Publications by Year: 2026

OBJECTIVE: Antiseizure medication (ASM) may affect autonomic nervous system (ANS) activity in patients with epilepsy (PWE). We examined the relationship between ASM dosage and multimodal correlations among ANS signals recorded from wearables in pediatric PWE.

METHODS: We evaluated evening (ASM intake from 5 p.m. to 3 a.m.) multimodal recordings (heart rate [HR], electrodermal activity [EDA], temperature [TEMP], and respiratory rate [RR]) from wearables (Empatica E4) worn by pediatric PWE during long-term monitoring at Boston Children's Hospital between 2015 and 2021. Within-patient comparisons were performed in two groups: patients with both high- and no-dose ASM days, and with both high- and low-dose ASM days. Multimodal interactions were assessed using principal component and canonical correlation analysis, and repeated measure analyses of variance with time and dose as factors.

RESULTS: Of the 52 patients (median age = 12.8 years), 34 total patients had both high- and low-dose ASM days, and 24 total patients had both high- and no-dose days. An interaction between dose and time emerged in the high- versus no-dose comparison (p = .002), indicating divergent trajectories of multimodal autonomic correlations across medication states; correlations increased on high-dose days and decreased on no-dose days. EDA increased (p = .003) and HR decreased (p = .036) from baseline to peak window for patients with both high- and low-dose days. No time effects or dose-time interactions were found for TEMP and RR. Subanalyses by ASM mechanism of action showed no differential effects on individual ANS measures. Cox modeling showed a dose effect on time to seizure (chi-squared = 6.98, p = .031), with higher hazard on low- versus high-dose days (p < .01) and no difference between no- and high-dose days (p = .626).

SIGNIFICANCE: ASM dosage was related to multimodal autonomic correlations, suggesting central autonomic regulation and seizure vulnerability. Wearable-based monitoring of these correlations could support seizure risk assessment and inform personalized treatment strategies.

PURPOSE OF REVIEW: To summarize recent animal, postmortem and in vivo human studies examining the role of the noradrenergic and serotonergic system in the pathophysiology and symptomatology of Alzheimer's disease (AD).

RECENT FINDINGS: Early in adulthood, the locus coeruleus and raphe nucleus accumulate tau, undergo morphological changes, and exhibit hyperexcitability, which contributes to the development of neuropsychiatric symptoms. As cortical AD pathology increases, these nuclei become hypoactive, but elevated neurotransmitter levels persist in the cortex, presumably driving amyloid-related hyperexcitability and contributing to tau spreading and cognitive decline.

SUMMARY: The pathologic changes occurring within these monoaminergic systems temporally align with the observation that neuropsychiatric symptoms precede cognitive changes in AD, indicating that these systems link the earliest pathobiology of the disease to the evolution of the symptoms. The proposed monoaminergic framework intends to guide researchers into investigating the temporal dynamics between monoaminergic changes, AD pathology, and symptoms, with the ultimate goal of evaluating and developing effective precision therapeutic approaches taking into account the disease stage and symptom profile.

Background: Emerging evidence suggests that COVID-19 may influence obstructive sleep apnea (OSA) pathophysiology by affecting upper airway collapsibility, ventilatory control, and arousal responses, raising the possibility of a bidirectional relationship. This study examined whether individuals with a history of COVID-19 show altered OSA-related physiological traits compared with those without prior infection. Methods: In a case-control study, 60 participants with a history of COVID-19 were compared to 60 matched controls who underwent overnight in-hospital polysomnography before the pandemic. The matching criteria included age (±5 years), gender, body mass index (BMI) (±5 kg/m2), and OSA presence. Key pathophysiological traits (collapsibility, loop gain, arousal threshold, muscle compensation) estimated from polysomnographic signals were compared, with adjustment for age, sex, BMI, and apnea-hypopnea index. Results: The participants (78% male, mean age 55 ± 12 years, BMI 29.4 ± 5.0 kg/m2) exhibited no meaningful differences in their average levels of collapsibility (Adj dif [95% CI]; Vpassive: -1 [-4, 2] %eupnea, p = 0.7), loop gain (LG1: 0.01 [-0.04, 0.06], p = 0.7), or arousal threshold levels (-1 [-7, 4] %eupnea) and showed similar levels of muscle compensation (Vcomp: 5 [-1, 11], p = 0.12). However, a greater ventilatory response to arousal (7 [1, 12] %eupnea) was associated with COVID-19 history. Conclusions: COVID-19 history is not associated with differences in key OSA pathophysiological traits, suggesting it is unlikely to explain observed differences in OSA presentation. The increased ventilatory response to arousal may have implications for treatment responses and outcomes.

