Evaluation of Image-Defined Risk Factor (IDRF) Assessment in Patients With Intermediate-risk Neuroblastoma: A Report From the Children's Oncology Group Study ANBL0531.

BACKGROUND: The International Neuroblastoma Risk Group (INRG) classifier utilizes a staging system based on pretreatment imaging criteria in which image-defined risk factors (IDRFs) are used to evaluate the extent of locoregional disease. Children's Oncology Group (COG) study ANBL0531 prospectively examined institutional determination of IDRF status and compared that to a standardized central review. METHODS: Between 9/2009-6/2011, patients with intermediate-risk neuroblastoma were enrolled on ANBL0531 and had IDRF assessment at treating institutions. Paired COG pediatric surgeons and radiologists performed blinded central review of diagnostic imaging for the presence or absence of IDRFs. Second blinded review was performed in cases of discordance. Comparison of local and central review was performed using the Kappa coefficient to determine concordance in IDRF assessment. RESULTS: 211 patients enrolled in ANBL0531 underwent IDRF assessment; 3 patients were excluded due to poor image quality. Central reviewer pairs agreed on the presence or absence of any IDRF in 170/208 (81.7%; κ = 0.48) cases. Thirteen (6.3%) cases could not be adjudicated after second blinded review. Radiologists were more likely to identify IRDFs as present than surgeons (p < 0.001). Local and central reviewers agreed on the presence or absence of any IDRF in only108/208 (51.9%; κ = 0.06) cases. CONCLUSIONS: Among experienced pediatric surgeons and radiologists participating in central review, concordance was moderate, with agreement in 81.7% of cases. On comparison of local and central assessment of IDRFs, concordance was poor. These data indicate that greater standardization, education, technology, and training are needed to improve the assessment of IDRFs in children with neuroblastoma. LEVEL OF EVIDENCE: Treatment Study, Level III.

Pain Phenotypes and Pain Multimorbidity Among Medicare Beneficiaries With Cerebral Palsy.

This cohort study assesses the association of pain phenotypes and pain multimorbidity with cerebral palsy subtypes among Medicare beneficiaries.

Long-term follow-up of patients with intermediate-risk neuroblastoma treated with response- and biology-based therapy: A report from the Children's Oncology Group study ANBL0531.

BACKGROUND: We previously reported excellent three-year overall survival (OS) for patients with newly diagnosed intermediate-risk neuroblastoma treated with a biology- and response-based algorithm on the Children's Oncology Group study ANBL0531. We now present the long-term follow-up results. METHODS: All patients who met the age, stage, and tumor biology criteria for intermediate-risk neuroblastoma were eligible. Treatment was based on prognostic biomarkers and overall response. Event-free survival (EFS) and OS were estimated by the Kaplan-Meier method. RESULTS: The 10-year EFS and OS for the entire study cohort (n = 404) were 82.0% (95% confidence interval (CI), 77.2%-86.9%) and 94.7% (95% CI, 91.8%-97.5%), respectively. International Neuroblastoma Staging System stage 4 patients (n = 133) had inferior OS compared with non-stage 4 patients (n = 271; 10-year OS: 90.8% [95% CI, 84.5%-97.0%] vs 96.6% [95% CI, 93.9%-99.4%], p = .02). Infants with stage 4 tumors with ≥1 unfavorable biological feature (n = 47) had inferior EFS compared with those with favorable biology (n = 61; 10-year EFS: 66.8% [95% CI, 50.4%-83.3%] vs 86.9% [95% CI, 76.0%-97.8%], p = .02); OS did not differ (10-year OS: 84.4% [95% CI, 71.8%-97.0%] vs 95.0% [95% CI, 87.7%-100.0%], p = .08). Inferior EFS but not OS was observed among patients with tumors with (n = 26) versus without (n = 314) 11q loss of heterozygosity (10-year EFS: 68.4% [95% CI, 44.5%-92.2%] vs 83.9% [95% CI, 78.7%-89.2%], p = .03; 10-year OS: 88.0% [95% CI, 72.0%-100.0%] vs 95.7% [95% CI, 92.8%-98.6%], p = .09). CONCLUSIONS: The ANBL0531 trial treatment algorithm resulted in excellent long-term survival. More effective treatments are needed for subsets of patients with unfavorable biology tumors.

