Citations

Abstract Gangliosides are structurally complex glycosphingolipids that regulate cellular signaling via interactions with extracellular binding partners and by influencing protein function within the membrane. Their comprehensive analysis remains analytically challenging, in part due to low endogenous abundance, extensive structural diversity, and the frequent occurrence of isomeric species arising from both glycan and ceramide moieties. Here, we present a hydrophilic interaction liquid chromatography (HILIC) nanoelectrospray ionization tandem mass spectrometry (nanoESI-MS/MS) method specifically designed to achieve isomer-resolved analysis and molecular species-level quantification of gangliosides. To improve characterization of low-abundance fatty acyl fragments, the workflow was extended by combining nanoESI with online fraction collection and subsequent direct infusion. The method demonstrated stable chromatographic performance, high sensitivity, and reproducible quantitative results across ten mouse tissues. Application of the workflow enabled quantification of 80 ganglioside molecular species belonging to 18 subclasses and revealed pronounced tissue-specific differences in subclass distribution and ceramide composition. Overall, this study establishes a robust and sensitive platform for comprehensive ganglioside analysis, providing new opportunities to investigate ganglioside diversity, regulation, and function in complex biological systems.

Importance Tofersen is a disease-modifying antisense oligonucleotide therapeutic for people living with SOD1 –amyotrophic lateral sclerosis ( SOD1 -ALS). Autopsy tissue donors have provided the first opportunity to study the distribution of intrathecally administered tofersen in human central nervous system tissues. Objectives To determine the tissue distribution of tofersen and to provide the first estimates of SOD1 reduction in human somatic motor systems tissues. Design, Setting, and Participants This was a cross-sectional autopsy tissue case series conducted between 2018 and 2026. Autopsies were performed at 3 US academic medical institutions. Tissue samples from 8 deceased patients who lived with SOD1 -ALS, participated in tofersen clinical trials (ClinicalTrials.gov Identifiers NCT02623699 [An Efficacy, Safety, Tolerability, Pharmacokinetics and Pharmacodynamics Study of BIIB067 (Tofersen) in Adults With Inherited Amyotrophic Lateral Sclerosis (ALS)] and NCT03070119 [Long-Term Evaluation of BIIB067 (Tofersen)]) or the Expanded Access Program, and whose families authorized autopsies were eligible for this study. All autopsy tissue donors known at the time of this study were included (none were excluded). Analyses were conducted between August 2020 and January 2026. Exposures Participants received multiple intrathecal 20- to 100-mg tofersen doses. Main Outcomes and Measures Tofersen tissue concentrations were measured using hybridization enzyme-linked immunosorbent assay (ELISA). SOD1 messenger RNA (mRNA) and protein reduction estimates, defined as percentage SOD1 levels in this study’s recently treated autopsy tissue donors compared to a cohort of samples from tofersen-naive SOD1 -ALS autopsy tissue donors, were measured using quantitative reverse transcription polymerase chain reaction (PCR) and ELISA. Histological localization of tofersen and SOD1 transcripts were studied using immunohistochemistry and in situ hybridization assays. Results In 8 tofersen-treated autopsy tissue donors (5 male and 3 female donors; age range, 42-66 years), spinal cord and motor cortical tissue tofersen concentrations strongly correlated with predictions based on individual dosing histories and a preclinical pharmacokinetic model. For 3 recently treated autopsy tissue donors, reductions in lumbar spinal cord tissue SOD1 mRNA and protein levels ranged from 45% to 84% despite not having been administered 1 to 2 scheduled doses before autopsy. Residual somatic motor neurons demonstrated tofersen transduction and low SOD1 mRNA probe hybridization. Misfolded SOD1 protein inclusions were detected in residual motor neurons of tofersen-naive SOD1- ALS tissue donor controls and tofersen-treated tissue donors. Meningeal and perivascular lymphocytic immune responses were observed in 5 recently treated tissue donors but were not apparent in tissue donors with remote final tofersen doses. Conclusions and Relevance This case series presents the first emerging autopsy tissue data confirming the predicted distribution of tofersen and robust SOD1 protein reduction in human somatic motor systems tissues.

