Citations

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with exposure to repetitive head impacts (RHI). In CTE, hyperphosphorylated tau (p-tau) aggregates are found in neurons at the depth of cortical sulci close to the gray matter/white matter (GM/WM) boundary. To date, CTE can only be diagnosed postmortem by neuropathological examination. Traumatic encephalopathy syndrome (TES) is the clinical syndrome purported to be associated with CTE pathology. The aim of this study is to investigate microstructural properties at the GM/WM boundary in individuals with a history of exposure to RHI and clinical features of CTE (i.e., TES). Diffusion magnetic resonance imaging (dMRI), TES diagnoses, and cerebrospinal fluid (CSF) biomarkers were acquired from 165 male former American football players (age: 57.29 ± 8.23 years) from the DIAGNOSE CTE Research Project, a multicenter, observational cohort study. Fractional anisotropy (FA) was measured at the GM/WM boundary of the whole brain. In addition, a widely used method (tract-based spatial statistics [TBSS]) was applied to measure FA of central WM. We used analyses of covariance to test associations between FA and TES. Furthermore, we used linear regressions to test associations between FA and nine CSF biomarkers (i.e., p-tau-181, -217, -231, total tau, amyloid β [Aβ] 1–40 , Aβ 1–42 , glial fibrillary acidic protein [GFAP], neurofilament light [NfL], and soluble triggering receptor expressed on myeloid cells-2 [sTREM2]). We report an association between higher FA at the GM/WM boundary and higher levels of certainty for CTE pathology ( F (1, 147) = 5.781, 95% confidence interval (CI) = 0.0003–0.003, p = 0.035) as well as neurobehavioral dysregulation ( F (1, 148) = 7.559, 95% CI = 0.001–0.009, p = 0.020), and functional dependence/dementia ( F (1, 148) = 5.046, 95% CI = 0.0004–0.006, p = 0.039). In addition, we report an association between higher FA at the GM/WM boundary and higher CSF p-tau-181 (β = 0.272, 95% CI = 0.078–0.466, p = 0.029) and p-tau-217 (β = 0.295, 95% CI = 0.102–0.488, p = 0.027). FA of the central WM was not associated with TES diagnoses. Taken together, these findings suggest that dMRI at the GM/WM boundary could be used to investigate microstructural alterations suggestive of tau pathology-associated neurodegeneration in individuals with TES, the clinical presentation of CTE. Future studies are needed to validate this approach and to identify clinically useful cutoff values for dMRI metrics.

Malignant glioma is considered invariably recalcitrant, thus necessitating development of new therapeutic approaches. Spontaneously arising canine glioma exhibits important molecular and pathological similarities to malignant pediatric glioma, making it an invaluable model for testing novel therapies. We evaluated safety and activity of RNA lipid particle aggregates (LPAs) designed to provoke cancer immunogenicity in 10 dogs with histologically confirmed glioma. Vaccine manufacturing was feasible in all subjects and generally well tolerated. Median survival time was 123 and 155 days in dogs receiving three (Group A) or four (Group B) vaccines, respectively; this was increased from historical reporting of subjects receiving palliative care. Responding animals had a robust cytokine response following infusions. In animals receiving non-specific RNA-LPAs, there was localization of messenger RNA (mRNA) payloads to the brain tumor microenvironment and a rapid shift in immunologic gene signatures consistent with a viral response. These data demonstrate the ability to induce rapid viremic response in the tumor microenvironment following a single peripherally administered mRNA vaccine. Since RNA-LPAs are amenable to repeat boosts, these formulations may overcome challenges of tumor immunosuppression and therapeutic access and are currently under evaluation in first-in-human trials ( NCT04573140 , NCT06389591 ).

Abstract This short review highlights recent findings related to transcription factor-mediated RNA polymerase II (Pol II) pause release at enhancers and its role in regulating cell identity. We discuss how the transcriptional state of Pol II, either paused or released, shapes enhancer–promoter interactions, thereby influencing gene expression programs that define cell identity. We further summarize current knowledge of DNA-binding transcription factors that regulate Pol II pause release at enhancers and explore how this process influences cell identity. We propose a novel concept of therapy-induced molecular amnesia, where temporary inhibition of enhancer-proximal Pol II pause release and enhancer RNA transcription affects enhancer–promoter interactions differently in distinct cellular contexts. In some contexts, preservation of enhancer–promoter interactions allows rapid transcriptional reactivation and maintenance of cell identity upon recovery. In other contexts, repeated inhibition of enhancer RNA transcription leads to the permanent dissociation of enhancer–promoter interactions and loss of cell identity. Our model suggests that manipulating Pol II pause release at enhancers could selectively reverse certain aggressive tumor cell identities, limit tumor cell plasticity, and improve therapy responsiveness.

