Citations

Aging plays a major role in the development of numerous chronic diseases, one of which is a marked decline in skeletal health. Beyond diminishing bone mass and strength, mammals of advanced age experience a decline in skeletal mechanotransduction—that is, the ability of the skeleton to respond adaptively to mechanical perturbation. One possibility for the loss of mechanotransduction in bone with aging is an age-associated increase in the population density of senescent cells—those cells that have undergone irreversible cell cycle arrest, resistance to apoptosis, and production of a modified secretome (the SASP) that has damaging effects to nearby healthy (non-senescent) cells. We investigated whether the presence of senescent cells might drive some of the diminished mechanical response observed in aged bone, by testing the hypothesis that the clearance of senescent cells via intermittent senolytic treatment promotes mechanical responsiveness in an aged skeleton. C57BL/6 mice aged 6 months and 22 months were treated weekly with the senolytic cocktail Dasatinib and Quercetin (D + Q) for 1 month, then subjected to low level in vivo mechanical loading of the ulna for 1 week. The 6-month-old mice exhibited a doubling of load-induced ulnar periosteal bone formation when treated with D + Q, compared to vehicle-treated mice, but the periosteal response to loading was not significantly altered by D + Q in the aged (22-month) mice. We further probed the efficacy of D + Q in mechanotransduction by switching to an endocortical model—the axial tibia loading system. Here, the 22-month-old mice had nearly double the load-induced endocortical bone formation compared to vehicle-treated mice. We further assayed the cortical bone gene expression profile in loaded and control tibias from treatment-naïve 6-month and 22-month mice, to determine whether there is significant overlap between mechanically induced signaling genes and SASP genes. We found significant load-induced changes among several SASP genes, suggesting that inhibition of the SASP (i.e., senomorphics) might interfere with mechanical signaling from otherwise healthy cells. In summary, clearance of senescent cells via intermittent D + Q treatment is effective at improving endocortical mechanical responsiveness in the aged skeleton, which is commonly diminished throughout the course of aging.

Objective The effects of deep brain stimulation (DBS) manifest across multiple timescales, spanning seconds to months, and involve direct electrical effects, neuroplasticity, and network reorganization. In epilepsy, the delayed impact of DBS on seizures presents challenges for optimization. Single‐pulse stimulation and resulting brain stimulation evoked potentials (BSEPs) provide a means to assess effective connectivity and network excitability. This study integrates BSEPs and short trials of DBS during stereoelectroencephalography (sEEG) to map seizure network engagement, modulate network dynamics, and monitor excitability and interictal abnormalities for biomarker informed neuromodulation. Methods Ten individuals with drug resistant epilepsy undergoing clinical sEEG were enrolled in this retrospective cohort study of epilepsy neuromodulation biomarkers. Each patient underwent a trial of high frequency (145Hz) thalamic DBS. BSEPs were acquired before and after DBS trials. Baseline BSEP amplitude assessed seizure network engagement, and modulation of amplitude (pre vs post DBS) assessed change in network excitability. Interictal epileptiform discharges were tracked by an automated classifier. Results Baseline BSEPs delineated distinct patterns of network engagement between thalamic subfields with maximal frontotemporal engagement achieved with stimulation of the anterior nucleus of the thalamus‐ventral anterior nucleus junction. DBS delivered for >1.5 hours reduced BSEP amplitudes compared to baseline, and the degree of modulation correlated with baseline connectivity strength. Shorter DBS trials did not induce reliable BSEP amplitude suppression, but did immediately suppress interictal epileptiform discharge rates in well‐connected seizure networks. Interpretation BSEPs and trials of DBS during sEEG provide novel network biomarkers to evaluate the modulation of large‐scale networks across multiple timescales, advancing biomarker informed neuromodulation. ANN NEUROL 2026;99:748–760

