Citations

Abstract Hereditary hemorrhagic telangiectasia (HHT) results in recurrent severe epistaxis, chronic gastrointestinal bleeding, and other morbid manifestations. Pomalidomide was recently demonstrated to be efficacious for bleeding in HHT in the landmark PATH-HHT trial. Given that the vascular remodeling that results in bleeding improvement may require several months, characteristics associated with treatment response would be invaluable to plan treatment. Using data from PATH-HHT (NCT03910244), we identified characteristics associated with change from baseline in Epistaxis Severity Score (ESS; a well-validated 10-point HHT bleeding scale and the trial’s primary end point) using multivariable-adjusted repeated-measures models. Characteristics associated with a better response to pomalidomide at weeks 16 to 24 of the trial included a higher (more severe) baseline ESS (change from baseline, −0.76 [95% confidence interval (CI), −0.99 to −0.54] points per 1-point higher baseline score, P< .001) and concomitant antifibrinolytic therapy (−0.73 [95% CI, −1.48 to 0.01] vs no therapy, P = .05). Characteristics associated with a less robust response were older age (0.29 [95% CI, 0.05-0.53] per 10 years older, P = .02) and underlying ACVRL1 germ line mutation (0.62 [95% CI, −0.04 to 1.27] vs ENG, SMAD4, or mutation not known, P = .06]. Characteristics notably associated with placebo response (placebo effect) were patient-reported outcome measures, such that those experiencing more severe disease at baseline had less placebo effect. In conclusion, several baseline patient and disease characteristics were associated with pomalidomide response, findings that may help guide patient selection for the use of pomalidomide in HHT. This trial was registered at www.Clinicaltrials.gov as NCT03910244.

BACKGROUND AND OBJECTIVES: Ventriculoperitoneal shunt (VPS) placement is a common treatment for idiopathic normal pressure hydrocephalus (iNPH), but patients may require VPS revision. This study aims to evaluate the effectiveness of a standardized VPS placement protocol by comparing indications and rates of shunt revision compared with a historical institutional cohort. METHODS: All patients treated with VPS for “suspected” iNPH at a tertiary care center between January 2000 and January 2023 were retrospectively reviewed and divided into temporally distinct historical (before 2017) and standardized (after 2017) cohorts. Cumulative incidence and timing of VPS revision were compared using competing risks analyses. RESULTS: A total of 561 patients (median age 75.0 years) were identified with 324 (57.8%) in the historical and 237 (42.2%) in the standardized cohorts. Significant variations in surgical technique and shunt hardware were noted between the cohorts. With a median follow-up of 11.4 months for historical and 12.4 months for standardized cohort, shunt revisions occurred in 19.4% and 8.4% of patients in the historical and standardized cohorts, respectively ( P < .001). Revision indications also varied significantly with lower rates of overdrainage ( P < .001), infection ( P < .001), and proximal malfunction ( P = .042) but higher rate of distal malfunction ( P = .03) in the standardized cohort. Notably, no infections were noted in the standardized cohort. CONCLUSION: Risk of shunt revision among iNPH patients may be associated with modifiable factors related to surgical technique and shunt hardware selection. Importantly, no short-term complications such as hemorrhage, infection, or catheter malposition were observed with the standardized protocol. Development and refinement of standardized shunt protocols for iNPH patients should be commonplace to facilitate tracking, identification, and modification of modifiable technical risk factors.

Abstract Response Assessment in Pediatric Neuro-Oncology (RAPNO) is an international working group dedicated to developing standardized recommendations for response assessment in children with central nervous system tumors enrolled on clinical trials. This standardization facilitates easier and more reliable comparison of responses across trials. Since the first RAPNO publication in 2013, response guidelines have been issued for medulloblastoma (MB), low-grade glioma (LGG), high-grade glioma (HGG), diffuse intrinsic pontine glioma, ependymoma, and craniopharyngioma. Many of these guidelines have already been incorporated into clinical trials to evaluate their effectiveness and accuracy. RAPNO has always been predicated on the idea that these consensus recommendations will require updates over time as they are applied in practice given technological advancements, evolving treatment approaches, and growing knowledge of disease pathology. A half-day RAPNO symposium sponsored by the Society of Neuro-Oncology was held in San Diego, California, United States, on May 15, 2025. This event coincided with the 8th Biennial Pediatric Society of Neuro-Oncology meeting. The main objectives were to identify ongoing RAPNO challenges, discuss potential updates, and plan future initiatives across 3 specific groups: (1) LGG/Craniopharyngioma, (2) HGG/diffuse midline glioma (DMG)/Ependymoma, and (3) MB and other seeding tumors. This manuscript reviews the symposium proceedings and highlights key topics and challenges discussed, as well as outlining future RAPNO initiatives.

