the most articles and geographic trends. METHODS: We searched the Altmetric database for cervical spine surgery articles since inception using the search phrase "cervical" and "spine." We ranked journals that contributed the most articles and calculated their AAS, contributing social media outlets (eg, Twitter, Facebook, News, etc) and citation counts. We also ranked the top 100 most popular cervical spine articles on social media and compared them to the most cited articles. Countries were assessed based on their mentions through the most contributing social media platform. RESULTS: Of the 527 total journals identified in our search, the top 10 journals were responsible for contributing 60.2% of the total articles. The 3 journals that contributed the most articles were Spine (18.9%), European Spine Journal (11.8%), and The Spine Journal (10.3%). The journals with the highest AAS scores included Journal of Neurosurgery: Spine (11.3), Spine (8.8), and Journal of Manipulative & Physiological Therapeutics (5.8). Social media outlets that contributed the most mentions per article were Twitter (4.4), Facebook (0.5), and news sources (0.3). Among all countries contributing Twitter mentions, the 3 countries with the most cervical spine posts included the United States (23.3%), the United Kingdom (10.3%), and Spain (5.5%). CONCLUSION: Our evaluation of cervical spine literature revealed Twitter, Facebook, and news sources are the most common social media outlets influencing title dissemination. Journals contributing the most articles did not necessarily have the highest average AAS. CLINICAL RELEVANCE: Spinal surgeons should consider utilization of social media outlets, such as Twitter, Facebook, and news sources, to potentially increase the dissemination of their articles.

Epidemiological Relevance of Elevated Preoperative Patient Health Questionnaire-9 Scores on Clinical Improvement Following Lumbar Decompression.

BACKGROUND: Limited research exists regarding the influence of preoperative depression on postoperative mental health, physical function, and pain in lumbar decompression (LD) patients. This study aims to evaluate the association of depressive symptoms as measured by the Patient Health Questionnaire-9 (PHQ-9) with other mental health and physical function clinical outcomes among patients undergoing LD. METHODS: A prospectively maintained surgical registry was reviewed for primary LD from March 2016 to May 2019. Patients were stratified into 3 preoperative PHQ-9 score subgroups. Higher PHQ-9 scores indicated greater depressive symptoms. We assessed demographic and perioperative characteristics among subgroups with appropriate statistical testing. We also evaluated outcome instruments and postoperative improvement for the following outcomes: PHQ-9, Short Form 12 (SF-12), Veterans RAND 12-Item (VR-12), Patient-Reported Outcomes Measurement Information System Physical Function (PROMIS-PF), visual analog scale (VAS) leg, and VAS back. RESULTS: The 351-subject cohort was 70.4% men with an average age of 47 years; 186 subjects had minimal preoperative depressive symptoms (PHQ-9 <5), 94 had moderate (5≤ PHQ-9 ≤10), and 71 had severe (PHQ-9 >10). Subgroups with more severe symptoms of depression had worse mental health outcome scores (PHQ-9, 12-Mental Health Composite Score [12-MCS], and VR-12-MCS) and a positive linear association with greater pre- to postoperative mental health improvements at all timepoints. Subgroups with more severe symptoms of depression had worse PROMIS-PF scores at all timepoints, though VAS pain scores had no depression symptom association by 1 year. CONCLUSION: Patients with more severe preoperative depressive symptoms, as evaluated by PHQ-9, have a greater improvement in PHQ-9, SF-12, and VR-12 scores, but more severe PHQ-9 scores are associated with worse overall physical function scores. This study demonstrates the relevance of preoperative depressive symptoms and their necessity in future risk factor models. CLINICAL RELEVANCE: Severity of preoperative PHQ-9 acts as a significant risk factor to postoperative pain and mental and physical health improvement.