Immunologic changes are detectable in the peripheral blood transcriptome of clinically asymptomatic Chagas cardiomyopathy patients.

Chagas disease, caused by the protozoan parasite Trypanosoma cruzi, is a neglected parasitic disease that affects approximately 6 million individuals worldwide. Of those infected, 20-30% will go on to develop chronic Chagas cardiomyopathy (CCC), and ultimately many of these individuals will progress to advanced heart failure. The mechanism by which this progression occurs is poorly understood, as few studies have focused on early CCC. In this study, we sought to understand the physiologic changes associated with T. cruzi infection and the development of CCC. We analyzed gene expression in the peripheral blood of asymptomatic Chagas patients with early structural heart disease, Chagas patients without any signs or symptoms of disease, and Chagas-negative patients with and without early structural heart disease. Our analysis shows that early CCC was associated with a downregulation of various peripheral immune response genes, with gene expression changes suggestive of reduced antigen presentation and T cell activation. Notably, these genes and processes were distinct from those of early cardiomyopathy in Chagas-negative patients, suggesting that the processes mediating CCC may be unique from those mediating progression to other cardiomyopathies. This work highlights the importance of the immune response in early CCC, providing insight into the early pathogenesis of this disease. The changes we have identified may serve as biomarkers of progression and could inform strategies for the treatment of CCC in its early stages, before significant cardiac damage has occurred.

Musculoskeletal Morbidity Among Adults Living With Spina Bifida and Cerebral Palsy.

Background: Individuals living with cerebral palsy (CP) or spina bifida (SB) are at heightened risk for chronic health conditions that may develop or be influenced by the impairment and/or the process of aging. Objectives: The objective of this study was to compare the incidence of and adjusted hazards for musculoskeletal (MSK) morbidities among adults living with and without CP or SB. Methods: A retrospective, longitudinal cohort study was conducted among adults living with (n = 15,302) CP or SB and without (n = 1,935,480) CP or SB. Incidence estimates of common MSK morbidities were compared at 4 years of enrollment. Survival models were used to quantify unadjusted and adjusted hazard ratios for incident MSK morbidities. The analyses were performed in 2019 to 2020. Results: Adults living with CP or SB had a higher 4-year incidence of any MSK morbidity (55.3% vs. 39.0%) as compared to adults without CP or SB, and differences were to a clinically meaningful extent. Fully adjusted survival models demonstrated that adults with CP or SB had a greater hazard for all MSK disorders; this ranged from hazard ratio (HR) 1.40 (95% CI, 1.33 to 1.48) for myalgia to HR 3.23 (95% CI, 3.09 to 3.38) for sarcopenia and weakness. Conclusion: Adults with CP or SB have a significantly higher incidence of and risk for common MSK morbidities as compared to adults without CP or SB. Efforts are needed to facilitate the development of improved clinical screening algorithms and early interventions to reduce risk of MSK disease onset/progression in these higher risk populations.

The paradoxical relationship between severity of cerebral palsy and renal function in middle-aged adults: better renal function or inappropriate clinical assessment?