ABSTRACT Autoantibody internalization has been implicated in autoimmune disease pathogenesis, yet its mechanisms, and generality across different diseases, cell types, and affected tissues remain poorly defined. Using bulk RNA sequencing, we identified reproducible, autoantibody-specific transcriptomic signatures consistent with autoantigen dysfunction in muscle biopsies from patients with anti-Mi2 dermatomyositis and anti-PM/Scl scleromyositis across independent cohorts. Electroporation of purified patient IgG into primary cultures of healthy cells was sufficient to induce the corresponding transcriptomic programs in vitro . Direct immunofluorescence demonstrated immunoglobulin internalization into subcellular compartments matching the localization of the autoantigen in different affected tissues. Spatial transcriptomic analyses revealed that antibody-secreting cells translocated cytoplasmic material (i.e., immunoglobulin RNA) into adjacent affected cells expressing autoantibody-specific transcripts. The disease-specific transcripts were present not only in muscle fibers, but also in other cells, including macrophages, endothelial cells, and fibroblasts. Autoantibody-induced transcriptomic programs were associated with cell damage and autoantibody-specific reactive inflammatory programs, including activation of type I interferon and TGF-ß1 signaling in anti-Mi2 dermatomyositis and activation of type II interferon in anti-PM/Scl scleromyositis. Antibody internalization was also observed in different tissues from patients with other autoimmune diseases, including anti-U1RNP mixed connective tissue disease, anti-Ku overlap syndrome, and anti-Scl70 systemic sclerosis. Together, these findings establish autoantibody internalization as a shared pathogenic mechanism across diverse autoimmune diseases, providing a unifying framework for conditions driven by autoantibodies against intracellular antigens.

ABSTRACT Magnetic Resonance Spectroscopy Imaging (MRSI) offers spatially-resolved, neurometabolic information, acquired non-invasively at whole-brain scales from human subjects. Analysis of MRSI however, is extremely challenging. The metabolic information is highly convolved, and sparsely distributed across millions of spatial-spectral datapoints, allowing for little direct human interpretation. Conversely, the overall low signal-to-noise with high-intensity artifacts can confound unsupervised machine learning approaches. These technical barriers have left much of the potential of MRSI unrealized. We acquired MRSI data from 4 human subjects with a diagnosis of multiple sclerosis (MS), incorporating experimental design into an informed machine learning approach. MRSI acquisitions were registered to anatomical MRI to label 105k spectra from brain tissue and 162 spectra from white matter hyperintensities (WMHs), an imaging biomarker associated with MS lesions. Spectral labels were then used in contrastive principal component analysis (cPCA) to filter artifacts and background features in the MRSI data from lesion salient features and clustered into statistically significant states based on features that could be interpreted from the original data. Our approach renders MRSI data into testable representations of neurometabolism, enabling the method for fundamental and clinical research. Graphical Abstract Analysis workflow for neurometabolic profiling of MS lesions. MRSI and anatomical MRI is acquired and processed in parallel for spectral data and anatomical labels. Spectra are then labeled and separated into experimental vs background data for contrastive PCA. Spectra are clustered for similarity, further labeled, and projected onto a brain atlas for a neurometabolic view.

