SLC29A3 Pathogenic Variants Resulting in Dural Based Fibroinflammatory Mass Lesions and H Syndrome Treated With Cobimetinib: A Case Report.

Objectives: Pathogenic SLC29A3 variants are known to cause autosomal recessive disease with a spectrum of systemic involvement. We sought to expand on the spectrum of SLC29A3 variants and describe potential treatment. Methods: We describe a case of newly diagnosed SLC29A3-related disorder, also known as H syndrome or familial histiocytosis, associated with CNS inflammatory pseudotumor and spinal cord compression. Results: We present a 25-year-old man with recurrent dural based masses resulting in spinal cord and brain compression, hyperpigmented skin patches, proptosis, short stature, and elevated serum and spinal fluid inflammatory markers. Panel genetic testing revealed homozygous pathogenic variant c.1309G>A in the SLC29A3 gene resulting in a missense alteration (p. Gly437Arg). The patient was treated with cobimetinib with clinical, serologic, and radiographic improvement at 1-month follow-up. Discussion: SLC29A3 variant may cause fibroinflammatory lesions involving the dura resembling the clinical spectrum of Rosai-Dorfman disease. Patients with SLC29A3 disease and neurologic signs or symptoms should undergo screening MRI for CNS involvement. MEK inhibition represents a novel treatment for this disorder.

Global Presence and Penetrance of CSF1R-Related Disorder.

Objectives: To highlight the worldwide presence of CSF1R-related disorder (CSF1R-RD), discuss its penetrance, and provide the first haplotype analysis. Methods: Data on patients worldwide were collected, including demographics, genotype, family history, and clinical status. For haplotype analysis, polymorphisms of short tandem repeats in 3 distinct families with CSF1R p.Ile794Thr variant were examined. Results: Nineteen new patients were included, at a mean age of 38.7 years (ranging from 11 to 74 years), from 14 families from the Americas, Asia, Australia, and Europe, including the first from Mexico, North Macedonia, and Ukraine. Fifteen CSF1R variants were found, including 8 novel. Three patients were compound heterozygotes with disease onset at 1, 4, and 22 years. Patients with heterozygous CSF1R variants developed symptoms at a mean of 39.0 years (range 8-71 years). Four patients died at a mean of 3.3 years from onset (range 2-5 years). Negative family history was noted in 7 patients. In haplotype analysis, 2 families exhibited shared haplotype encompassing ∼6-Mb region downstream of the CSF1R while the third family displayed a different haplotype. Discussion: CSF1R-RD has a global prevalence. The reasons for negative family history include de novo variants (as shown by the haplotype analysis), mosaicism, and incomplete penetrance, which are possibly modulated by environmental and genetic factors.

Preinjury and Event-Related Characteristics of Pediatric Firearm Injuries: The American College of Surgeons Firearm Study, United States, March 2021‒February 2022.

Objectives. To assess differences in contextual factors by intent among pediatric firearm injury patients and determine factors associated with data missingness. Methods. We retrospectively queried the American College of Surgeons Firearm Study database (March 1, 2021-February 28, 2022) for patients aged 18 years or younger. We stratified preinjury, firearm-related, and event-related factors by intent and compared them by using Fisher exact, χ2, or 1-way analysis of variance testing. Secondary analysis estimated the adjusted odds of missingness by using generalized linear modeling with binominal logit link. Results. Among 17 395 patients, 2974 (17.1%) were aged 18 years or younger; 1966 (66.1%) were injured by assault, 579 (19.5%) unintentionally, and 76 (2.6%) by self-inflicted means. Most contextual factors differed by intent, including proportion of youths with previous adverse childhood experiences, mental illness, and violent assaults or injury, firearm type and access, perpetrator relationship, and injury location. In adjusted analyses, age, trauma center designation, intent, and admission status were associated with missingness. Conclusions. Contextual factors related to pediatric firearm injury vary by intent. Specific predictors associated with missingness may inform improved future data collection. Public Health Implications. Contextual factors related to pediatric firearm injury can be obtained in a systematic manner nationally to inform targeted interventions. (Am J Public Health. 2024;114(10):1097-1109. https://doi.org/10.2105/AJPH.2024.307754).