PURPOSE: To determine the association between severity of cerebral palsy with serum creatinine (sCr) and sCr-based equations to estimate glomerular filtration rate (eGFR), a marker of renal function. METHODS: A clinic-based sample of 30-64 year-olds with cerebral palsy was examined and stratified by motor impairment: gross motor function classification system (GMFCS) I/II (n = 79), GMFCS III (n = 78), and GMFCS IV/V (n = 137). sCr, which is influenced by muscle mass, was obtained and sCr-based eGFR was calculated using the Modification of Diet in Renal Disease (MDRD) and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations. RESULTS: sCr was lower with increasing GMFCS. The opposite pattern was observed for eGFR: GMFCS IV/V had significantly higher eGFR derived from MDRD compared to other GMFCS groups; GMFCS III had significantly higher eGFR compared to GMFCS I/II. The pattern was similar for CKD-EPI derived eGFR. CONCLUSIONS: According to widely used clinical assessment methods for renal function, higher severity of cerebral palsy among adults is associated with better renal function, which is incongruent with their other biological systems. This paradoxical relationship is likely driven by lower muscle rather than true renal function, and thus, sCr-based eGFR may overestimate renal function, especially for GMFCS IV/V. Further prospective studies are needed.Implications for rehabilitationCommon methods of clinical assessment may over-estimate renal function for adults with cerebral palsy (CP), potentially giving a false positive for normal renal health due to their reliance on muscle mass.This study of a clinic-based sample of middle-aged adults with CP highlights the paradoxical relationship between severity of CP and renal function, which is likely driven by methodological limitations in the presence of low muscle mass rather than actual better renal function.It is recommended that clinicians have a high suspicion of abnormal renal function and the need for a nephrology consultation, especially with changes in creatinine levels, even within the normal range.Rehabilitation for adults with CP must have a strong focus on muscle and kidney health, especially for patients with more severe forms of CP.

Navigating the Pathway to Care in Adults With Cerebral Palsy.

As individuals with cerebral palsy (CP) age, they face unique challenges which complicate their ability to access and receive appropriate health care. These problems exist at the level of the health care system, the clinician, and the individual. At the system level, there is an inadequate number of professionals who are informed of and interested in the care of adults with CP. Pediatric clinicians prefer treating children, and adult caregivers are not knowledgeable about and may feel less competent about CP. Pediatric care does not translate well to the adult population, and information about best practices for adults is just starting to develop. Differences in the physiologic development of individuals with CP render well-established clinical protocols for risk screening of chronic diseases less effective. Moreover, lack of supportive resources decreases a caregiver's sense of self-efficacy in treating this population. The patient's ability to navigate these barriers is complicated by the high prevalence of comorbid cognitive impairment and mental health issues including anxiety, depression, and other psychiatric disorders; a bidirectional relationship between challenges in navigating care/needs and comorbid mental health conditions appears likely. Many patients have additional barriers related to social determinants of health, such as access to transportation, accessible health care facilities, and other personal and environmental factors that may impede health maintenance and wellness. Increasing and disseminating knowledge, harnessing the power of new technologies such as telemedicine, and addressing mental health issues are some of the methods that are available to help adults with CP navigate this road.

Shared Physiologic Pathways Among Comorbidities for Adults With Cerebral Palsy.

Objective: Aging with cerebral palsy is accompanied by a declining health and function status across neurological and non-neurological systems. There is a need to understand the shared pathophysiology among comorbidities for adults with cerebral palsy, to inform clinical assessment and guidelines for interventions to improve healthful aging. To begin defining multimorbidity, this study identified the most common comorbidity combinations and their association with mortality among a representative sample of adults with cerebral palsy. Methods: Data from 2016 to 2018 were used from a random 20% sample from the fee-for-service Medicare database. Adults ≥18 years with cerebral palsy and 25 neurological and non-neurological comorbidities were obtained from 2016. Principal component (PC) analysis identified the most common comorbidity combinations, defined as individual PCs. Cox regression estimated the hazard ratio (HR) of 2-year mortality including all PCs and demographics in a single model. To facilitate comparisons, PC scores were transformed into quintiles (reference: lowest quintile). Results: Among the 16,728 adults with cerebral palsy, the most common comorbidity combinations (PCs) in order were: cardiorespiratory diseases, dysphagia, and fluid/electrolyte disorders; metabolic disorders (e.g., diabetes, renal disease, hypertension); neurologic-related disorders (e.g., dementia, cerebrovascular disease); gastrointestinal issues; and orthopedic-related disorders. During the 2-year follow-up, 1,486 (8.9%) died. In the adjusted model, most PCs were associated with an elevated mortality rate, especially the first PC (5th quintile HR = 3.91; 95%CI = 3.29-4.65). Discussion: This study identified the most common comorbidity combinations for adults with cerebral palsy, many of them were deadly, which may inform on the underlying pathophysiology or shared characteristics of multimorbidity for this population.