Human RAD52 is a prime target for synthetic lethality approaches to treat cancers with deficiency in homologous recombination. Among multiple cellular roles, RAD52's functions in homologous recombination repair and stalled replication fork protection appear to substitute for those of the tumor suppressor protein BRCA2. However, the mechanistic details of how RAD52 substitutes for BRCA2 functions are only beginning to emerge. RAD52 forms an oligomeric ring enveloped by ∼200-residue-long disordered regions, forming a highly multivalent and branched protein complex that promotes supramolecular assembly. Here, we demonstrate that RAD52 undergoes homotypic phase separation, forming condensates that recruit key homologous recombination factors, including single-stranded DNA (ssDNA), replication protein A (RPA), and the RAD51 recombinase. Furthermore, we show that RAD52 phase separation is regulated by its interaction partners such as ssDNA and RPA. Through fluorescence microscopy, we observe that RAD52 promotes the formation of RAD51-ssDNA fibrillar structures. To resolve the fine architecture of these fibrils, we employed single-molecule super-resolution imaging via DNA-PAINT and atomic force microscopy, revealing that RAD51 fibrils comprise bundles of individual RAD51 nucleoprotein filaments. Additionally, we show that RAD52 induces end-to-end tethering of RAD51 nucleoprotein filaments. Collectively, these findings highlight distinctive macromolecular organizational features of RAD52 that may underpin its diverse cellular functions.

Mycoplasmas are pathogens causing infectious diseases in various animals, including humans. They are also common contaminants of cell culture. Although it is suggested that mycoplasmas alter nucleic acid metabolism of host cells through their nucleases, the actual impact of the nucleases on host cell RNAs is unknown. Here we report that Mycoplasma hyorhinis, a common laboratory contaminant species, promotes cleavage of host cell transfer RNAs (tRNAs) through a membrane-associated nuclease. When infected by M. hyorhinis, scraping of cells as well as cell lysis induced a marked cleavage of host RNAs. Further analysis suggested that the protein encoded by the membrane nuclease A (mnuA) gene is responsible for the host RNA cleavage. MnuA protein demonstrates DNase and RNase activities dependent on Ca2+/Mg2+ ions. Purified MnuA protein acts as an atypical sugar non-specific nuclease: while it possesses broad DNase activities, its RNase activity is highly specific to tRNAs in live cells. Mutational analysis shows that the nuclease activity is mediated by a domain which is highly similar to DNase I. Furthermore, M. hyorhinis promoted cleavage of host tRNAs under amino acid deprivation, suggesting that M. hyorhinis infection may alter RNA metabolism in host cells under certain physiological stress. As mnuA genes are conserved in various mycoplasma species, our findings provide novel insights into the effects of MnuA nucleases on host cell RNAs under mycoplasma infection.

Ribosomes are central to protein synthesis in all organisms. In mammals, the ribosome functional core is highly conserved. Remarkably, two rodent species, the naked mole-rat (NMR) and tuco-tuco, display fragmented 28S ribosomal RNA (rRNA), coupled with high translational fidelity and long lifespan. The unusual ribosomal architecture in the NMR and tuco-tuco has been speculated to be linked to high translational fidelity. Here, we show, by single-particle cryo-electron microscopy, that despite the fragmentation of their rRNA, NMR and tuco-tuco ribosomes retain their core functional architecture. Compared to ribosomes of the guinea pig, a phylogenetically related rodent without 28S rRNA fragmentation, ribosomes of NMR and tuco-tuco exhibit poorly resolved density for certain expansion segments. In contrast, the structure of the guinea pig ribosome shows high similarity to the human ribosome. Enhanced translational fidelity in the NMR and tuco-tuco may stem from subtle, allosteric effects in dynamics, linked to rRNA fragmentation.

BACKGROUND: Diagnosis and risk stratification of acute heart failure (HF) in the emergency department (ED) remains challenging. N-terminal pro-B type natriuretic peptide (NT-proBNP) measurement is useful in evaluating acute dyspnea. The objective of this study was to evaluate the diagnostic performance of a new Access NT-proBNP assay in a large cohort of ED patients presenting with suspected acute HF.

METHODS: This prospective study enrolled 2701 ED patients across 17 US sites (Nov 2019 to May 2022). Diagnoses were adjudicated by a blinded Clinical Events Committee. The diagnostic performance of the new NT-proBNP assay was evaluated by sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). Secondary analyses included association of NT-proBNP levels with HF severity and 90-day major adverse cardiovascular events (MACE).

RESULTS: Among 2384 patients, 45.5% had acute HF. The Access NT-proBNP assay demonstrated an area under the receiver operating characteristic curve (AUC) of 0.87 (P < 0.001). Sensitivity across age-based cutoffs was high: 96% (<300 ng/L), 90% (<450 ng/L under age 50), 85% (<900 ng/L ages 50 to 75), and 79% (<1800 ng/L over age 75). At a 300 ng/L threshold, NPV was 95% and PPV was 73%. Higher NT-proBNP levels correlated with greater HF severity and predicted shorter MACE-free survival. The Access assay showed similar performance (AUC 0.8536 vs 0.8562) as the Elecsys proBNP II assay.

CONCLUSIONS: The new Access NT-proBNP assay provides strong diagnostic and prognostic performance in ED patients with suspected acute HF, with results comparable to a reference NT-proBNP assay.