Abstract Candida auris is an emerging fungal pathogen with high rates of multidrug resistance, posing a significant global health threat. Immunosuppressed patients are particularly vulnerable to multidrug-resistant (MDR) C. auris infections. This systematic review and meta-analysis (SR-MA) aimed to assess the global prevalence of MDR-C. auris isolates in humans and their resistance to antifungal drugs, primarily fluconazole (FLZ), voriconazole (VOR), and amphotericin B (AmB). A comprehensive search was conducted in PubMed, Scopus, and ScienceDirect databases on published studies regarding clinical C. auris isolates and the use of antifungal susceptibility testing assay from 17 March 2015 to 1 February 2024. Meta-analysis was conducted using random-effects models to determine the estimated pooled prevalence of MDR-C. auris isolates and their antifungal resistance profiles from immunosuppressed humans. A total of 81 research studies were included in the final analysis, with the overall pooled prevalence of the three most important antifungal drugs; FLZ (92.5% | 95% CI: 89.5–94.7), VOR (49.0% | 95% CI: 37.6–60.4), and AmB (51.0% | 95% CI: 42.3–59.7). According to the subgroup analyses, FLZ-resistant C. auris was the most prevalent isolate observed in the five continents reporting compared to the VOR- and AmB-resistant C. auris having lower pooled prevalence. Further, higher pooled prevalence of MDR-C. auris isolates were observed from males (68.2%, n = 578) compared to females (37.1%, n = 283). Finally, the global pooled prevalence for mortality in immunosuppressed patients with MDR-C. auris from 13 research studies was 41.5% (95% CI: 29.9–54.2). This SR-MA study establishes the variation of MDR-C. auris resistance patterns observed from different continents and the importance to conduct further research studies using potent antifungal drugs. Accordingly, it is imperative to establish stringent surveillance on the increasing prevalence of antifungal resistance particularly in low-income regions with limited research resources to prevent increasing prevalence of MDR-C. auris.

Background: Inappropriate facial scarring can lead to significant physical and psychosocial morbidity. There is a need to better understand how scar perception varies across ethnic groups, and how it impacts broader quality-of-life domains such as career and sexual well-being. This study evaluates White and Asian patients’ perceptions of facial scars related to symptoms, appearance, psychosocial health, and career/sexual well-being. Methods: Facial surgery patients from 5 providers were recruited to complete the SCAR-Q and Career/Sexual Well-Being (CS) scales through phone or email. Higher scores on both assessments indicate more positive patient perceptions. Results: Among the 147 respondents, 50.3% were Asian and 49.7% were White. Procedures included blepharoplasty (n=56), rhinoplasty (n=20), eyelid revision (n=19), facelift (n=18), Mohs surgery (n=7), chin augmentation (n=6), craniotomy (n=6), and other facial procedures (n=16). White patients scored significantly higher than Asian patients on the SCAR-Q total (median=260 versus 234), appearance (76 versus 59), psychosocial (100 versus 87), and CS (16 versus 12.5) scales ( P =0.004, P <0.001, P =0.026, and P <0.001, respectively). Symptom scores positively correlated with time since surgery in both groups (Asian: r =0.326, P =0.004; White: r =0.319, P =0.011). Conclusions: Asian patients reported more negative perceptions of scar appearance, symptoms, psychosocial impact, and career/sexual well-being than White patients. These findings underscore the importance of tailored follow-up care and counseling to address ethnic differences in scar perception and quality-of-life outcomes.

ABSTRACT Background The Extracorporeal Life Support Organization recommends daily antithrombin monitoring and supplementation to achieve > 50%–80% activity during extracorporeal membrane oxygenation (ECMO). Evidence supporting this practice is uncertain, and whether it confers clinical benefit or harm is unclear. Methods This was a systematic review with meta‐analysis to evaluate the safety and efficacy of antithrombin supplementation during ECMO. We systematically searched databases and registers for studies comparing patients on ECMO who received antithrombin supplementation to those who did not. Random effects meta‐analysis was performed. Risk of bias was independently assessed by two investigators. A priori subgroup and sensitivity analyses were performed to explore reasons for heterogeneity. Results A total of 11 studies were identified. In the pooled meta‐analysis, antithrombin supplementation resulted in no difference in bleeding events (OR 1.38, 95% CI, 0.88–2.17, p = 0.16), thrombotic events (OR 1.57, 95% CI, 0.84–2.90, p = 0.15), or mortality (OR 1.21, 95% CI, 0.81–1.81, p = 0.35) when compared to those who did not receive antithrombin. Subgroup analysis revealed no difference in bleeding events or mortality in pediatric or adult patients; however, pediatric patients that received antithrombin were more likely to experience a thrombotic event (OR 1.70, 95% CI, 1.51–1.91). Sensitivity analysis in only low risk of bias studies confirmed these findings. Conclusions Antithrombin supplementation was not associated with differences in mortality or hemostatic outcomes during ECMO support and may be associated with harm in pediatric patients on ECMO.