Community-Level Disadvantage of Adults With Firearm- vs Motor Vehicle-Related Injuries.

Importance: Motor vehicle crash (MVC) and firearm injuries are 2 of the top 3 mechanisms of adult injury-related deaths in the US. Objective: To understand the differing associations between community-level disadvantage and firearm vs MVC injuries to inform mechanism-specific prevention strategies and appropriate postdischarge resource allocation. Design, Setting, and Participants: This multicenter cross-sectional study analyzed prospectively collected data from the American College of Surgeons (ACS) Firearm Study. Included patients were treated either for firearm injury between March 1, 2021, and February 28, 2022, or for MVC-related injuries between January 1 and December 31, 2021, at 1 of 128 participating ACS trauma centers. Exposures: Community distress. Main outcome and Measure: Odds of presenting with a firearm as compared with MVC injury based on levels of community distress, as measured by the Distressed Communities Index (DCI) and categorized in quintiles. Results: A total of 62 981 patients were included (mean [SD] age, 42.9 [17.7] years; 42 388 male [67.3%]; 17 737 Black [28.2%], 9052 Hispanic [14.4%], 36 425 White [57.8%]) from 104 trauma centers. By type, there were 53 474 patients treated for MVC injuries and 9507 treated for firearm injuries. Patients with firearm injuries were younger (median [IQR] age, 31.0 [24.0-40.0] years vs 41.0 [29.0-58.0] years); more likely to be male (7892 of 9507 [83.0%] vs 34 496 of 53 474 [64.5%]), identified as Black (5486 of 9507 [57.7%] vs 12 251 of 53 474 [22.9%]), and Medicaid insured or uninsured (6819 of 9507 [71.7%] vs 21 310 of 53 474 [39.9%]); and had a higher DCI score (median [IQR] score, 74.0 [53.2-94.8] vs 58.0 [33.0-83.0]) than MVC injured patients. Among admitted patients, the odds of presenting with a firearm injury compared with MVC injury were 1.50 (95% CI, 1.35-1.66) times higher for patients living in the most distressed vs least distressed ZIP codes. After controlling for age, sex, race, ethnicity, and payer type, the DCI components associated with the highest adjusted odds of presenting with a firearm injury were a high housing vacancy rate (OR, 1.11; 95% CI, 1.04-1.19) and high poverty rate (OR, 1.17; 95% CI, 1.10-1.24). Among patients sustaining firearm injuries patients, 4333 (54.3%) received no referrals for postdischarge rehabilitation, home health, or psychosocial services. Conclusions and Relevance: In this cross-sectional study of adults with firearm- and motor vehicle-related injuries, we found that patients from highly distressed communities had higher odds of presenting to a trauma center with a firearm injury as opposed to an MVC injury. With two-thirds of firearm injury survivors treated at trauma centers being discharged without psychosocial services, community-level measures of disadvantage may be useful for allocating postdischarge care resources to patients with the greatest need.

Modification of Firearm Law-Firearm Injury Association by Economic Disadvantage.

