Citations

Our study shows an early increase in kynurenine pathway metabolism in at-risk subjects with systemic sclerosis who develop pulmonary arterial hypertension (PAH). We show that kynurenine pathway upregulation precedes clinical diagnosis and that this metabolic shift is associated with increased disease severity and shorter survival times. We also show that gene expression of TDO2, an enzyme that generates kynurenine from tryptophan, rises with PAH development.

OBJECTIVE The American Association of Neurological Surgeons (AANS)/Congress of Neurological Surgeons (CNS) Joint Spine Section awards highlight outstanding abstracts submitted to the AANS/CNS Section on Disorders of the Spine and Peripheral Nerves by trainees interested in spine surgery, although the academic trajectory of awardees has not been studied. The aim of this study was to assess the academic career progression of prior recipients of the Journalistic and Academic Neurosurgical Excellence (JANE), Mayfield, and Kuntz research awards. METHODS Prior JANE, Mayfield, and Kuntz award recipients were identified using awardee records accrued between 1984 and February 2022. Awardee sex, country of residence, specialty, subspecialty focus, and current academic appointment status (if applicable) were searched online. Awardee h-indices and number of peer-reviewed publications were assessed via Google Scholar profiles (or Scopus if unavailable) and PubMed, respectively. Receipt of federal research funding as principal investigator (PI) was determined using the websites of the National Institutes of Health, the National Science Foundation, and the Department of Defense Congressionally Directed Medical Research Programs. The abstract-to-publication rate was assessed. RESULTS A total of 7 JANE awards, 57 Mayfield awards, and 149 Kuntz awards were identified. Of the JANE awardees, all recipients were male. Of the 4 unique JANE awardees who completed training, 2 (50.0%) held academic appointments at the time of the study. All of the JANE abstracts were published in peer-reviewed journals. The mean h-index of all JANE awardees was 28 and the mean number of publications was 126. None of the awardees have received federal research funding. Of the Mayfield awards, 98.2% were awarded to males. Of the 43 unique Mayfield awardees who completed training, 20 (46.5%) held faculty appointments at academic medical centers. All of the Mayfield abstracts since 2011 were published in peer-reviewed journals. The mean h-index of all Mayfield awardees was 26 and the mean number of publications was 82. Five Mayfield awardees received National Institutes of Health funding as PI, and 7 awardees received Department of Defense funding as PI. Of the Kuntz awards, 95.3% were awarded to males. Most awards were given to current residents and fellows (46.3%). Of the 55 unique Kuntz awardees who completed training, 31 (56.4%) held faculty appointments at academic medical centers. The abstract-to-publication rate of the total Kuntz abstracts was 70.5%. The mean h-index of all Kuntz awardees was 15 and the mean number of publications was 58. Five Kuntz awardees (3.4%) received federal research funding as PI. CONCLUSIONS Many recipients of the JANE, Mayfield, and Kuntz Joint Spine Section awards have successfully translated award abstracts into peer-reviewed publications. Furthermore, approximately one-third of the awardees are active in academic neurosurgery, with some having secured federal research funding.

Importance Transthyretin gene silencing is an emerging treatment strategy for hereditary transthyretin (ATTRv) amyloidosis. Objective To evaluate eplontersen, an investigational ligand-conjugated antisense oligonucleotide, in ATTRv polyneuropathy. Design, Setting, and Participants NEURO-TTRansform was an open-label, single-group, phase 3 trial conducted at 40 sites across 15 countries (December 2019-April 2023) in 168 adults with Coutinho stage 1 or 2 ATTRv polyneuropathy, Neuropathy Impairment Score 10-130, and a documented TTR variant. Patients treated with placebo from NEURO-TTR ( NCT01737398 ; March 2013–November 2017), an inotersen trial with similar eligibility criteria and end points, served as a historical placebo (“placebo”) group. Interventions Subcutaneous eplontersen (45 mg every 4 weeks; n = 144); a small reference group received subcutaneous inotersen (300 mg weekly; n = 24); subcutaneous placebo weekly (in NEURO-TTR; n = 60). Main Outcomes and Measures Primary efficacy end points at week 65/66 were changes from baseline in serum transthyretin concentration, modified Neuropathy Impairment Score +7 (mNIS+7) composite score (scoring range, –22.3 to 346.3; higher scores indicate poorer function), and Norfolk Quality of Life Questionnaire–Diabetic Neuropathy (Norfolk QoL-DN) total score (scoring range, –4 to 136; higher scores indicate poorer quality of life). Analyses of efficacy end points were based on a mixed-effects model with repeated measures adjusted by propensity score weights. Results Among 144 eplontersen-treated patients (mean age, 53.0 years; 69% male), 136 (94.4%) completed week-66 follow-up; among 60 placebo patients (mean age, 59.5 years; 68% male), 52 (86.7%) completed week-66 follow-up. At week 65, adjusted mean percentage reduction in serum transthyretin was −81.7% with eplontersen and −11.2% with placebo (difference, −70.4% [95% CI, −75.2% to −65.7%]; P < .001). Adjusted mean change from baseline to week 66 was lower (better) with eplontersen vs placebo for mNIS+7 composite score (0.3 vs 25.1; difference, −24.8 [95% CI, −31.0 to −18.6; P < .001) and for Norfolk QoL-DN (−5.5 vs 14.2; difference, −19.7 [95% CI, −25.6 to −13.8]; P < .001). Adverse events by week 66 that led to study drug discontinuation occurred in 6 patients (4%) in the eplontersen group vs 2 (3%) in the placebo group. Through week 66, there were 2 deaths in the eplontersen group consistent with known disease-related sequelae (cardiac arrhythmia; intracerebral hemorrhage); there were no deaths in the placebo group. Conclusions and Relevance In patients with ATTRv polyneuropathy, the eplontersen treatment group demonstrated changes consistent with significantly lowered serum transthyretin concentration, less neuropathy impairment, and better quality of life compared with a historical placebo. Trial Registration ClinicalTrials.gov Identifier: NCT04136184 ; EU Clinical Trials Register: EudraCT 2019-001698-10