Timecourse of Morbidity Onset Among Adults Living With Cerebral Palsy.

INTRODUCTION: Despite the greater risk of an array of morbidities, little is known about when morbidities occur for adults with cerebral palsy. The objective of this study is to determine the timecourse of morbidity risk/development for adults with cerebral palsy and the effect by patient-level factors. METHODS: Cross-sectional data from 2016 were used from a random 20% sample from the fee-for-service Medicare database. Diagnosis codes identified adults aged ≥18 years with cerebral palsy and 16 clinically relevant morbidities. Qualitative and quantitative approaches identified the age where each morbidity became exceedingly prevalent. The effect of the timecourse by sex, race, and co-occurring intellectual disabilities and epilepsy was examined. Data were sequestered and analyzed in 2020. RESULTS: Among 16,818 adults with cerebral palsy, the prevalence of most morbidities was already high among those aged 18-30 years, and all morbidities increased with age except liver disease and anxiety. Hypertension and diabetes exhibited a positive linear trend with age. Of the morbidities that did not exhibit a linear trend, the qualitative and quantitative approaches were consistent considering that the cardiorespiratory diseases, osteoarthritis, renal disease, and dementia became exceedingly more prevalent at age >50 years, whereas the threshold was >60 years for depression, cancer, and metastatic cancer. There were interactions with sex, race, and co-occurring intellectual disabilities and epilepsy for some of the morbidities. CONCLUSIONS: Morbidity prevalence is already elevated early in adulthood among individuals living with cerebral palsy, with an abrupt increase by age 50 years. Preventive efforts should be adopted early in the lifespan and not later than age 50 years for adults with cerebral palsy.

Corrigendum: Shared Physiologic Pathways Among Comorbidities for Adults With Cerebral Palsy.

[This corrects the article DOI: 10.3389/fneur.2021.742179.].

Polypharmacy is a risk factor for mortality, severe chronic kidney disease, and liver disease among privately insured adults with cerebral palsy.

