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Abstract Background Relapsed medulloblastoma remains a significant therapeutic challenge as it is near universally fatal. The tumor microenvironment of medulloblastoma plays a critical role in tumor progression, influencing tumor growth, immune evasion, and therapeutic resistance. We hypothesized that defining tumor-immune interactions in diagnostic and relapsed medulloblastoma may uncover mechanisms of immune evasion and identify novel therapeutic targets. Methods We analyzed paired primary and recurrent RNA-sequencing data from 140 medulloblastoma patients to profile immune cell composition and validate spatial relationships within the TME. To identify key tumor-immune interactions, we developed a novel algorithm to detect receptor-ligand pairs using single-cell RNA-sequencing data. These interactions were validated across RNA and proteomic datasets. Their functional significance was empirically demonstrated in newly developed immunocompetent models of recurrent medulloblastoma that closely recapitulate the human disease. Results We observed a shift toward a heightened immunosuppressive TME at relapse. Using our algorithm, we identified biologically significant receptor-ligand interactions, most notably MIF-CD74, constitutively expressed at RNA and protein levels across medulloblastoma subgroups, at diagnosis and relapse. Disrupting MIF-CD74 interactions led to significant alterations in the tumor microenvironment, highlighting its functional significance. Conclusions Our multifaceted approach identified key tumor-immune interactions in medulloblastoma. Among these, MIF-CD74 was validated as a targetable interaction, demonstrating the utility of our integrative approach for identifying novel therapeutic targets across multiple tumor types.

Abstract Objective Dravet syndrome (DS) is the prototypic developmental and epileptic encephalopathy, characterized by drug‐resistant seizures, developmental slowing, and many other morbidities. Detailed characterization of behavioral phenotypes and social–emotional skill development are limited. Methods We prospectively assessed behavioral and social–emotional problems in the ENVISION natural history study (NCT04537832) of children with DS associated with SCN1A pathogenic variants ( SCN1A + DS) enrolled at <5 years of age. Assessments every 3 months for up to 2 years included the Child Behavior Checklist (CBCL), Strengths and Difficulties Questionnaire (SDQ), Brief Infant‐Toddler Social and Emotional Assessment (BITSEA), and Vineland Adaptive Behavior Scales, 3rd Edition (VABS‐3). Results Fifty‐eight children with DS enrolled at 16 sites worldwide. Problematic behaviors—inattention, aggressive or oppositional behaviors, and withdrawn and autistic behaviors—began before age 3 years, became more evident with age, and were clinically significant in many children by age 3–4 years. CBCL Total, Externalizing, and Internalizing Problems T‐scores rose by approximately 3 points per year, and BITSEA Problem scale scores increased by 2.3 points annually ( p = .002). SDQ Hyperactivity scores worsened over time ( p = .013), whereas emotional difficulties remained stable. VABS‐3 Socialization domain scores, which were already more than 1 SD below the normative mean at baseline, decreased further, particularly in younger participants. Correlation analyses showed that poorer communication abilities were associated with increased problematic behaviors ( R = −.55 for CBCL Total Problems and VABS‐3 Communication scores). Mixed‐effects modeling identified age as the strongest predictor of worsening behavioral outcomes. Significance We found that behavioral and social–emotional problems are inherent components of DS that present in toddlerhood and worsen throughout early childhood. This highlights the need to diagnose and manage these issues early. Targeted therapy may alleviate the wide‐ranging morbidities that are intrinsic to DS, including the social–emotional and behavior problems that frequently emerge.