Background: Spinal epidural abscesses (SEA) are rare, occurring 2.5–3 times per 10,000 hospital admissions. While streptococcus species comprise 7% of reported SEAs, Group A Streptococcus (GAS) has been described only once in the medical literature to our knowledge. Case presentation: We present a case of GAS pharyngitis with subsequent paraplegia from a GAS SEA. A 33-year-old female presented to the emergency department (ED) and was initially diagnosed with GAS pharyngitis and a suspected strained lower back. Following treatment with amoxicillin, she returned with worsened back pain, radiculopathy, and leukocytosis, for which she was treated with cyclobenzaprine. On her third presentation, she had new bilateral lower extremity weakness with decreased sensation, bilateral ankle clonus, and hyperreflexia. MRI of the thoracic and lumbar spine revealed a multiloculated SEA at T5-T10 requiring laminectomy and abscess evacuation. Intraoperative cultures grew Streptococcus pyogenes. Despite surgery, medical management, and physical therapy, she remained paraplegic. Conclusions: To our knowledge, this is the first report of SEA preceded by GAS pharyngitis. This case exposes the critical association between a recent infection, progression of back pain, eventual neurologic symptoms, and inflammatory markers that should trigger concern for SEA and early evaluation with MRI.

PURPOSE Incorporation of structured data elements within the electronic health record generates real-time data for many potential uses. However, this requires a change in documentation practices, which may increase documentation effort. The best strategies to support structured documentation interventions have not been thoroughly investigated. Herein, we report the results of extending a data capture tool across multiple disease sites and practice locations. METHODS A note-based data capture tool was developed to collect five data elements using minimum common oncology data elements language. Soft-stop close visit validation (CVV), offloading of data entry tasks to allied health staff, group education, individualized e-mails, and one-on-one assistance were used to support utilization. Baseline and follow-up surveys were collected. For each provider, we compared data capture in the 6 months before and after their CVV go-live. RESULTS Forty-five providers participated (31 physicians, 14 nurse pracationers and physician assistants [NPPAs]), resulting in 23,274 encounters pre-CVV go-live and 23,146 post-CVV go-live visits. Median percentage of all data elements captured increased from 69.5% to 82.6% across all providers. The effect of CVV was immediate and sustained. When surveyed, most respondents agreed with the value propositions of understanding practice population, outcomes, selecting trials to open, and identifying patients for trial enrollment. Most respondents (15/20, 75%) felt the soft stop was a helpful reminder. CONCLUSION Structured data can be successfully collected in provider notes with >80% data capture. Personalized assistance incorporating the structured data elements into users' preexisting templates and soft-stop CVV, along with monitoring the results of implementation and personalized follow-up, was used to support the structured data capture intervention.

Abstract Objective This study was undertaken to provide an overview of the research landscape and evaluate the impact of lifestyle modifications on seizure reduction and quality of life in people with epilepsy receiving standard medical treatment. Methods Following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta‐Analyses) guidelines, we conducted a systematic review of major databases (Medline, Embase, American Psychological Association PsycInfo, Cochrane Library, and Web of Science) through November 2025. After screening 5151 articles, 118 studies met inclusion criteria: prospective trials reporting seizure frequency in adults or mixed populations with epilepsy. Four epilepsy‐trained reviewers independently assessed studies. A random‐effects meta‐analysis was performed on studies reporting ≥50% seizure reduction or data allowing its calculation. Short‐term response was defined as the earliest postintervention time point, and long‐term response as the final reported time point. Results The 118 studies covered diet ( n = 33), supplements ( n = 20), biofeedback ( n = 14), psychosocial/behavioral therapy ( n = 13), yoga/meditation/mindfulness ( n = 8), music therapy ( n = 7), and others. Fifty‐two (44%) included control groups, whereas 91 (77%) reported statistical analysis of seizure frequency. Among those, 68% showed significant seizure reduction. Quality of life was assessed in 31 studies, 68% reporting improvement. Seventy‐one studies (60%) were included in the meta‐analysis. Overall, the ≥50% seizure reduction response rate was 44% for short‐term outcomes (95% confidence interval [CI] = 38%–50%) and 50% for long‐term outcomes (95% CI = 44%–56%). Dietary interventions had the largest evidence base ( n = 33), with short‐ and long‐term response rates of 40% and 51%, respectively. Meditation/yoga/mindfulness had the highest response rate (62% short term, 79% long term), whereas exercise and supplements had the lowest (30%–35%). Significance Lifestyle modifications may offer beneficial, adjunctive effects on seizure control. However, the current evidence is limited by variability in study design and quality. Larger, well‐designed trials with standardized outcomes are needed to clarify how these interventions can complement epilepsy treatment. This systematic review and meta‐analysis serves as a foundation for future research to better define the role of lifestyle interventions in epilepsy care.

Dynamic gadopiclenol-enhanced nodal and pedal MR lymphangiography was safe, with no adverse events, and feasible for imaging peripheral and central conducting lymphatic anatomy.

