Citations

Abstract Emotional experiences during focal seizures are often misinterpreted as psychiatric disorders. We aimed to evaluate symptoms involving affective symptoms at seizure onset. We aimed to identify the most prevalent affective symptoms at seizure onset and characterize their localizing and lateralizing value. We performed a scoping review based on Preferred Reporting Items for Systematic reviews and Meta‐Analyses–extension for Scoping Reviews guidelines. A systematic search identified records from 4 databases: PubMed, Embase, CINAHL (via EBSCOhost), and Web of Science. Two reviewers independently screened titles/abstracts and full texts; discrepancies were resolved by consensus. This review focused on patients with focal seizures, as affective symptoms may occur in generalized epilepsies. The affective symptoms: fear, anxiety, panic, sadness, mystic, ecstatic, sexual, and mirth were identified, and semiology was evaluated in accordance with ILAE guidelines. Symptom onset, frequency, brain localization, and video‐EEG monitoring technique were evaluated to assess localization and lateralization of regional networks. Scalp EEG, invasive EEG recordings, and electrical stimulation were analyzed. A total of 1276 documents were identified, with 98 studies included for review. Fear was the most frequently reported ictal emotion, identified in 274 patients (66%), predominantly in temporal lobe epilepsy. Sadness and sexual, ecstatic symptoms were also consistently associated with temporal networks. Mirth was more frequently reported with frontal onset seizures. Evidence, primarily from Class IV studies, reported right hemispheric predominance for ecstasy, mystic, and sexual symptoms at seizure onset. Ictal affective symptoms at seizure onset yield localizing information. The limbic system, especially the temporal lobe, followed by the frontal lobe, was the most common site of origin. Fear was the most common spontaneous and electrically elicited symptom, followed by anxiety. While bi‐hemispheric lateralization occurred, right lateralization predominated. Recognizing paroxysmal affective symptoms as ictal phenomena may reduce misdiagnosis and aid presurgical evaluation in drug‐resistant focal epilepsy.

Background: The limb symmetry index (LSI) is a measure comparing strength and functional movement between the surgical and nonsurgical limbs, used after anterior cruciate ligament reconstruction (ACLR) to guide rehabilitation and assess return-to-sport readiness. With increasing use of the quadriceps tendon autograft (QT-ACLR), limited data exist on whether the LSI score correlates with patient-reported outcome measures (PROMs). Hypothesis/Purpose: To evaluate the predictive value of postoperative strength and functional LSI tests at 3, 6, and 9 months for short-term PROMs, determine Patient Acceptable Symptom State (PASS) thresholds, and assess differences based on PASS achievement. It was hypothesized that quadriceps strength LSI score would more strongly predict 2-year PROMs than hamstring strength LSI score, and that higher 9-month isokinetic quadriceps LSI scores would be associated with higher International Knee Documentation Committee (IKDC) and Lysholm scores. Study Design: Case series; Level of evidence, 4. Methods: Patients undergoing primary QT-ACLR from 2021 to 2024 with LSI testing during rehabilitation (isometric and isokinetic lower extremity strength, Y-Balance, hop testing) and no revision or additional knee surgery were included. The LSI score was assessed at 3, 6, and 9 months, and PROMs, including Lysholm and IKDC scores, were collected at a mean follow-up of 2.0 ± 0.7 years. Multivariable linear regression was used to evaluate associations between LSI measures and PROMs after adjusting for age, sex, and body mass index (BMI). Receiver operating characteristic analysis was used to determine PASS thresholds. Results: A total of 100 knees in 100 patients (mean age, 25.3 ± 11.2 years; BMI, 25.9 ± 6.5 kg/m 2 ; 52% male) were included. Quadriceps and hamstring strength and functional performance progressively improved from 3 to 9 months, with the LSI score reaching 77% to 81% for quadriceps strength and 98% to 100% for hamstring strength by 9 months postoperatively. At a mean follow-up of 2.0 ± 0.7 years, the mean satisfaction score was 8.4 of 10, the Lysholm score was 90.7, and the IKDC score was 77.8. Linear regression, adjusted for age, sex, and BMI, demonstrated that 3-month isometric quadriceps LSI score had a strong effect on IKDC score, explaining substantial variance (β = 3.9; adjusted R 2 [Adj R 2 ] = 0.36; P < .03); 6-month isokinetic quadriceps and hamstrings showed moderate but significant effects (β = 2.9-3.7; Adj R 2 = 0.13-0.17; P < .05) on IKDC score; and 9-month fast quadriceps had a strong effect explaining substantial variance in Lysholm and IKDC scores (β = 3.9-4.7; Adj R 2 = 0.34-0.35; P ≤ .003). Lysholm and IKDC scores correlated with satisfaction and accurately discriminated PASS thresholds (area under the curve, 0.927-0.937; P < .001). Patients achieving the IKDC PASS demonstrated higher LSI scores across time points and all PROMs. Conclusion: After QT-ACLR, strength-associated LSIs were independently associated with PROMs at a mean 2-year follow-up, after adjusting for age, sex, and BMI. Early isometric quadriceps strength at 3 months predicted higher 2-year IKDC scores, with PASS achievers generally attaining a 60% to 70% LSI score by 3 months. Isokinetic quadriceps strength at 9 months predicted both IKDC and Lysholm scores. These findings highlight the importance of early quadriceps strength recovery and the value of LSI measures in predicting PROMs and informing early rehabilitation.