Introduction: Plasma biomarkers of Alzheimer’s disease (AD), including amyloid-β (Aβ42/Aβ40), phosphorylated tau (p-tau181), neurofilament light (NfL), and glial fibrillary acidic protein (GFAP) have shown strong reliability in predicting dementia risk. White matter hyperintensities (WMH) represent a major vascular contributor to dementia. We investigated how plasma biomarkers of AD interact with WMH on MRI to influence incident dementia risk. Methods: We included dementia-free participants from the Atherosclerosis Risk in Communities (ARIC) Study who underwent MRI and plasma biomarker assessment at Visit 5 (2011–2013). WMH was quantified and considered continuously (log-transformed and standardized), and in tertiles. Plasma biomarkers were log-base-2-transformed. Cox proportional hazards models were used to estimate dementia risk over 10 years associated with plasma biomarkers and WMH, independently and multiplicatively. Models were adjusted for demographic variables (age, sex, race, and education), vascular risk factors (hypertension, diabetes, smoking status, body mass index, and estimated glomerular filtration rate), and APOE ε4 status. Results: Among 1,538 participants (aged 67- 90 years, 29% Black), 30% ( N = 462) developed dementia over the 10-year follow-up period. For every doubling of plasma Aβ42/Aβ40 , indicating lower amyloid burden, dementia risk decreased, while doubling of p-tau 181 , NfL, and GFAP were each associated with increased dementia risk, in separate models; each of these associations was independent of WMH (Table 1). Additionally, dementia risk increased per SD increase in WMH, independent of each plasma biomarker. Although no multiplicative interaction terms reached statistical significance (p<0.05), there was suggestive evidence that Aβ42/Aβ40 and GFAP have smaller effect sizes on dementia risk in subgroups at the highest WMH tertile (p-interactions<0.10; see Table 2). Discussion: Plasma biomarkers and WMH independently predict dementia risk over 10 years, though there remained limited evidence of multiplicative effects. Plasma biomarkers may be less important for dementia risk in individuals who also have extensive WMH. These findings emphasize the importance of incorporating both AD-specific plasma markers as well as indicators of cerebral small vessel disease, such as WMH, into dementia risk profiling.

Objective: Epidemiological data have suggested that late-life depression (LLD) occurs as a consequence of cerebrovascular and neurodegenerative disorders, but there is also some evidence suggesting that the relationship may occur in the other direction, namely that LLD may be a risk factor for cerebrovascular and neurodegenerative disorders. However, the neurobiological basis of these associations remain unclear. This study investigated the associations of LLD with markers of cerebrovascular pathology, brain volumes, and cortical thickness from 3-Tesla brain magnetic resonance imaging (MRI). Methods: Participants from the Atherosclerosis Risk in Communities Study received brain MRI scans in late-life (ages 67-90). The following neuroimaging outcomes were assessed: cortical infarcts, lacunar infarcts, any microhemorrhages, lobar microhemorrhages, subcortical microhemorrhages, white matter hyperintensity volume, total and regional brain volumes (z-scores), and total average and regional cortical thickness (z-scores). At the same visit, LLD was evaluated with the 11-item Center for Epidemiological Studies Depression Scale (CES-D) and defined as CES-D score≥9. Associations between LLD and neuroimaging outcomes were examined using logistic and linear regression models, and were adjusted for age, race-center, sex, education level, vascular risk factors, stroke, cognitive status, APOE e4 carrier status, and total intracranial volume when assessing volumes. Results: Among 1,857 participants, the median age was 76 years, 59.5% were female, 28.3% were Black, and 6.8% had LLD. LLD was not associated with infarcts or microhemorrhages. There was no evidence of an association between LLD and total white matter hyperintensity volume or total average cortical thickness. However, LLD was independently associated with smaller volume (SD) of the rostral anterior cingulate (b 1 : -0.18; 95% CI: -0.33, -0.04) and greater cortical thickness (SD) in the medial orbitofrontal cortex (b 1 : 0.19; 95% CI: 0.01, 0.38), though effect sizes were small and did not survive correction for multiple comparisons. Conclusion: Findings from this study suggest LLD is not cross-sectionally associated with neuroimaging markers of cerebrovascular disease. While LLD may be linked to subtle volume and cortical thickness changes in specific regions of interest, future longitudinal research is warranted to validate and clarify these associations and explore their potentially bidirectional relationship.