Objectives: Gain insights into the pathophysiology of idiopathic subglottic stenosis (iSGS) by investigating differences in transcriptome of subglottic mucosal tissue between patients with iSGS and controls, and between tracheal and subglottic tissue within patients. Methods: RNA sequencing was conducted on biopsied mucosal samples collected from subglottic and tracheal (in-patient control) regions in iSGS patients, and from subglottis in controls. The gene expression differences were validated on a protein level by (1) staining the tissue samples obtained from a second cohort of patients and controls; and (2) in vitro functional assays using primary subglottic epithelial cells from both iSGS patients and healthy donors. Results: We found 7 upregulated genes in the subglottic region of iSGS patients relative to both the tracheal mucosa and subglottic region of controls. A gene ontology enrichment analysis found that the epithelial cell differentiation and cornification pathways are significant, involving specifically 3 of the genes: involucrin ( IVL), small proline rich protein 1B ( SPRR1B), and keratin 16 ( KRT16). Involvement of these pathways suggests squamous metaplasia of the epithelium. Histological analyses of epithelium in subglottic mucosal biopsies revealed squamous metaplasia in 41% of the samples from iSGS patients and in 25% from controls. Immunohistochemical evaluation of the samples presented with squamous epithelium revealed increased expression of the protein encoded by SPRR1B, hyperproliferative basal cells, shedding of apical layers, and accompanying lesions in iSGS compared to CTRL. Cultured primary subglottic epithelial cells from iSGS patients had higher proliferation rates compared to healthy donors and squamous metaplastic differentiation formed thinner epithelia with increased expression proteins encoded by INV, SPRR1B, and KRT16, suggesting intrinsic dysfunction of basal cells in iSGS. Conclusions: Abnormal squamous differentiation of epithelial cells may contribute to the pathogenesis of iSGS. Patients having metaplastic epithelial phenotype may be sensitive to drugs that reverse it to a normal phenotype.

Background: Normative changes in right ventricular (RV) structure and function have not been characterized in the context of treatment-associated functional recovery (RV functional recovery [RVFnRec]). The aim of this study is to assess the clinical relevance of a proposed RVFnRec definition. Methods: We evaluated 63 incident patients with pulmonary arterial hypertension by right heart catheterization and cardiac magnetic resonance imaging at diagnosis and cardiac magnetic resonance imaging and invasive cardiopulmonary exercise testing following treatment (≈11 months). Sex, age, ethnicity matched healthy control subjects (n=62) with 1-time cardiac magnetic resonance imaging and noninvasive cardiopulmonary exercise testing were recruited from the PVDOMICS (Redefining Pulmonary Hypertension through Pulmonary Vascular Disease Phenomics) project. We examined therapeutic cardiac magnetic resonance imaging changes relative to the evidence-based peak oxygen consumption (VO 2peak )>15 mL/(kg·min) to define RVFnRec by receiver operating curve analysis. Afterload was measured as mean pulmonary artery pressure, resistance, compliance, and elastance. Results: A drop in RV end-diastolic volume of −15 mL best defined RVFnRec (area under the curve, 0.87; P =0.0001) and neared upper 95% CI RV end-diastolic volume of controls. This cutoff was met by 22 out of 63 (35%) patients which was reinforced by freedom from clinical worsening, RVFnRec 1 out of 21 (5%) versus no RVFnRec 17 out of 42, 40% (log-rank P =0.006). A therapy-associated increase of 0.8 mL/mm Hg in compliance had the best predictive value of RVFnRec (area under the curve, 0.76; [95% CI, 0.64–0.88]; P =0.001). RVFnRec patients had greater increases in stroke volume, and cardiac output at exercise. Conclusions: RVFnRec defined by RV end-diastolic volume therapeutic decrease of −15 mL predicts exercise capacity, freedom from clinical worsening, and nears normalization. A therapeutic improvement of compliance is superior to other measures of afterload in predicting RVFnRec. RVFnRec is also associated with increased RV output reserve at exercise.