OBJECTIVE: To evaluate the effect of joint preparation and patient factors on outcomes and complications in patients treated acutely with hindfoot fusion nails for ankle and pilon fractures. METHODS: Design: Retrospective chart review. Setting: Thirteen US trauma centers and 2 UK trauma centers. Patient Selection Criteria: Ankle and pilon fractures (AO-OTA types A-C) from 2010 to 2020 acutely treated definitively with hindfoot fusion nail were reviewed. Patients at least 18 years old and with minimum 6 months follow-up or earlier diagnosis of complication were included. Exclusion criteria included nonambulatory at baseline, prior internal fixation that failed and underwent revision, and prior tibiotalar or subtalar arthrodesis. Outcome Measurements and Comparisons: The primary outcome was final postoperative ambulatory status. Secondary outcomes were infectious and fracture-related complications. RESULTS: One hundred forty-nine patients (75 men; 74 women; age 20–99; median 63 years) were treated for ankle (104) or pilon (45; 8A, 13B, 24C) fractures. Eighty-five patients (44%) had open fractures and 55 (37%) had diabetes. Thirty-six patients (24%) had joint preparation at the time of surgery. Forty-five (30%) were made weight bearing as tolerated postoperatively; the median time to mobilize was 1.5 days (0–210) and to full weight bearing was 35 days (0–1462). Fifty-seven patients (85%) returned to their preinjury ambulatory status, which was not affected by joint preparation (50% vs. 59%, P = 0.327). Joint preparation led to higher articular fusion rates (94% vs. 24%; P = 0.001) and fewer hardware removals (19% vs. 42%, P = 0.013), but trended toward a higher fracture nonunion rate (19% vs. 8%, P = 0.053). Forty-five patients (30%) had infectious complications, 60 (40%) had a fracture-related complication, and 67 (45%) had additional procedures. Open fractures did not lead to any differences in superficial or deep infection. Insulin-dependent diabetes was associated with higher rates of infectious complications (31% vs. 15%, P = 0.028) and amputation (17% vs. 4%, P = 0.029). CONCLUSIONS: Hindfoot fusion nails for acute ankle and pilon injuries had high complication rates. More complications occurred in patients with insulin-dependent diabetes. While 95% regained ambulation, only 57% returned to preoperative status. Joint preparation led to higher rates of articular fusion (94% vs. 24%, P < 0.001) but not fracture union (81% vs. 66%, P = 0.106). LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Background: Preparation for radioiodine (RAI) therapy in differentiated thyroid cancer (DTC) often requires thyroid hormone withdrawal (THW) to achieve thyrotropin (TSH) stimulation. Current guidelines recommend TSH ≥30 mIU/L, a target that prolongs hypothyroidism and worsens quality of life, yet rests on limited evidence. Objective: To evaluate the association between pre-RAI TSH levels and oncologic outcomes in adults with DTC prepared by THW. Methods: We conducted a systematic review and meta-analysis of studies comparing outcomes across pre-RAI TSH thresholds (<30 vs. ≥30, <60 vs. ≥60, and <90 vs. ≥90 mIU/L) in adults with DTC prepared by THW. Primary outcomes included disease-specific mortality, recurrence, and response to therapy. Searches in MEDLINE, Embase, Cochrane, and Scopus (inception to March 2025) identified eligible studies. Risk of bias was assessed using the CLARITY tool and certainty of evidence using GRADE. Pooled relative risks (RRs) were calculated using random-effects models. This systematic review was registered in PROSPERO (CRD42020158354). Results: This meta-analysis included eight retrospective cohort studies comprising a total of 4651 DTC patients, predominantly women (68.5%) with a mean age of 46 years. All patients underwent THW before RAI. Across all TSH thresholds examined (<30, <60, and <90 mIU/L), higher pre-RAI TSH levels were not associated with better treatment response, lower recurrence, or reduced mortality. Specifically, patients with higher pre-RAI TSH levels (≥30 mIU/L) did not have better oncologic outcomes compared with those with lower levels (<30 mIU/L). At 2- and 3-year follow-up, no significant differences were observed in excellent (pooled RR = 0.87; confidence interval [CI] 0.68–1.11) or indeterminate (RR = 1.28; CI 0.72–2.27) response rates. Similarly, recurrence rates did not differ (RR = 1.45; CI 0.83–2.55), and no study demonstrated a difference in disease-specific mortality across follow-up periods extending up to 10 years. The certainty of evidence for all outcomes was rated very low due to risk of bias, heterogeneity, and imprecision. Conclusions: The current evidence base is insufficient to support or refute the routine use of a specific TSH threshold before RAI administration. These findings question the recommendation to achieve TSH ≥30 mIU/L before RAI and highlight the need for trials to define the minimal effective level of TSH stimulation.

GGGGCC (G 4 C 2 ) repeat expansion in C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Toxicity is thought to result from the accumulation of either repeat RNAs and/or dipeptide repeat proteins (DPRs) translated from repeat-containing transcripts through repeat-associated non-AUG (RAN) translation. To disentangle RNA from DPR toxicity, we mutated a CUG codon predominantly used to initiate DPR translation from all three reading frames. This mutation disrupted DPR synthesis while preserving the expression of repeat-containing RNAs. Despite the accumulation of RNA foci, behavioral deficits and pathological abnormalities, including p-TDP-43 inclusions, STING activation, motor neuron loss, neuroinflammation, and increased plasma neurofilament concentration, were alleviated in C9ORF72 mice. Base editing of the CUG codon also improved molecular phenotypes and survival in patient induced pluripotent stem cell–derived neurons, which highlights the potential of therapeutically targeting DPR production rather than repeat RNAs.