Jacobs Institute

Abstract Meningiomas are typically benign extra-axial tumors treated with surgery or radiosurgery, but extracranial extension from skull base lesions is rare and poorly defined. This study reports outcomes of stereotactic radiosurgery for skull base meningiomas with extracranial extension, focusing on tumor control, clinical outcomes, and patterns of failure. We conducted a retrospective single-institution review of patients treated with gamma knife radiosurgery (GKRS) for skull base meningiomas with extracranial extension. Clinical, radiographic, and treatment variables—including extension patterns, cranial nerve involvement, and dosimetry—were analyzed. Tumor control and symptom outcomes were assessed using univariate and multivariable analyses. Kaplan–Meier and Cox regression analyses compared primary versus salvage GKRS. A management algorithm was developed based on a literature review. Thirty-four patients were included: 13 treated with primary GKRS and 21 with salvage GKRS after prior treatment. The most common extracranial extension sites were the pterygopalatine fossa and orbit, and visual changes were the most frequent symptom. Symptomatic deterioration was associated with larger tumor volume, higher maximum dose, foraminal extension, female sex, and prior treatment. Hyperostosis, prior treatment, and higher histologic grade predicted retreatment. At the last follow-up, over 90% of patients achieved radiographic tumor control and symptom stability. Primary GKRS was associated with fewer complications and better tumor control than salvage treatment. GKRS provides durable tumor control and favorable clinical outcomes for selected skull base meningiomas with extracranial extension. When feasible, primary radiosurgery may be preferable to salvage therapy. Predominant intracranial marginal progression supports targeted surveillance and a multidisciplinary, risk-adapted management strategy.

Shared decision-making (SDM) aligns treatment recommendations with patient values, and has been shown to positively affect surgical outcomes. We aimed to characterize the variation in levels of SDM among surgeons using CollaboRATE, a validated patient-reported tool for assessing SDM in clinical care. This multicenter retrospective cohort study analyzed American College of Surgeons (ACS) National Surgical Quality Improvement Program (NSQIP) Patient-Reported Outcomes (PRO) data from 30,957 surgical patients treated by 2,921 surgeons across 65 hospitals between 2020 to 2023. Patient-reported scores were analyzed to (1) characterize the distribution of patient scores, (2) explore the distribution of surgeon-level performance, and (3) identify patient, surgeon, and hospital-level factors associated with higher and lower performance. Multilevel logistic regression, adjusted for clustering at the hospital level, assessed factors associated with surgeon-level performance. Of patient responses, 64% reported adequate SDM (a composite score of 27). No single CollaboRATE domain disproportionately accounted for inadequate patient ratings. Among 977 surgeons, only 1.2% achieved mean scores of 27, whereas 80.6% of surgeons achieved a median score of 27. Multivariable analysis revealed that lower surgeon performance associated with male gender (OR 2.75, 95% CI [2.34-3.23]), cardiothoracic specialty (OR 5.78 [4.41-7.57], rural setting (OR 5.55 [1.19-25.82]), and greater than 31 years of practice (OR 2.29 [2.02-2.59]). Using CollaboRATE to describe surgeon-level variability will be useful for both benchmarking and targeted quality improvement. These results suggest SDM might be a modifiable skill warranting targeted improvement efforts and surgeon-specific training.

Background Online grocery shopping interventions using optimal defaults have improved the nutritional quality of grocery purchases, but no studies have explored impacts on dietary intake. This analysis examines the potential of an optimal defaults online grocery shopping intervention to promote healthier intake by assessing (1) the relationship between the nutritional quality of grocery shopping purchases and the nutritional quality of intake, and (2) intervention effects on the nutritional quality of participants' dietary intake. Methods A randomized controlled trial tested the effects of an optimal defaults intervention promoting grocery purchases consistent with a diabetic diet. As part of the 5-week, 3-arm study, participants were randomly assigned to grocery shop either (1) in person as usual (control group), (2) online (online group), or (3) online with a prefilled, default grocery shopping cart (defaults group) during a 3-week intervention. All groups received recipes corresponding to the Dietary Approaches to Stop Hypertension diet. Participants submitted grocery receipts and completed interviews weekly. Fifty-five adults provided a complete food frequency questionnaire post intervention. Linear regression tested the relationship between the nutritional quality of grocery shopping purchases and the nutritional quality of intake. Analysis of variance examined the effect of study group on the nutritional quality of dietary intake. Results The nutritional quality of household grocery purchases was positively associated with the nutritional quality of participants' intake ( P < .001). The effect of study group on the nutritional quality of intake was not significant ( P = .07), although trend-level results were in the expected direction with the defaults group having the highest nutritional quality of the 3 groups. Conclusions Optimal defaults interventions' effects on grocery purchases may extend to dietary intake. Future research using more precise and objective measures of dietary intake could elucidate potential effects.