BACKGROUND: Adults with cerebral palsy (CP) have an increased risk for polypharmacy, premature mortality, and early development of several morbidities, including conditions associated with excess medication exposure, such as chronic kidney disease (CKD) and liver disease. To date, very little is known about the consequence of polypharmacy for adults with CP. OBJECTIVE: To determine if polypharmacy is associated with an increased risk for mortality, severe CKD, and liver disease among adults with CP, before and after adjusting for comorbid neurodevelopmental disabilities (NDDs) and multimorbidity. METHODS: This is an exploratory treatment effectiveness study. Data from the Optum Clinformatics Data Mart were used for this retrospective cohort study. Adults aged 18 years or older with a diagnosis of CP and without severe CKD (stages IV+) and liver disease were identified from the calendar year 2013 and were subsequently followed from January 1, 2014, to death, severe CKD, liver disease, loss to follow-up, or end of study period (December 31, 2017). Diagnosis codes were used to identify NDDs (intellectual disabilities, epilepsy, autism spectrum disorders, spina bifida) and 24 relevant morbidities at baseline (i.e., calendar year 2013). Polypharmacy was defined as ≥ 5 medications and hyperpolypharmacy was defined as ≥ 10 medications at baseline. Cox regression models were developed to examine the association (as HR and 95% CI) between polypharmacy and hyperpolypharmacy with mortality, severe CKD, and liver disease separately, before and after adjusting for covariates (demographics, NDDs, multimorbidity). Exploratory analyses examined the mediating effect of incident severe CKD or liver disease on the association between the exposure (polypharmacy or hyperpolypharmacy) on outcomes. RESULTS: Of the 9,238 adults with CP, 58.5% had polypharmacy and 29.5% had hyperpolypharmacy. The fully adjusted HR for mortality was 2.14 (95% CI = 1.59-2.89) for polypharmacy and 1.65 (95% CI = 1.31-2.09) for hyperpolypharmacy. The fully adjusted HR for severe CKD was 1.66 (95% CI = 1.17-2.36) for polypharmacy and 1.67 (95% CI = 1.27-2.19) for hyperpolypharmacy. The fully adjusted HR for liver disease was 1.57 (95% CI = 1.27-1.94) for polypharmacy and 1.72 (95% CI = 1.42-2.08) for hyperpolypharmacy. Incident liver disease mediated 5.37% (polypharmacy) and 7.54% (hyperpolypharmacy) of the association between the exposure with incident severe CKD for nonelderly (aged < 65 years), while incident severe CKD mediated 7.05% (polypharmacy) and 6.64% (hyperpolypharmacy) of the association between the exposure with incident liver disease for elderly (aged ≥ 65 years). CONCLUSIONS: Polypharmacy and hyperpolypharmacy are robust risk factors for risk of mortality, severe CKD, and liver disease among privately insured adults with CP. While incidence of severe CKD and liver disease had negligible effects on the association between polypharmacy with mortality, there is evidence that they mediate a considerable portion of one another and require further examination. DISCLOSURES: During the work for this study, Whitney was supported by the University of Michigan Office of Health Equity and Inclusion Diversity Fund and American Academy for Cerebral Palsy and Developmental Medicine. The funding sources had no role in the design or conduct of the study; collection, management, analysis, or interpretation of the data; preparation, review, or approval of the manuscript; or the decision to submit the manuscript for publication. The authors have no conflicts of interest to report.

Advanced CKD Among Adults With Cerebral Palsy: Incidence and Risk Factors.

RATIONALE & OBJECTIVE: Recent evidence suggests that adults with cerebral palsy have an elevated risk for developing advanced chronic kidney disease (CKD). To develop effective interventions, the objective was to identify whether demographics and preexisting medical conditions are risk factors for advanced CKD among adults with cerebral palsy. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: Data were from the Optum Clinformatics Data Mart. Adults 18 years or older with cerebral palsy and without advanced CKD (CKD stage 4 or later) were identified from 2013 and subsequently followed up from January 1, 2014, to the development of advanced CKD, death, loss to follow-up, or end of the study period (December 31, 2017), whichever came first. Diagnostic, procedure, and diagnosis-related group codes were used to identify cerebral palsy, incident cases of advanced CKD, comorbid intellectual disability, and 10 preexisting medical conditions. EXPOSURES: Demographic variables and 10 preexisting medical conditions: CKD stages 1-3, hypertension, diabetes, heart and cerebrovascular disease, non-CKD urologic conditions, bowel conditions, respiratory disease, skeletal fragility, arthritis, and dysphagia. OUTCOME: Incidence of advanced CKD. ANALYTIC APPROACH: Crude incidence rate (IR) of advanced CKD and IR ratios with 95% CIs were estimated. Cox proportional hazards regression models that were adjusted for demographics, intellectual disability, and preexisting medical conditions were used to evaluate the adjusted independent effect of predictor variables. RESULTS: 237 of the 8,011 adults with cerebral palsy developed advanced CKD during follow-up (IR, 10.16/1,000 person years; 95% CI, 8.87-11.46). In the crude analysis, all preexisting medical conditions were associated with an elevated IR and IR ratio of advanced CKD. In the fully adjusted Cox proportional hazards regression model, the HR was elevated for older age, CKD stages 1-3 (HR, 3.32; 95% CI, 2.39-4.61), diabetes (HR, 2.69; 95% CI, 2.03-3.57), hypertension (HR, 1.54; 95% CI, .10-2.16), heart and cerebrovascular disease (HR, 1.53; 95% CI, 1.12-2.07), and non-CKD urologic conditions (HR, 1.39; 95% CI, 1.05-1.84). LIMITATIONS: Private insurance database, short follow-up period, and lack of laboratory values, such as albuminuria/proteinuria. CONCLUSIONS: Advanced CKD was common among adults with cerebral palsy and its development was associated with both traditional and nontraditional urologic risk factors.