Abstract Rationale Idiopathic Pulmonary Fibrosis (IPF) is characterized by chronic progressive pulmonary fibrosis and high mortality. Genetic markers, summarized into a polygenic risk score (PRS), associate with IPF in well-phenotyped research cohorts. Objectives To evaluate the performance of the PRS using real-world data from routinely captured electronic healthcare records. Methods We conducted an observational study evaluating the association of a PRS for IPF with electronic healthcare record diagnosis of IPF as well as lung transplant-free survival in four independent cohorts; the Mass General Brigham Biobank (MGBB), Mayo Clinic Biobank (MCBB), Mayo Clinic Tapestry Cohort (Tapestry), and U.K. Biobank (UKBB). We used multivariable logistic regression and multivariable Cox proportional hazards models adjusting for age, gender, and principal components of ancestry. The cohorts then underwent fixed and random effects meta-analysis. Measurements and Main Results Of 37,709; 44,195; 43,202; and 447,422 participants from MGBB, MCBB, Tapestry and UKBB respectively, 1,015 (2.7%) 2,879 (6.5%), 1,310 (3.0%), and 2,742 (0.6%) participants had an IPF diagnosis. Meta-analysis demonstrated a high-risk PRS associated with IPF diagnosis, OR 2.88 (95%CI 2.41-3.44) compared to all other individuals. A high-risk PRS also associated with the composite endpoint of mortality or lung transplant among those with an IPF diagnosis, HR 1.23(95%CI 1.11-1.35) compared to all other individuals. Conclusions A PRS can identify those at risk for an IPF diagnosis and mortality in biobank-scale data, which may have implications for clinical decisions. Further work is necessary to evaluate the utility of adding genetics in clinical settings.

BACKGROUND: Aortic enlargement is a powerful predictor of dissection and rupture, yet it is rarely evaluated during routine myocardial perfusion imaging, despite the widespread availability of computed tomography (CT) attenuation correction scans. The aim of this study was to determine whether fully automated, opportunistically derived, artificial intelligence-based aortic measurements from myocardial perfusion imaging CT attenuation correction scans are associated with adverse outcomes in a large multicenter cohort. METHODS: CT attenuation correction scans from patients undergoing positron emission tomography/CT and single-photon emission CT/CT myocardial perfusion imaging across 10 centers were included. A deep learning model automatically segmented the thoracic aorta, and a postprocessing algorithm extracted maximum ascending and descending diameters. The aortic size index was calculated by indexing the diameter to body surface area. RESULTS: A total of 29 339 patients (56% men; median age, 66 years [interquartile range, 58–75 years]) were included. Over a median follow-up of 3.5 years (interquartile range, 1.9–5.0 years), 5083 (17.3%) patients died. Median ascending and descending aortic size index values were 1.8 cm/m 2 (interquartile range, 1.6–2.0) and 1.5 cm/m 2 (interquartile range, 1.4–1.6), respectively, with an increase with age and higher values in females. Elevated aortic size index thresholds (ascending >2.2 cm/m 2 ; descending >1.6 cm/m 2 ) were significantly associated with increased all-cause mortality (ascending: adjusted hazard ratio, 1.16 [95% CI, 1.07–1.26], P <0.001; descending: adjusted hazard ratio, 1.23 [95% CI, 1.14–1.31]; P <0.001). Notably, the prognostic value of an abnormal aortic size index persisted independent of age, sex, and perfusion abnormalities. CONCLUSIONS: Artificial intelligence can unlock previously unused information within routine myocardial perfusion imaging CT attenuation correction scans by rapidly and automatically quantifying aortic size at scale. Opportunistic aortic measurements derived from CT attenuation correction may serve as an adjunctive risk biomarker and could add prognostic value to standard myocardial perfusion imaging without additional imaging or radiation.

Autonomous robotic-assisted surgery (RAS) has emerged as a promising objective in biomedical technology, further enhanced by miniaturization toward microrobotic-assisted surgery (μ-RAS). This reduction in scale promises minimally invasive, partially or fully automated surgical procedures, with the potential to reduce patient recovery times, lower medical costs, and enable previously unavailable procedural options. This perspective highlights the specific advances in RAS that potentially map to the microscale (μ-RAS), organized across five surgical domains: endovascular, endoluminal, laparoscopic, ophthalmic, and orthopedic. We examine both clinical demands and technological advances in surgical robotics and identify the key innovations required for progress across these surgical fields. Our contribution is distinct in combining the perspectives of both surgical experts and bioengineering innovators, outlining a roadmap for the advancement and eventual integration of autonomous RAS and μ-RAS into mainstream surgical practice.