Abstract DDX3X dysfunction causes an X-linked multisystem disorder with high penetrance and variable expressivity. The phenotypic spectrum spans from learning disability without somatic involvement to profound intellectual disability with severe impairments in the central nervous system and other organs. A few multicenter studies and single case reports have previously highlighted some common phenotypic patterns but were unable to delineate correlations between underlying DDX3X variants and phenotypic findings.From the second largest patient cohort published to date, we analysed clinical, psychometric and diagnostic findings of 52 female and 7 male individuals, harbouring de novo and inherited DDX3X variants. These female patients revealed previously unknown quantitative correlations between variant type and localization and specific phenotypic findings (growth features, epilepsy, brain anomalies, dysmorphisms, motor-focused neurological findings). Moreover, by analysing the in silico folding and RNA binding capability of mutant DDX3X monomers, we were able to delineate novel correlations between DDX3X monomer misfolding grade and phenotypic severity.

The author presents the case of a middle-aged woman who had a left parietal lobe infarct. Due to severe aortic regurgitation limiting her activity and aortic root aneurysm, the patient underwent aortic valve and aortic graft replacement, in addition to PFO closure. During this hospitalization, aortic root pathology was noted, leading to an ultimate diagnosis of giant cell aortitis.

Objectives: Diabetes mellitus and chronic pancreatitis are established risk factors for pancreatic ductal adenocarcinoma (PDAC). The co-occurrence of exocrine and endocrine pancreatic dysfunction may increase the risk of progression to PDAC and could play a role in early detection. We sought to explore this hypothesis by comparing PDAC risk among patients with diabetes mellitus (DM) and low fecal elastase (FE) in a real-world cohort of patients. Materials and Methods: A retrospective cohort study was conducted using the TriNetX research network including adults with continuous follow-up from 2016 to 2023. The cohort was stratified into 4 groups based on the presence or absence of DM, and normal FE (>200 µg/g) or low FE (<200 µg/g). The 4 groups included: (1) low FE and DM, (2) low FE without DM, (3) normal FE and DM, (4) normal FE without DM. Propensity score matching was performed to balance covariates including age, sex, race, comorbidities to allow for a 6-way comparison of PDAC risk between groups. Time-to-event analyses were conducted with Kaplan-Meier curves and Cox proportional hazards models to estimate hazard ratios (HR) and 95% CIs for the primary outcome of PDAC incidence. Results: Of the study cohort, 29,207 had fecal elastase levels. Low FE (<200 µg/g) was observed in 33% (n = 9585) of these patients. After 6-way comparisons, we observed a higher PDAC risk among individuals with both DM and low FE compared with other groups. The highest PDAC risk was observed in patients with both a low FE (<200 µg/g) and DM compared with those with a normal FE and without a history of DM (HR: 3.68; 95% CI, 2.07–6.53; P < 0.001). Sensitivity analysis using a stricter fecal elastase cutoff of <100 µg/g showed a similar finding, with the highest hazard ratio for PDAC among patients with both DM and very low FE levels (HR: 3.07, 95% CI, 1.37–6.91; P = 0.004). Conclusions: The coexistence of low fecal elastase and DM amplifies the risk of pancreatic ductal adenocarcinoma in our cohort of patients. These results suggest that fecal elastase values may be used to enrich the diabetic population for future PDAC risk stratification, though more studies are needed to validate these findings.

Background Despite the widespread adoption of established and emerging forensic training and education modalities, there is limited evidence supporting effective ways in which to systematically evaluate their adoption into forensic nursing practice. To address this, our team developed the Sexual Assault Nurse Examiner (SANE) Practice Integrated Competency Evaluation (SPICE) as an innovative tool to support self-reflection, goal setting, and an evaluation of role development. Aim To establish expert consensus on the content and capacity of SPICE to evaluate role development across essential forensic nurse competencies, responsibilities, and clinical practice expectations. Method We utilized a modified Delphi method to establish expert consensus. Results We engaged forensic experts in multiple rounds of review. A deductive, rapid thematic analysis synthesized qualitative discussion. Survey-based results were summarized descriptively. Discussion The expert consensus approach we describe here highlights the potential and promising utility of SPICE to evaluate, guide, and enhance SANE role performance and ongoing professional development.

Abstract Background Allowable total error (ATE) is a quality concept that defines acceptable analytical performance for a clinical laboratory assay. ATE will vary in terms of the amount of error permissible not only between assays but also based on the test setting and the assay’s clinical use. In the clinical laboratory, ATE limits are routinely applied, for example, when evaluating new analytical methodology or equipment for patient testing, troubleshooting unacceptable quality control, or in evaluating instrument comparability. Content Currently, there are no universally applicable standards for defining the maximum magnitude of allowable error. However, there are several resources available for users to consider when setting ATE limits. Examples include clinical outcomes studies, biological variation of the measurand, state-of-the-art, professional organizations, and requirements set by regulatory agencies and proficiency testing/external quality assessment scheme organizers. Each of these approaches varies in terms of the resulting magnitude of allowable error for the same assay. This review describes these resources in more detail and discusses the strengths and weaknesses of each approach. Summary ATE users should be aware of different resources and their limitations before defining acceptance criteria for an assay in their clinical laboratory.