Polypharmacy Among Privately Insured Adults with Cerebral Palsy: A Retrospective Cohort Study.

BACKGROUND: Adults with cerebral palsy (CP) have increased risk for developing various secondary chronic diseases, especially when they have other neurodevelopmental disabilities (NDDs). Multiple medications are likely prescribed to manage the greater morbidity-related burden for adults with CP; however, because health care delivery and care coordination is suboptimal for this population, adults with CP may have an increased risk for polypharmacy. To date, very little is known about the prescribing practices and extent of polypharmacy for adults with CP. OBJECTIVE: To determine the prevalence and adjusted odds of polypharmacy among adults with CP only and those with CP+NDDs, compared with adults without CP. METHODS: Data from 2017 Optum Clinformatics Data Mart, a U.S. private administrative database, was used for this retrospective cohort study. Diagnosis codes were used to identify adults (aged ≥ 18 years) with CP, NDDs (e.g., intellectual disabilities, epilepsy, and autism spectrum disorders), and 24 relevant morbidities. Polypharmacy was examined as 0-4 versus ≥ 5, 0-9 versus ≥ 10, and 0-14 versus ≥ 15 medications. Logistic regression estimated the OR and 95% CI of polypharmacy before and after adjusting for age, sex, region of residence, and multimorbidity (as 0, 1, 2, 3, 4-5, and ≥ 6 morbidities). Exploratory analyses were conducted to compare polypharmacy among young (18-40 years) and middle-aged (41-64 years) adults with CP only and CP + NDDs with elderly (≥ 65 years) adults without CP. RESULTS: Adults with CP only (n = 5,603) and CP + NDDs (n = 2,474) had higher unadjusted prevalence and adjusted OR for each polypharmacy definition compared with adults without CP (n = 9.0 million; e.g., ≥ 5 medications: adjusted OR for CP only = 1.38, 95% CI = 1.30-1.47; CP + NDDs: OR = 2.42, 95% CI = 2.20-2.67). Adults with CP+NDDs had higher unadjusted prevalence and adjusted OR of each polypharmacy definition compared with CP only. Compared with elderly without CP, the unadjusted prevalence of polypharmacy was lower for young adults with CP only (e.g., ≥ 5 medications: 60.2%, 43.8%), similar for young adults with CP+NDDs (e.g., ≥ 15 medications: 10.9%, 12.5%), and elevated for middle-aged CP only and CP + NDDs (e.g., ≥ 10 medications: 28.7%, 34.3%, 41.7%). CONCLUSIONS: Privately insured adults with CP only and CP + NDDs have an elevated prevalence of polypharmacy compared with adults without CP, even after accounting for multimorbidity. Importantly, adults aged 18-40 years with CP have a similar (CP + NDDs) prevalence of polypharmacy compared with the general geriatric population, with the prevalence increasing further for CP by middle age. DISCLOSURES: Whitney was supported by the University of Michigan Office of Health Equity and Inclusion Diversity Fund and the American Academy of Cerebral Palsy and Developmental Medicine. These funding sources had no role in the design or conduct of the study; collection, management, analysis, or interpretation of the data; preparation, review, or approval of the manuscript; or the decision to submit the manuscript for publication. The other authors have no conflicts of interest to disclose.