Background: Stroke is a leading cause of death and disability despite advances in risk factor management. Many risk factors for stroke have also been implicated as risk factors for mild cognitive impairment (MCI) and dementia. Given these shared risk factors, cognitive impairment (CI) may represent an accumulation of neurological injury that is associated with an elevated risk of stroke. In ARIC-NCS, we aimed to 1) understand the independent relationship between pre-stroke CI (MCI or Dementia) and incident stroke; 2) explore mortality differences in stroke patients with vs without pre-stroke CI; and 3) evaluate modifiers of these relationships. Methods: 5434 stroke-free participants were evaluated for cognitive status at an in-person visit in 2011-13 (visit 5; ages 66-90), based on cognitive testing and informant interviews. Incident definite or probable strokes (ischemic or hemorrhagic) from visit 5 through 2022 were identified via ongoing surveillance (semi-annual telephone calls, with expert classification). Using Cox proportional hazards regression models adjusted for demographics and vascular risk factors, we evaluated associations between CI (MCI or dementia) and incident stroke, and between CI and death among individuals with stroke. Finally, we tested effect modification by age at visit 5, sex, education, and race, via stratified models and formal interaction terms. Results: Compared to those without CI, individuals with CI (23%) were older (77 vs 75 years, p<0.001), and more frequently male (48% vs 40%). Over 10+ years, CI was independently associated with an increased risk of incident stroke (HR:1.52, 95% CI:1.18-1.96). Among individuals with stroke, risk of death was also higher in CI vs non-CI patients (HR 1.78, 95% CI 1.27-2.50). In stratified analysis, we found a significant interaction by sex (p-interaction=0.04): in males, CI was associated with elevated stroke risk (HR:2.01, 95% CI:1.39-2.91) without a similar risk in females (HR:1.22, 95% CI:0.85-1.75). Interactions by race, age, and educational level were not statistically significant, but effect sizes were qualitatively larger in White participants and individuals with more education. Conclusion: CI is associated with incident stroke independent of shared risk factors, especially in men. This work adds to our understanding of populations at risk for stroke, thus aiding efforts to optimize stroke prevention in at-risk populations.

Abstract Cancer occurs in ∼1 per 1000 pregnancies; thousands of patients may require radiation procedures for diagnosis and treatment each year in the United States alone. This rare but high-risk scenario, coupled with fear of radiation, has created ambiguity in the ideal management of pregnant patients. Without a comprehensive guide for the use of radiation in imaging and treatment for pregnant cancer patients, it is difficult for providers to offer optimal patient-centered care without introducing disparities. The goal of this paper is to provide guidance on the use of radiation for screening, diagnosis, staging, and treatment of cancer, while highlighting gaps in existing knowledge and guidelines. The intention is that physicians, medical physicists, and patients could use this document as a resource for shared decision-making, ensuring safe and effective practice. A team of physicians and medical physicists with expertise in imaging, radiotherapy, and maternal fetal medicine was assembled, along with a patient advocate and lawyer. Existing guidelines and recent literature were reviewed. Authors also drew from their experience where published guidance was lacking. The resulting document discusses best practice to guide use of radiation for cancer, as well as patient-centered care management and legal considerations. Overall, it is possible to safely and effectively deliver radiation to pregnant patients in numerous circumstances. Use of radiation or other modalities should be discussed through shared decision-making with the physician and patient, contextualizing the maternal and fetal risk from treatments. Healthcare providers should support wide access to reproductive healthcare to allow equitable, evidence-based, patient-centered healthcare.

Background: For women in the United States desiring implant-based breast reconstruction, the maximum volume of commercially available silicone breast implants has, to date, been 800 cc. The authors evaluated the safety of Mentor larger-size MemoryGel Ultra-High Profile breast implants (≥930 cc) in women undergoing postmastectomy breast reconstruction. Methods: This 10-year, multicenter, open-label, prospective, investigational study assessed the safety and effectiveness of larger-volume implants in women undergoing postmastectomy 2-stage primary or revision reconstruction. Three-year Kaplan-Meier curves and multivariable Cox regression analyzed the association between patient and treatment characteristics and surgical outcomes. The BREAST-Q was used to assess effectiveness at 3 years. Results: A total of 400 women were enrolled (225 primary and 175 revision reconstruction). Mean body mass index was 35.8 kg/m 2 ; 81% had a body mass index greater than or equal to 30 kg/m 2 . At 3 years, the cumulative incidence of postoperative complications (excluding rupture) was 63.0% (95% confidence interval, 58.1% to 67.9%). The reoperation rate was 24.5% (95% CI, 20.4% to 29.1%), and the explantation rate was 15.8% (95% CI, 23.5% to 19.9%). Independent predictors of complications included radiation therapy and a history of smoking. There were no significant associations between postoperative complications and implant volume greater than or equal to 1135 cc or less than 1135 cc. BREAST-Q scores at year 3 showed significant improvements from baseline in Satisfaction with Breasts, Psychosocial Well-Being, Sexual Well-Being, and Physical Well-Being (all P < 0.0001). The mean score for Satisfaction with Outcome was 79.9. Conclusions: These 3-year results demonstrate that larger-volume silicone breast implants represent a safe and effective option for patients with larger breasts who are requesting postmastectomy implant-based reconstruction.