Cognitive, memory, and learning impairments are common features of many lysosomal sphingolipidoses, yet the underlying synaptic mechanisms remain poorly defined. Here, we examined the impact of galactosylceramidase (GALC) deficiency on synaptic structure and function in the Twitcher (TWI) mouse model of Krabbe disease (KD). In vivo electrophysiological recording revealed significant cell autonomous reductions in paired-pulse facilitation and excitatory postsynaptic potential amplitude in hippocampal neurons of TWI mice. These functional impairments were accompanied by notable decreases in dendritic spine density, disrupted synaptic vesicle distribution, and reduced size of postsynaptic densities, affecting both excitatory and inhibitory synapses. Mechanistically, we found that psychosine, the pathological sphingolipid in KD, accumulated preferentially in presynaptic membranes and synaptic vesicles. Moreover, its higher biosynthetic rate in synaptosome fractions suggests local synthesis within the synaptic compartment. Deregulation of the SNARE protein SNAP25 and increased formation of SNARE complexes pointed to reduced vesicle docking and fusion at the presynaptic membrane. In vitro assays confirmed that psychosine disrupts synaptic vesicle cycling and SNARE-mediated fusion. Comparative analysis of other disease-associated sphingolipids-including gangliosides, sulfatides, glucosylsphingosine, globotriaosylceramide, sphingomyelin, and sphingosine-revealed distinct effects on vesicle trafficking, underscoring convergent yet lipid-specific mechanisms across inherited sphingolipidoses. Collectively, these findings identify presynaptic sphingolipid accumulation and impaired vesicle docking and fusion as shared mechanisms contributing to synaptic failure in several inherited sphingolipidoses, with potential relevance in adult-onset neurodegenerative diseases where lysosomal function is also compromised.

Abstract RNA modifications play essential roles in cellular physiology by modulating RNA structure, stability, and translation efficiency. Among these, dihydrouridine is a conserved tRNA modification synthesized by the flavin-dependent enzymes DusA, DusB, and DusC, which introduces flexibility at defined uridine positions in the D-loop. While structural and biochemical studies in Escherichia coli have clarified Dus enzymes substrate specificities, their functional relevance in other bacterial pathogens remains uncharacterized. Here, we present the first functional characterization of the contribution of Dus enzymes to an important urinary tract pathogen, Proteus mirabilis. Insertional mutants were generated in dusA, dusB , and dusC in P. mirabilis strain HI4320 for evaluation of virulence-relevant phenotypes. All mutants grew similarly to wild-type under multiple culture conditions, although loss of dusB caused a fitness defect during growth in human urine. Disruption of dusB also resulted in increased biofilm biomass, impaired swimming motility, enhanced outer membrane permeability, and increased susceptibility to detergents and certain antibiotics, while disruption of dusA or dusC only impacted biofilm formation and susceptibility to detergents. In a murine model of catheter-associated urinary tract infection , dusB was also critical for fitness in all organs during co-challenge against wild-type as well as overall colonization and ascending infection during independent challenge. In contrast, dusC did not contribute to fitness and dusA showed a modest, compartment-specific contribution to fitness, as the dusA::Kan mutant was outcompeted in the bladder. Together, these findings identify DusB as a key regulator of motility, membrane integrity, and host fitness in P. mirabilis , linking tRNA modification to virulence.