Cardiometabolic Morbidity in Adults With Cerebral Palsy and Spina Bifida.

PURPOSE: The purpose of this study was to compare the incidence of, and adjusted hazards for, cardiometabolic morbidities among adults with and without cerebral palsy or spina bifida. METHODS: Privately insured beneficiaries were included if they had an International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnostic code for cerebral palsy or spina bifida (n = 15,302). Adults without cerebral palsy or spina bifida were also included (n = 1,935,480). Incidence estimates of common cardiometabolic morbidities were compared at 4 years of enrollment. Survival models were used to quantify unadjusted and adjusted hazard ratios (HRs) for incident cardiometabolic morbidities. RESULTS: Adults living with cerebral palsy or spina bifida had a higher 4-year incidence of any cardiometabolic morbidity (41.5% vs 30.6%) as compared to adults without cerebral palsy or spina bifida, and differences were to a clinically meaningful extent. Fully adjusted survival models demonstrated that adults with cerebral palsy or spina bifida had a greater hazard for any cardiometabolic morbidity (HR: 1.52; 95% confidence interval [CI]: 1.47, 1.57), and all but 1 cardiometabolic disorder (nonalcoholic fatty liver disease) and ranged from HR: 1.20 (1.15, 1.25) for hypercholesterolemia to HR: 1.86 (1.74, 1.98) for heart failure. CONCLUSIONS: Adults with cerebral palsy or spina bifida have a significantly higher incidence of, and risk for, common cardiometabolic morbidities, as compared to adults without cerebral palsy or spina bifida. Efforts are needed to facilitate the development of improved clinical screening algorithms and early interventions to reduce risk of cardiometabolic disease onset and progression in these higher-risk populations.

Incidence Rate of Advanced Chronic Kidney Disease Among Privately Insured Adults with Neurodevelopmental Disabilities.

PURPOSE: Due to complex medical profiles, adults with neurodevelopmental disabilities (NDDs) may have a heightened risk for early development of chronic kidney disease (CKD) and accelerated CKD progression to advanced stages and kidney failure. The purpose of this study was to estimate the incidence rate of advanced CKD for adults with NDDs and compare the incidence rate to adults without NDDs. PATIENTS AND METHODS: Data were used from the Optum Clinformatics® Data Mart to conduct this retrospective cohort study. The calendar year 2013 was used to identify eligible participants: individuals ≥18 years of age and without advanced CKD. Participants were followed from 01/01/2014 to advanced CKD, loss to follow-up, death, or end of the study period (12/31/2017), whichever came first. Diagnostic, procedure, and diagnosis-related group codes identified NDDs (intellectual disabilities, cerebral palsy, autism spectrum disorders), incident cases of advanced CKD (CKD stages 4+), diabetes, cardiovascular diseases, and hypertension present in the year 2013. Crude incidence rates (IR) of advanced CKD and IR ratios (IRR), comparing adults with vs without NDDs (with 95% CI) were estimated. Then, Cox regression estimated the hazard ratio (HR and 95% CI) for advanced CKD, comparing adults with NDDs to adults without NDDs while adjusting for covariates. RESULTS: Adults with NDDs (n=33,561) had greater crude IR of advanced CKD (IRR=1.32; 95% CI=1.24-1.42) compared to adults without NDDs (n=6.5M). The elevated rate of advanced CKD among adults with NDDs increased after adjusting for demographics (HR=2.19; 95% CI=2.04-2.34) and remained elevated with further adjustment for hypertension and diabetes (HR=2.01; 95% CI=1.87-2.15) plus cardiovascular disease (HR=1.84; 95% CI=1.72-1.97). Stratified analyses showed that the risk of advanced CKD was greater for all NDD subgroups. CONCLUSION: Study findings suggest that adults with NDDs have a greater risk of advanced CKD than do adults without NDDs, and that difference is not explained by covariates used in our analysis.

Risk of advanced chronic kidney disease among adults with spina bifida.