INTRODUCTION: Firearm-related injuries in the U.S. have risen 37% since 2015. Understanding how the association between firearm incidents and state-level firearm restrictiveness is modified by community-level distress and economic connectedness (EC) may inform upstream injury prevention efforts. METHODS: A national cross-sectional study of firearm incidents (interpersonal and unintentional firearm events) occurring between 1/2015 and 12/2021 was performed using the Gun Violence Archive. The exposures were community distress (Distressed Communities Index, DCI), EC, and year-state-level firearm restrictiveness. The primary outcome was mean annual urban firearm incidence rate per ZIP Code Tabulation Area. Generalized linear mixed models were fit to evaluate the modification of the firearm law-firearm incident association by DCI and EC. Data analyses took place in 2022. RESULTS: About 266,020 firearm incidents were included. The mean rate was higher with each DCI tertile, with a RR of 3.18 (95% CI: 3.06, 3.30) in high versus low distress communities. Low EC was associated with over 1.8 times greater rate of firearm-related injury. The least restrictive firearm laws were associated with 1.20 times higher risk of firearm incidents (95% CI: 1.12, 1.28). The association between restrictive laws and lower incidence rates was strongest in low and medium distress and high EC communities. CONCLUSIONS: Stricter firearm laws are associated with lower rate of firearm incidents. The magnitude of this association is smallest for communities experiencing the greatest economic disadvantage.

Firearm injuries in Missouri.

Firearm deaths continue to be a major public health problem, but the number of non-fatal firearm injuries and the characteristics of patients and injuries is not well known. The American College of Surgeons Committee on Trauma, with support from the National Collaborative on Gun Violence Research, leveraged an existing data system to capture lethal and non-lethal injuries, including patients treated and discharged from the emergency department and collect additional data on firearm injuries that present to trauma centers. In 2020, Missouri had the 4th highest firearm mortality rate in the country at 23.75/100,000 population compared to 13.58/100,000 for the US overall. We examined the characteristics of patients from Missouri with firearm injuries in this cross-sectional study. Of the overall 17,395 patients, 1,336 (7.7%) were treated at one of the 11 participating trauma centers in Missouri during the 12-month study period. Patients were mostly male and much more likely to be Black and uninsured than residents in the state as a whole. Nearly three-fourths of the injuries were due to assaults, and overall 7.7% died. Few patients received post-discharge services.

Firearm Injuries treated at Trauma Centers in the United States.

BACKGROUND: While firearm injuries and deaths continue to be a major public health problem, the number of non-fatal firearm injuries and the characteristics of patients is not well known. The American College of Surgeons (ACS) Committee on Trauma leveraged an existing data system to collect additional data on fatal and non-fatal firearm injuries presenting to trauma centers. This report provides an overview of this initiative and highlights the challenges associated with capturing actionable data on firearm-injured patients. METHODS: 128 trauma centers that are part of the ACS Trauma Quality Improvement Program (TQIP) collected data on individuals of any age arriving alive between March 1, 2021 and February 28, 2022 with a firearm injury. In addition to the standard data collected for TQIP, abstractors also extracted additional data specific to this study. We linked data from the Distressed Community Index (DCI) to patient records using zip code of residence. RESULTS: A total of 17,395 patients were included, with mean (SD) age of 30.2 (13.5) years, 82.5% were male and the majority were Black and non-Hispanic. The mean proportion of variables with missing data varied among trauma centers, with a mean of 20.7% missing data. Injuries occurred most commonly in homes (31.2%) or on the street (26.6%); 70.4% of injuries were due to assaults. Nearly one-third of patients were discharged from the ED, 25.9% were admitted directly to the operating room, 10.9% to the ICU; 5.9% died in the ED and 10.3% died overall during their course of care. Nearly two-thirds of patients lived in the two highest distressed categories of communities; only 7.5% lived in the least distressed quintile. CONCLUSIONS: Utilizing trauma center data can be a valuable tool to improve our knowledge of firearm injuries if clinical practices and documentation of patient risks and circumstances are standardized. LEVEL OF EVIDENCE: III Level, epidemiological.

Neurological Manifestations of Histiocytic Disorders.

PURPOSE OF REVIEW: Histiocytic disorders, including Erdheim-Chester disease (ECD), Langerhans cell histiocytosis (LCH), and Rosai-Dorfman disease (RDD), are rare neoplasms that may present with a spectrum of neurologic involvement. Diagnostic delay is common due to heterogeneity in presentation and challenging pathology. RECENT FINDINGS: Recent advances in the treatment of these diseases targeted towards mutations in the MAP kinase pathway have led to an improved prognosis in these patients with neurologic involvement. It is critical for clinicians to have a high index of suspicion to allow for early targeted treatment and optimize neurologic outcomes. A systematic approach to diagnosis is presented in this article to allow for accurate diagnosis of these rare diseases.