The prevalence of childhood obesity increases throughout development. Obesity results from a positive energy balance, which suggests different trajectories of energy intake and energy expenditure as children age. Rapid development of reward processes that motivate eating and sedentary over physically active behaviors coupled with slower development of executive functions that allow youth to focus on long-term goals rather than immediate gratification may influence the imbalance in energy intake and expenditure. Children are motivated to engage in activities that have strong reinforcing value in early childhood, including eating palatable foods, and engaging with sedentary activities. Valuing activities that offer long-term rewards, including healthy food consumption and physical activity, increases as children develop more mature executive functions. We present a conceptual overview of how reinforcer pathology theory, or a combination of the high value of immediate reinforcers such as food and high rates of delay discounting, can be used to understand the balance between the motivation to eat and be active or sedentary within a developing executive function system that prioritizes immediate gratification over delayed rewards are related to changes in obesity prevalence through development. We suggest areas for future study and the potential for reinforcer pathology theory for developing prevention and treatment programs.

We read with great interest the study by Murin et al., “Uncovering Hidden Profiles: From Pain-Centric to Multi-Symptom Small Fiber Neuropathy.” The authors describe a cohort of 203 patients with small fiber neuropathy (SFN) with only 20% of the entire cohort having severe neuropathic pain, which was termed the “algesic” group. The other 80% of patients had significant fatigue, myalgia, and generalized weakness, and either no or mild neuropathic pain [1]. Importantly, most patients also experienced autonomic symptoms, with the most common being dry eyes, dry mouth, and GI dysmotility prior to undergoing a skin biopsy, compared to healthy controls [1]. Noteworthy is that patients in cluster 2 (termed “myalgic”) consisting of 60% of the cohort had especially severe fatigue compared to other symptoms—more intense than neuropathic symptoms. In this cluster, patients also experienced significantly more severe weakness and myalgias than burning pain [1]. Interestingly, autonomic symptoms were present in all three clusters [1]. It's important to note that traditionally, neuropathic pain was required for a diagnosis of SFN, and the absence of neuropathic pain as a feature often excluded neuropathy from the differential diagnoses in patients presenting with fatigue, myalgia, and generalized muscle weakness. The study by Murin et al. illustrates that neuropathic pain may be mild or absent, but SFN may still be present, as confirmed via reduced epidermal nerve fiber density [1]. We emphasize that at least 50% of patients with postural orthostatic tachycardia syndrome (POTS) and Long COVID and nearly a third of patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) were found to have SFN when assessed via skin biopsy, quantitative sudomotor axon reflex test, corneal microscopy or microneurography [2, 3]. However, many patients with these disorders do not experience severe—or any—neuropathic pain and, instead, typically present with fatigue, lightheadedness/dizziness, generalized weakness, and myalgia [1, 3]. Murin et al.'s study compellingly demonstrates that SFN can present predominantly with fatigue and weakness rather than pain, challenging conventional diagnostic assumptions [1]. The fact that patients with fatigue and generalized weakness may have SFN without exhibiting neuropathic pain or significant abnormalities on neurologic exam should be emphasized in neurology training, which we believe is essential to improving diagnostic accuracy and optimizing treatment outcomes. Finally, autoimmune conditions and abnormal autoimmune markers were common in this and other cohorts of patients with SFN [1, 3-5], suggesting an autoimmune and immune-mediated etiology, which is similarly identified as a major pathophysiologic mechanism in patients with POTS, Long COVID and ME/CFS. Additionally, dysautonomia more broadly is a common manifestation of a wide variety of systemic disorders, many of which are autoimmune, immune-mediated, inflammatory and post-acute infectious in nature [3, 4]. Currently, the mechanistic interplay between SFN and dysautonomia, and whether SFN is an underlying mechanism of dysautonomia or an associated comorbidity in the autoimmune and immune-mediated pathways that drive both conditions, is unknown. Regardless, immunotherapies for patients with SFN, POTS, ME/CFS, and Long COVID, especially when accompanied by comorbid autoimmune conditions or abnormal autoimmune or immunologic markers, may be considered, and carefully designed randomized controlled trials are needed to assess their efficacy in each disorder [5]. Svetlana Blitshteyn: conceptualization, writing – original draft, investigation, writing – review and editing. Michael Stingl: writing – review and editing. Jill R. Schofield: writing – review and editing. The authors have nothing to report. The authors have nothing to report. The authors declare no conflicts of interest. Data sharing not applicable to this article as no datasets were generated or analysed during the current study.