Abstract Historically, the study of cellular metabolism and the cellular proteome have largely focused on specific proteins and metabolites in certain cellular pathways. With the advent of new “omics” technologies, researchers have been able to probe disruptions and alterations in cellular homeostasis on a near proteome-wide and metabolome-wide basis. Yet the truly interconnected and interdependent nature of the cellular metabolome and proteome has only become more evident with the discovery of proteome-wide protein post-translational modifications (PTMs) such as lysine acylation by acetyl-CoA or succinyl-CoA. Such PTMs link proteome function to fluctuating concentrations of tricarboxylic acid (TCA) cycle metabolites. Tumorigenesis in TCA cycle-defective tumors that upregulate acylating agents such as succinyl-CoA and acetyl-CoA provides a relevant context for understanding the breadth of protein acylation in disease. In particular, succinate dehydrogenase (SDH)-loss chromaffin cells can be transformed to the neuroendocrine tumors pheochromocytoma and paraganglioma (PPGL), but sensitive diagnostic and effective therapeutic options for metastatic disease remain limited. Interrogating cell models of SDH-loss PPGL provides a unique opportunity to capture the effects of SDH loss on cellular metabolism and protein acylation while exploring new avenues for improved diagnostics and novel therapeutic targets in these rare diseases.

Background African American adults experience a disproportionate burden of dementia, shaped by structural and clinical factors that remain unclear. Objective To quantify associations between multimorbidity, polypharmacy, and cognition in the context of neighborhood disadvantage. Methods This study is a cross-sectional analysis of 348 African American adults aged 45–92 years (mean 64.3 years; 73.6% female) from the Aging Research Characterizing Health Exposome via Social drivers (ARCHES) cohort. Comorbidity burden was assessed using a modified Charlson Comorbidity Index (CCI), polypharmacy as ≥5 medications, and neighborhood disadvantage using the Area Deprivation Index (ADI). Linear regression estimated associations with a Preclinical Alzheimer’s Cognitive Composite (PACC). The polypharmacy model included modified CCI as a covariate, and effect modification by ADI was assessed using an interaction term between polypharmacy and ADI. Results Higher modified CCI was associated with lower cognitive performance (B = −0.071; 95% CI: −0.130, −0.012). Polypharmacy was not independently associated with cognition after modified CCI adjustment (B = −0.081; β = −0.057; p = 0.257). No significant ADI interaction was found (p = 0.064).

The bone marrow immune microenvironment (BMME) is a critical factor in multiple myeloma (MM) pathogenesis. Despite higher incidence of MM among self-identified African Americans, the relationship between African genetic similarity and the BMME remains unclear. We present the largest analysis to date assessing the impact of Ancestry on the BMME in myeloma (N=320, including 64 with ≥50% African genetic similarity, AFR-High) leveraging our recently generated Immune Atlas. AFR-High was associated with enrichment of late T-effector cells, driven by rare cytotoxic CD4⁺ T cells, suggesting a distinct adaptive BMME. AFR-High exhibited expansion of late-differentiated adaptive NK cells with high cytotoxic GNLY and GZMH expression. AFR-High depicted reduced CD14⁺ monocytes, increased CD16⁺ non-classical monocytes, and expansion of macrophage-like monocyte populations with enrichment of metabolic adaptation, efferocytosis and phagocytic clearance programs, and immunoregulatory pathways. These findings reveal a shift from an innate inflammatory immune landscape toward adaptive cytotoxic and immunoregulatory remodeling associated with African genetic similarity in MM.