Characteristics of Progressive Multifocal Leukoencephalopathy Associated With Sarcoidosis Without Therapeutic Immune Suppression.

Importance: Progressive multifocal leukoencephalopathy can occur in the context of systemic sarcoidosis (S-PML) in the absence of therapeutic immune suppression and can initially be mistaken for neurosarcoidosis or other complications of sarcoidosis. Earlier recognition of S-PML could lead to more effective treatment of the disease. Objective: To describe characteristics of patients with S-PML. Design, Setting, and Participants: For this case series, records from 8 academic medical centers in the United States were reviewed from 2004 to 2022. A systematic review of literature from 1955 to 2022 yielded data for additional patients. Included were patients with S-PML who were not receiving therapeutic immune suppression. The median follow-up time for patients who survived the acute range of illness was 19 months (range, 2-99). Data were analyzed in February 2023. Exposures: Sarcoidosis without active therapeutic immune suppression. Main Outcomes and Measures: Clinical, laboratory, and radiographic features of patients with S-PML. Results: Twenty-one patients with S-PML not receiving therapeutic immune suppression were included in this study, and data for 37 patients were collected from literature review. The median age of the 21 study patients was 56 years (range, 33-72), 4 patients (19%) were female, and 17 (81%) were male. The median age of the literature review patients was 49 years (range, 21-74); 12 of 34 patients (33%) with reported sex were female, and 22 (67%) were male. Nine of 21 study patients (43%) and 18 of 31 literature review patients (58%) had simultaneous presentation of systemic sarcoidosis and PML. Six of 14 study patients (43%) and 11 of 19 literature review patients (58%) had a CD4+ T-cell count greater than 200/µL. In 2 study patients, a systemic flare of sarcoidosis closely preceded S-PML development. Ten of 17 study patients (59%) and 21 of 35 literature review patients (60%) died during the acute phase of illness. No meaningful predictive differences were found between patients who survived S-PML and those who did not. Conclusions and Relevance: In this case series, patients with sarcoidosis developed PML in the absence of therapeutic immune suppression, and peripheral blood proxies of immune function were often only mildly abnormal. Systemic sarcoidosis flares may rarely herald the onset of S-PML. Clinicians should consider PML in any patient with sarcoidosis and new white matter lesions on brain magnetic resonance imaging.

Association between sociodemographic factors and cholesterol-lowering medication use in U.S. adults post-myocardial infarction.

INTRODUCTION: Cholesterol-lowering medications offer effective secondary prevention after myocardial infarction (MI). Our objective was to evaluate the association between sociodemographic factors and cholesterol-lowering medication use in high-risk adults. METHODS: We conducted an analysis using weighted data from 31,408 participants in the 2017 and 2019 Behavioral Risk Factor Surveillance Systems cross-sectional surveys, who had a self-reported history of MI and high blood cholesterol. The sociodemographic factors evaluated were sex, age, race and ethnicity, annual household income, education level, relationship status, and reported healthcare coverage. We estimated the weighted prevalence of medication use, and weighted prevalence differences (with 95% confidence intervals) across categories, adjusting for sex, age group, healthcare coverage, smoking status, hypertension, and diabetes. RESULTS AND DISCUSSION: Overall, 83% of survey participants with a self-reported history of both MI and high blood cholesterol reported currently using a cholesterol-lowering medication. The prevalence of use was only 61% in those without self-reported healthcare coverage, compared to 85% of those with healthcare coverage (adjusted prevalence difference of -20%; 95% CI: -25% to -14%). Use of cholesterol-lowering medication was relatively low in younger adults and higher in older adults, leveling off after age 65 years. The proportion of Native Hawaiian or Pacific Islanders who were using a cholesterol-lowering medication was relatively low, but otherwise there was little variation by race and ethnicity. Household income, education level, and relationship status were weakly or not associated with medication use. CONCLUSIONS: Knowledge of characteristics of persons who are relatively less likely to be adherent with cholesterol-lowering medications for secondary prevention may be useful to policymakers and healthcare providers involved in the long-term treatment of MI patients. Policy makers might consider a reduced cost prescription coverage for persons without current healthcare coverage who have sustained an MI to reduce future cardiovascular morbidity and mortality.