PURPOSE: Adults with spina bifida (SB) may be susceptible to accelerated progression of chronic kidney disease (CKD) to advanced stages. However, little is known regarding risk of advanced CKD for this underserved population. The objective was to estimate the risk of advanced CKD among adults with vs. without SB. METHODS: Data were from Optum Clinformatics Data Mart. Adults (18+ years) without advanced CKD (CKD stages 4+) in 2013 were followed from 01/01/2014 to advanced CKD, death, loss to follow-up, or 12/31/2017. Diagnostic, procedure, and diagnosis-related group codes were used to identify SB, advanced CKD, and baseline cardiovascular diseases, hypertension, and diabetes. Incidence rate (IR) and IR ratio and their 95% confidence intervals (CIs) of advanced CKD were estimated. Cox regression estimated adjusted hazard ratio (HR) for incidence of advanced CKD. RESULTS: The crude IR of advanced CKD was 7.40 for adults with SB (n = 4295) and 6.25 for adults without SB (n = 6.6 M). After adjusting for demographics, adults with SB had greater risk of advanced CKD compared to adults without SB (HR = 2.12; 95% CI = 1.72-2.60), which remained elevated with further adjustment for cardiovascular diseases, hypertension, and diabetes (HR = 1.91; 95% CI = 1.55-2.35). CONCLUSIONS: Adults with SB may have greater risk of advanced CKD incidence compared to adults without SB.

NYX-2925 induces metabotropic N-methyl-d-aspartate receptor (NMDAR) signaling that enhances synaptic NMDAR and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor.

N-methyl-d-aspartate receptors (NMDARs) mediate both physiological and pathophysiological processes, although selective ligands lack broad clinical utility. NMDARs are composed of multiple subunits, but N-methyl-d-aspartate receptor subunit 2 (GluN2) is predominately responsible for functional heterogeneity. Specifically, the GluN2A- and GluN2B-containing subtypes are enriched in adult hippocampus and cortex and impact neuronal communication via dynamic trafficking into and out of the synapse. We sought to understand if ((2S, 3R)-3-hydroxy-2-((R)-5-isobutyryl-1-oxo-2,5-diazaspiro[3,4]octan-2-yl) butanamide (NYX-2925), a novel NMDAR modulator, alters synaptic levels of GluN2A- or GluN2B-containing NMDARs. Low-picomolar NYX-2925 increased GluN2B colocalization with the excitatory post-synaptic marker post-synaptic density protein 95 (PSD-95) in rat primary hippocampal neurons within 30 min. Twenty-four hours following oral administration, 1 mg/kg NYX-2925 increased GluN2B in PSD-95-associated complexes ex vivo, and low-picomolar NYX-2925 regulated numerous trafficking pathways in vitro. Because the NYX-2925 concentration that increases synaptic GluN2B was markedly below that which enhances long-term potentiation (mid-nanomolar), we sought to elucidate the basis of this effect. Although NMDAR-dependent, NYX-2925-mediated colocalization of GluN2B with PSD-95 occurred independent of ion flux, as colocalization increased in the presence of either the NMDAR channel blocker (5R,10S)-(-)-5-Methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate or glycine site antagonist 7-chlorokynurenic acid. Moreover, while mid-nanomolar NYX-2925 concentrations, which do not increase synaptic GluN2B, enhanced calcium transients, functional plasticity was only enhanced by picomolar NYX-2925. Thus, NYX-2925 concentrations that increase synaptic GluN2B facilitated the chemical long-term potentiation induced insertion of synaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor GluA1 subunit levels. Basal (unstimulated by chemical long-term potentiation) levels of synaptic GluA1 were only increased by mid-nanomolar NYX-2925. These data suggest that NYX-2925 facilitates homeostatic plasticity by initially increasing synaptic GluN2B via metabotropic-like NMDAR signaling. Cover Image for this issue: doi: 10.1111/jnc.14735.