Although preclinical studies suggest that omega-3 fatty acids may benefit skeletal health, there are few randomized controlled trials investigating effects of supplemental omega-3 on bone outcomes. This VITamin D and OmegA-3 TriaL (VITAL) ancillary study investigated effects of marine omega-3 (1 g/d; EPA+DHA in a 1.2:1 ratio) vs placebo supplements on fracture risk and bone density/structure. VITAL is a 2 × 2 factorial randomized placebo-controlled trial that studied effects of supplemental marine omega-3 fatty acids and/or vitamin D3 vs placebo on cancer and cardiovascular events. The intervention took place from November 2011 through December 2017; median follow-up was 5.3 yr. The study included 25 871 U.S. men (aged ≥50) and women (aged ≥55) without baseline cancer or cardiovascular disease, not selected for low bone density or fracture history. Primary outcomes were adjudicated incident total, nonvertebral, and hip fractures in the overall cohort. In a subcohort of 771 individuals, we measured 2-yr changes in areal BMD (aBMD) by DXA, and volumetric BMD (vBMD), cortical thickness, and bone strength indices at the radius and tibia by peripheral QCT. Supplemental omega-3 vs placebo had no effect on total (HR, 1.02; 95% CI, 0.92-1.13; p = .73), nonvertebral (HR, 1.01; 95% CI, 0.91-1.12; p = .80), or hip fractures (HR, 0.89; 95% CI, 0.61-1.30; p = .55). In the subcohort, omega-3 supplementation resulted in a small increase in whole body aBMD (+0.03% vs -0.41%, p = .006) and no effect on aBMD at the spine or hip, or vBMD or bone strength indices at the radius or tibia. No serious adverse effects were observed. Supplementation with marine omega-3 fatty acids did not reduce incident fracture risk. It led to a small increase in whole body aBMD but had no other effects on BMD or bone strength measures compared to placebo in generally healthy midlife and older adults.

BACKGROUND: Emergency department (ED) visits by older adults for falls are an opportunity to initiate fall prevention interventions. The GAPcare II trial tested an effective ED-based fall prevention program at two health systems. Our objective was to assess successful completion of intervention processes across sites including consultation completion rates, time to consultation, consultation duration, and types of recommendations made.

PARTICIPANTS AND SETTING: Community-dwelling adults ≥ 65 years old presenting to three EDs (two in Rhode Island, one in Colorado) within 7 days of an accidental fall who were expected to be discharged and were without mobility-limiting injuries.

METHODS: GAPcare II was a randomized controlled trial conducted from August 2021 to January 2025. Participants were randomly assigned to intervention (pharmacy and physical therapy (PT) consultations) or usual ED care arms. Pharmacists reviewed medications for fall risk and recommended modifications. Physical therapists performed validated mobility/balance assessments and provided recommendations for assistive devices, outpatient services, and disposition.

RESULTS: Of 852 eligible ED patients, 196 were enrolled (96 intervention, 100 control). Participants' median age was 78 years, 68% were female, and 83% were white. In the intervention arm, 93% received pharmacy consultations and 83% received PT consultations. Median time from initial consultation request to bedside evaluation was 24 min (pharmacy) and 47 min (PT). Pharmacists recommended changing medication timing (26%), stopping fall-risk medications (19%), and dose adjustments (18%). Physical therapists recommended assistive devices (66%), outpatient services (36%), and skilled nursing facility admission (25%). ED length of stay did not differ between the intervention and usual care arms (4.6 vs. 4.4 h, p = 0.90).

CONCLUSIONS: The GAPcare II trial demonstrated that an ED-based fall prevention program is feasible to implement across two health systems with varied operations, volume, and staffing with similar results. Consultations generated actionable recommendations and did not prolong ED length of stay.

AimThis study aimed to identify risk factors associated with non-optimal triptan response among migraine patients, leveraging the unique combination of genetic and longitudinal data available in the FinnGen project.MethodsWe analyzed register data from 5351 consistent triptan users within the FinnGen project, focusing on patients who switched triptan medications at least once within a two-year period. We assessed 528 variables, including disease diagnoses, drug purchases and socio-economic status, aiming to evaluate clinical risk factors. Moreover, a genome-wide association study (GWAS) was conducted to explore genetic predispositions to triptan switching behavior in the same cohort of patients. Since no significant single nucleotide polymorphisms (SNPs) were found in the GWAS, a supplementary analysis based on previously reported SNPs associated with migraine susceptibility and triptan response was performed.ResultsOur cohort consisted predominantly of women (87%) with an average age of 38 years at the time of their first triptan purchase. In this population of patients who consistently use triptans, 85% of patients did not switch medications, while 9% switched once, 3% switched twice and 3% switched three or more times. Younger patients were more likely to switch medications. Clinical risk factors for switching included fibromyalgia and the use of gastro-oesophageal reflux medications for those who switched twice, and oral cavity disorders, intestinal disorders and gynecological diagnoses for those who switched three or more times. No significant genetic associations were identified.ConclusionsNon-optimal triptan response in migraine patients is associated with several clinical characteristics, including prior medical diagnoses and the use of other medications. No genetic associations were observed in this cohort.