Tumefactive Demyelination in MOG Ab-Associated Disease, Multiple Sclerosis, and AQP-4-IgG-Positive Neuromyelitis Optica Spectrum Disorder.

BACKGROUND AND OBJECTIVES: Studies on tumefactive brain lesions in myelin oligodendrocyte glycoprotein-immunoglobulin G (IgG)-associated disease (MOGAD) are lacking. We sought to characterize the frequency clinical, laboratory, and MRI features of these lesions in MOGAD and compare them with those in multiple sclerosis (MS) and aquaporin-4-IgG-positive neuromyelitis optica spectrum disorder (AQP4+NMOSD). METHODS: We retrospectively searched 194 patients with MOGAD and 359 patients with AQP4+NMOSD with clinical/MRI details available from the Mayo Clinic databases and included those with ≥1 tumefactive brain lesion (maximum transverse diameter ≥2 cm) on MRI. Patients with tumefactive MS were identified using the Mayo Clinic medical record linkage system. Binary multivariable stepwise logistic regression identified independent predictors of MOGAD diagnosis; Cox proportional regression models were used to assess the risk of relapsing disease and gait aid in patients with tumefactive MOGAD vs those with nontumefactive MOGAD. RESULTS: We included 108 patients with tumefactive demyelination (MOGAD = 43; AQP4+NMOSD = 16; and MS = 49). Tumefactive lesions were more frequent among those with MOGAD (43/194 [22%]) than among those with AQP4+NMOSD (16/359 [5%], p < 0.001). Risk of relapse and need for gait aid were similar in tumefactive and nontumefactive MOGAD. Clinical features more frequent in MOGAD than in MS included headache (18/43 [42%] vs 10/49 [20%]; p = 0.03) and somnolence (12/43 [28%] vs 2/49 [4%]; p = 0.003), the latter also more frequent than in AQP4+NMOSD (0/16 [0%]; p = 0.02). The presence of peripheral T2-hypointense rim, T1-hypointensity, diffusion restriction (particularly an arc pattern), ring enhancement, and Baló-like or cystic appearance favored MS over MOGAD (p ≤ 0.001). MRI features were broadly similar in MOGAD and AQP4+NMOSD, except for more frequent diffusion restriction in AQP4+NMOSD (10/15 [67%]) than in MOGAD (11/42 [26%], p = 0.005). CSF analysis revealed less frequent positive oligoclonal bands in MOGAD (2/37 [5%]) than in MS (30/43 [70%], p < 0.001) and higher median white cell count in MOGAD than in MS (33 vs 6 cells/µL, p < 0.001). At baseline, independent predictors of MOGAD diagnosis were the presence of somnolence/headache, absence of T2-hypointense rim, lack of T1-hypointensity, and no diffusion restriction (Nagelkerke R 2 = 0.67). Tumefactive lesion resolution was more common in MOGAD than in MS or AQP4+NMOSD and improved model performance. DISCUSSION: Tumefactive lesions are frequent in MOGAD but not associated with a worse prognosis. The clinical, MRI, and CSF attributes of tumefactive MOGAD differ from those of tumefactive MS and are more similar to those of tumefactive AQP4+NMOSD with the exception of lesion resolution, which favors MOGAD.