Aim: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare blood disorder characterized by hemolytic anemia, bone marrow failure and thrombosis, and is associated with high healthcare burden. We evaluated the cost–effectiveness of pegcetacoplan, a proximal complement-3 inhibitor (C3i), compared with the C5i, eculizumab and ravulizumab, in complement treatment-naive adults with PNH, from the US healthcare payer perspective. Materials & methods: A de novo cost–effectiveness model based on a Markov cohort structure evaluated lifetime (55-year) PNH costs and outcomes. The 6-month cycles of the model reflected the follow-up period of PRINCE (NCT04085601), an open-label trial of pegcetacoplan compared with eculizumab in C5i-naive patients. Data from PRINCE informed the clinical, safety and health-related quality of life outcomes in the model. Results: Pegcetacoplan was associated with lifetime cost savings of USD1,176,808 and USD213,062 relative to eculizumab and ravulizumab, respectively (largely attributed to reduced drug costs and blood transfusions), and additional quality-adjusted life years (QALYs) of 0.25 and 0.24. Conclusion: In patients with PNH who are treatment-naive, the base-case cost–effectiveness analysis, scenario analysis and sensitivity analysis showed both lifetime cost savings and increased QALYs associated with pegcetacoplan compared with eculizumab or ravulizumab in the USA.

ObjectiveCo‐occurring anti‐tripartite motif‐containing protein 9 and 67 autoantibodies (TRIM9/67‐IgG) have been reported in only a very few cases of paraneoplastic cerebellar syndrome. The value of these biomarkers and the most sensitive methods of TRIM9/67‐IgG detection are not known.MethodsWe performed a retrospective, multicenter study to evaluate the cerebrospinal fluid and serum of candidate TRIM9/67‐IgG cases by tissue‐based immunofluorescence, peptide phage display immunoprecipitation sequencing, overexpression cell‐based assay (CBA), and immunoblot. Cases in which TRIM9/67‐IgG was detected by at least 2 assays were considered TRIM9/67‐IgG positive.ResultsAmong these cases (n = 13), CBA was the most sensitive (100%) and revealed that all cases had TRIM9 and TRIM67 autoantibodies. Of TRIM9/67‐IgG cases with available clinical history, a subacute cerebellar syndrome was the most common presentation (n = 7/10), followed by encephalitis (n = 3/10). Of these 10 patients, 70% had comorbid cancer (7/10), 85% of whom (n = 6/7) had confirmed metastatic disease. All evaluable cancer biopsies expressed TRIM9 protein (n = 5/5), whose expression was elevated in the cancerous regions of the tissue in 4 of 5 cases.InterpretationTRIM9/67‐IgG is a rare but likely high‐risk paraneoplastic biomarker for which CBA appears to be the most sensitive diagnostic assay. ANN NEUROL 2023;94:1086–1101

AbstractBackgroundThe incidence of mycobacterial infections in patients with hematologic malignancies and hematopoietic stem cell transplant (HSCT) recipients is increasing, contributing to significant mortality and morbidity. This review explores the epidemiology, risk factors, clinical presentation, diagnosis, and treatment of nontuberculous mycobacteria (NTM) in this population.MethodsA literature search was performed using PubMed with keywords and MeSH terms pertaining to the topics of nontuberculous mycobacteria, hematologic malignancies, hematopoietic stem cell transplant, cellular therapies, chimeric antigen therapies, epidemiology, diagnosis, and treatment. Additionally, we examined the reference lists of the included articles to identify other pertinent studies.ResultsDiagnosing mycobacterial disease among patients with hematologic disease and treatment‐associated immunosuppressive conditions is challenging due to the lack of distinctive clinical, radiographic, and laboratory markers, as well as the atypical manifestations compared to immunocompetent patients. Treatment involves using a combination of antibiotics for extended durations, coupled with strategies to achieve source control and reduce immunosuppression when feasible. This is complicated by the absence of clear data correlating in‐vitro drug susceptibility and clinical outcome for many antimicrobials use to treat NTM, adverse drug‐drug interactions, and the frequent challenges related to poor medication tolerability and toxicities.ConclusionThe rising incidence and corresponding clinical challenges of mycobacterial infections in this unique patient population necessitate a heightened awareness and familiarity of NTM disease by clinicians to achieve timely diagnosis and favorable treatment outcomes. image