Abstract Objective To measure the relative levels of signal and noise in expert diagnosis of epilepsy. Methods Twenty multinational epileptologists independently reviewed 50 vignettes of adult and pediatric patients presenting with suspected seizure(s) on two separate occasions with a ≥30‐day washout period. Experts provided a diagnosis of epilepsy or non‐epilepsy based on clinical information and, if requested, routine EEG and neuroimaging data. Cases had an established clinical diagnosis of epilepsy or non‐epilepsy based on capture of habitual paroxysmal events on video‐EEG or long‐term clinical follow‐up. Experts' judgments were analyzed to decompose variability into different sources: signal (objective differences between cases), level noise (experts' bias toward over/under‐diagnosis), pattern noise (experts' idiosyncratic reactions to specific case features), and occasion noise (inconsistency across occasions). Results The probability of an expert making a different diagnosis for a given case on two different occasions was 16%. The probability of two different experts making a different diagnosis for the same case was 26%. Signal (case “difficulty”) accounted for 66–69% of total variation, with 31–34% attributable to noise. Level noise was the largest contributor in the absence of EEG/neuroimaging results (23%), while pattern noise dominated when test results were available (24%). Occasion noise contributed relatively little (1%) but was still sufficient to cause diagnostic reversals in 16–22% between occasions. Significance The degree of noise in expert diagnosis of epilepsy is substantial, stemming primarily from physicians' idiosyncratic interpretations of case features and variable dispositions toward over‐ or under‐diagnosis. Strategies to improve reliability are needed, including standardized data collection protocols and structured decision algorithms. For “difficult cases,” where expert reliability and accuracy are lowest, our findings support current clinical practice which favors early referral for video‐EEG monitoring over reliance on diagnostic anchoring. This diagnostic pathway may become more accessible with advances in EEG technology (e.g., wearable devices) and artificial intelligence.

Objective The objective of this study was to investigate the association between dual seropositive, single seropositive, and seronegative rheumatoid arthritis (RA) with radiographic erosions, disease flares, and death. Methods We performed a retrospective, population‐based study of residents in Southern Minnesota with incident RA who fulfilled criteria for RA in 2003 to 2019. Radiographic erosions and flares were evaluated within one year of incident RA. All‐cause mortality was obtained from medical records and death certificates. Cox models adjusted for age, sex, smoking status, year of incident RA, and comorbidities were used. Results The study included 1,373 patients with RA. At RA incidence, 37% were dual seropositive, 13% seropositive for anti–cyclic citrullinated protein (anti‐CCP) only, 12% seropositive for rheumatoid factor (RF) only, and 38% seronegative. The highest proportion of radiographic erosions before or within one year of RA incidence was in the dual seropositive (31%) and lowest in those seropositive for anti‐CCP only (13%). Flares occurred in 69% of the dual seropositive and 51% of the seropositive for anti‐CCP only within the first year of RA incidence. Those seropositive for RF only had over a two‐fold increase in mortality rates compared with the seronegatives (adjusted hazard ratio [aHR] 2.18, 95% confidence interval [CI] 1.47–3.24). In contrast, the dual seropositives had only a >50% increase in mortality rates (aHR 1.66, 95% CI 1.21–2.28), and those seropositive only for anti‐CCP had a >30% increase in mortality rates (aHR 1.32, 95% CI 0.83–2.11). Conclusion Patients with RA seropositive for RF only have an increase in mortality rates compared with patients who are dual seronegative. RF positivity could be an indicator of inflammation that requires pharmacologic treatment to decrease mortality rates.