Ophthalmologic Involvement in Adults with Histiocytic Disorders: Clinical Presentation and Treatment Outcomes.

PURPOSE: To evaluate the clinical presentation, treatment, and outcomes in adult patients with histiocytic disorders with ocular, orbital, optic nerve, or cavernous sinus involvement. DESIGN: Observational, retrospective chart review. PARTICIPANTS: Adult patients (age ≥ 18 years) at Mayo Clinic from January 1, 1996, to July 1, 2021, with histiocytic disorders. Inclusion criteria were (1) histiocytic disorder by biopsy and appropriate clinical phenotype; (2) available medical records; and (3) ocular, orbital, optic nerve, or cavernous sinus involvement. METHODS: Retrospective chart review. MAIN OUTCOME MEASURES: Response to therapy, measured in clinical and radiographic impact. RESULTS: Thirty-two patients were identified: 7 with Langerhans cell histiocytosis (LCH); 15 with Erdheim-Chester disease (ECD); 1 with mixed LCH/ECD phenotype; 8 with Rosai-Dorfman disease (RDD); and 1 with mixed RDD/ECD phenotype. Ophthalmologic involvement was part of the initial presentation in 69% of patients (22/32). Eyelid edema (13/32, 41%) and proptosis (12/32, 38%) were the most frequent presentations. Isolated orbital or cavernous sinus involvement was present in 3 of 7 patients with LCH and 1 of 8 patients with RDD. Optic nerve sheath involvement was present in 2 of 7 LCH patients, 14 of 15 ECD patients, and 1 RDD/ECD patient. Diffuse (> 75%) orbital involvement was seen in 12 of 15 ECD patients and 1 of 7 LCH patients. Ocular involvement was seen in 1 of 15 ECD patients, 6 of 8 RDD patients, and 1 of 1 mixed RDD/ECD patient. The cavernous sinuses were involved in 1 of 7 LCH patients, 5 of 15 ECD patients, and both mixed phenotype patients. Visual acuity was affected in 14 patients (14/24, 58%) with a median logarithm of the minimum angle of resolution visual acuity of 0.1 (range, -0.12 to 3). BRAF V600E mutations were found in 75% (3/4) of LCH patients and 91% (10/11) of ECD patients. Patients received a variety of treatment, and response was variable across disease types. CONCLUSIONS: Orbital involvement was more commonly seen in LCH and ECD, whereas ocular involvement was more common in RDD. Visual acuity may be impacted from ocular involvement or compression of the optic nerve with diffuse orbital involvement.

Emerging Nondopaminergic Medications for Parkinson's Disease: Focusing on A2A Receptor Antagonists and GLP1 Receptor Agonists.

Parkinson's disease (PD) is a severe neurodegenerative disease characterized by classic motor features associated with the loss of dopaminergic neurons and appearance of Lewy bodies in the substantia nigra. Due to the complexity of PD, a definitive diagnosis in the early stages and effective management of symptoms in later stages are difficult to achieve in clinical practice. Previous research has shown that colocalization of A2A receptors (A2AR) and dopamine D2 receptors (D2R) may induce an antagonistic interaction between adenosine and dopamine. Clinical trials have found that the A2AR antagonist istradefylline decreases dyskinesia in PD and could be used as an adjuvant to levodopa treatment. Meanwhile, the incretin hormone glucagon-like peptide 1 (GLP1) mainly facilitates glucose homeostasis and insulin signaling. Preclinical experiments and clinical trials of GLP1 receptor (GLP1R) agonists show that they may be effective in alleviating neuroinflammation and sustaining cellular functions in the central nervous system of patients with PD. In this review, we summarize up-to-date findings on the usefulness of A2AR antagonists and GLP1R agonists in PD management. We explain the molecular mechanisms of these medications and their interactions with other neurotransmitter receptors. Furthermore, we discuss the efficacy and limitations of A2AR antagonists and GLP1R agonists in clinical practice.