The immune tumor microenvironment (iTME) plays a crucial role in disease biology of plasma cell (PC) dyscrasias, but remains poorly characterized in self-identified Black individuals, a population at increased risk. Mass cytometry and scRNA-seq of 128 bone marrow aspirates revealed significant changes in immune cell composition across the disease spectrum, including shifts from naïve to effector T cells with declines in B cells, MAIT, pDCs, and increases in monocytes with disease progression. Self-identified Black patients had higher relative proportions of terminally differentiated T cells and lower monocytes in newly diagnosed and treated multiple myeloma (MM). ScRNA-seq revealed genes overexpressed in self-identified Black individuals were enriched for E2F targets and G2-M checkpoints, while reduced genes were enriched for TNF-α/NF-kB, interferon and inflammatory responses pathways. These findings were supported by genetic ancestry and validated in an independent dataset of 286 patients with MM from the MMRF Immune Atlas. Self-identified race and African genetic similarity are significantly associated with remodeling the MM iTME, with potential implications for disease biology and treatment response.

Abstract We are interested in DNA stiffness in vitro and in vivo . Classical approaches for measuring this parameter in vitro involve tedious T4 DNA ligase-mediated cyclization kinetics experiments performed for one DNA fragment length at a time to establish effective local end-end concentrations ( J -factors). Protein-mediated DNA looping is a more relevant biological reaction. An efficient approach to determine length-dependent protein-mediated DNA J - loop values in vitro has been lacking. We describe LOOP-TAG, a massively-parallel method. We leverage intramolecular DNA looping and tagmentation catalyzed by Tn5 transposase (Tnp) tethered to the terminus of a ∼1,000-bp bead-bound duplex DNA. We detected loops terminating with Tnp. Counts of the resulting DNA looping-dependent bead-bound tagmentation products from deep sequencing determine DNA loop length probabilities at single-base pair resolution for all bead-bound fragments. When normalized to DNA fragment length probabilities from tagmentation using known concentrations of free Tnp, length-dependent J - loop values are directly determined. We demonstrate LOOP-TAG for Tnp tethered in two ways and in the presence of DNA-kinking architectural DNA binding protein Nhp6A. Intermediate length J-loop values are consistent with expectations of wormlike chain theory after accounting for strong sequence-dependence of Tnp. DNA loops are shifted to smaller sizes in the presence of Nhp6A, as predicted. (200/200 words)

Introduction: Frontotemporal lobar degeneration (FTLD) is a devastating disease that commonly results in early onset dementia, yet its rarity and heterogeneity limit large-scale research and clinical trials. Remote monitoring via low-burden digital health tools may overcome these barriers. We evaluated clinical utility of passive smartphone monitoring in FTLD using a multi-domain mobile assessment platform. Methods: Participants were 567 adults (53% clinically normal, 21% prodromal FTLD, 26% symptomatic FTLD) who completed an in-person study visit and downloaded the ALLFTD Mobile App on their personal smartphones. The app delivered unsupervised cognitive tests and passively collected continuous data on battery percentage (proxy for smartphone use) and step count. Longitudinal follow-up included smartphone monitoring and annual in-person study visits. Primary analyses examined associations between passive smartphone features and markers of disease severity at baseline and longitudinally, and tested whether passive features added incremental value beyond app-based cognitive testing. Results: Passive smartphone features were feasible to collect and showed excellent reliability with <2 weeks of monitoring (ICCs>0.9). Features capturing smartphone use and movement demonstrated sensitivity to gold-standard clinical measures of disease severity both at baseline and longitudinally. A classification model combining passive features, the app-based cognitive composite score, and demographics detected longitudinal functional decline (AUC=0.89); passive features alone (AUC=0.84) performed comparably to a cognitive screener (AUC=0.85). Discussion: Passive smartphone monitoring is a valid, zero-burden measure of disease severity and progression in FTLD that adds modest incremental value beyond app-based cognitive testing. Findings support its use as a scalable digital endpoint in longitudinal FTLD research.