Prostate cancer is the second most common cancer in U.S. men, with higher incidence and mortality among African Americans and those with genetic or familial risk. Despite guidelines promoting early detection, prostate-specific antigen (PSA) screening in primary care remains inconsistent. We assessed PSA screening patterns and the association between risk factors and testing. A retrospective analysis was conducted on men aged ≥40 seen at primary care clinics from 2020 to 2022. Risk scores were created based on the number of prostate cancer risk factors. Univariate and multivariate analyses assessed associations between the risk scores, PSA screening, and cancer diagnosis. Of 176,326 patients, 31.4% underwent PSA testing, rising to 78.1% with a risk score of 4. The predictive model was significant (χ 2 = 19,527.021, df = 11, p < .001). PSA testing odds were higher with Medicaid or commercial insurance (vs. Medicare) and lower for self-pay patients. Former and never smokers were more likely to be tested than current smokers. Age, African American race, and family history increased the odds of receiving PSA testing. Prostate cancer diagnosis reached 25% at a risk score of 5, with significant predictors including older age, African American race, family history, and mention of “prostate” in clinical notes. PSA screening remains underused in primary care, even among high-risk patients. More risk factors were linked to higher testing rates, but African American and low-income groups were under-tested. Provider education and decision-support tools may improve guideline adherence and equity.

Background/Objectives: Deep brain stimulation (DBS) of the globus pallidus interna (GPi) is a safe and established therapy for management of refractory motor fluctuations and dyskinesia in Parkinson’s disease (PD). However, the relationship between stimulation site connectivity and improvement of axial gait symptoms remains poorly understood, particularly when stimulating in the GPi. This study investigated functional and structural connectivity patterns specifically associated with axial symptom outcomes following bilateral GPi-DBS, and, as a secondary exploratory analysis, examined whether Volumes of tissue activated (VTAs)-based connectivity related to overall UPDRS-III change. Methods: We retrospectively analyzed 19 PD patients who underwent bilateral GPi-DBS at the University of Florida (2002–2017). Unified Parkinson’s Disease Rating Scale (UPDRS-III) axial gait subscores were assessed at baseline and 36-month follow-up. VTAs were reconstructed using Lead-DBS and coregistered to Montreal Neurological Institute (MNI) space. Structural connectivity was evaluated with diffusion tractography, and functional connectivity was estimated using normative resting-state fMRI datasets. Correlations between VTA connectivity and clinical improvement were examined using Spearman correlation and voxelwise analyses. Results: Patients with axial improvement in motor scales demonstrated specific VTA connectivity to sensorimotor and supplementary motor networks, particularly lobule V and lobules I–IV of the cerebellum. These associations were specific to axial gait subscores. In contrast, worsening axial gait symptoms correlated with connectivity to cerebellar Crus II, cerebellum VIII, calcarine cortex, and thalamus (p < 0.05). Total UPDRS-III scores did not show a significant positive correlation with supplementary motor area or primary motor cortex connectivity; a non-significant trend was observed for VTA–M1 connectivity (R = 0.41, p = 0.078). Worsening total motor scores were associated with cerebellar Crus II and frontal–parietal networks. These findings suggest that distinct connectivity patterns underlie differential trajectories in axial and global motor outcomes following GPi-DBS. Conclusions: Distinct connectivity profiles might underlie axial gait symptom outcomes following GPi-DBS. Connectivity to motor and sensorimotor pathways supports improvement, whereas involvement of Crus II and occipital networks predicts worsening. Additional studies to confirm and expand on these findings are needed, but our results highlight the value of connectomic mapping for refining patient-specific targeting and developing future programming strategies.