ImportanceSystematic data on the association between anticancer therapies and thromboembolic events (TEEs) in patients with COVID-19 are lacking.ObjectiveTo assess the association between anticancer therapy exposure within 3 months prior to COVID-19 and TEEs following COVID-19 diagnosis in patients with cancer.Design, Setting, and ParticipantsThis registry-based retrospective cohort study included patients who were hospitalized and had active cancer and laboratory-confirmed SARS-CoV-2 infection. Data were accrued from March 2020 to December 2021 and analyzed from December 2021 to October 2022.ExposureTreatments of interest (TOIs) (endocrine therapy, vascular endothelial growth factor inhibitors/tyrosine kinase inhibitors [VEGFis/TKIs], immunomodulators [IMiDs], immune checkpoint inhibitors [ICIs], chemotherapy) vs reference (no systemic therapy) in 3 months prior to COVID-19.Main Outcomes and MeasuresMain outcomes were (1) venous thromboembolism (VTE) and (2) arterial thromboembolism (ATE). Secondary outcome was severity of COVID-19 (rates of intensive care unit admission, mechanical ventilation, 30-day all-cause mortality following TEEs in TOI vs reference group) at 30-day follow-up.ResultsOf 4988 hospitalized patients with cancer (median [IQR] age, 69 [59-78] years; 2608 [52%] male), 1869 had received 1 or more TOIs. Incidence of VTE was higher in all TOI groups: endocrine therapy, 7%; VEGFis/TKIs, 10%; IMiDs, 8%; ICIs, 12%; and chemotherapy, 10%, compared with patients not receiving systemic therapies (6%). In multivariable log-binomial regression analyses, relative risk of VTE (adjusted risk ratio [aRR], 1.33; 95% CI, 1.04-1.69) but not ATE (aRR, 0.81; 95% CI, 0.56-1.16) was significantly higher in those exposed to all TOIs pooled together vs those with no exposure. Among individual drugs, ICIs were significantly associated with VTE (aRR, 1.45; 95% CI, 1.01-2.07). Also noted were significant associations between VTE and active and progressing cancer (aRR, 1.43; 95% CI, 1.01-2.03), history of VTE (aRR, 3.10; 95% CI, 2.38-4.04), and high-risk site of cancer (aRR, 1.42; 95% CI, 1.14-1.75). Black patients had a higher risk of TEEs (aRR, 1.24; 95% CI, 1.03-1.50) than White patients. Patients with TEEs had high intensive care unit admission (46%) and mechanical ventilation (31%) rates. Relative risk of death in patients with TEEs was higher in those exposed to TOIs vs not (aRR, 1.12; 95% CI, 0.91-1.38) and was significantly associated with poor performance status (aRR, 1.77; 95% CI, 1.30-2.40) and active/progressing cancer (aRR, 1.55; 95% CI, 1.13-2.13).Conclusions and RelevanceIn this cohort study, relative risk of developing VTE was high among patients receiving TOIs and varied by the type of therapy, underlying risk factors, and demographics, such as race and ethnicity. These findings highlight the need for close monitoring and perhaps personalized thromboprophylaxis to prevent morbidity and mortality associated with COVID-19–related thromboembolism in patients with cancer.

Myocarditis is most recognized in patients with moderate to severe, recent‐onset heart failure. However, less typical presentations including myocardial infarction with normal coronary arteries and arrhythmias are important manifestations but less commonly recognized to be caused by myocarditis. Most cases of myocarditis can be self‐limiting without specific treatment; however, appropriate identification of risk during the diagnostic process of myocarditis and once a diagnosis is established is of primordial importance to identify patients in need for more specific follow‐up and management. We propose a flexible, multitiered approach to the diagnostic process, allowing for capturing of the spectrum of myocarditis at an early time‐point, individualized use of diagnostic resources through disease severity phenotyping, and providing structured follow‐up care once myocarditis is confirmed. Such diagnostic processes allow for identification of specific etiologies with potential therapeutic consequences or allows for the comprehension of disease chronicity by understanding genetic contributions or elements of persistent immune dysregulation and degree of cardiac damage. The article highlights the evolving field of immunophenotyping in myocarditis, generating a potential for the development of targeted therapeutic approaches. Currently long‐term follow‐up should be titrated to the refined risk assessments of patients with a diagnosis of myocarditis and includes arrhythmia monitoring and imaging when the results will likely impact management. Genetic testing should be considered in selected cases, and histologic diagnosis may be considered in nonresponders even at later stages.