Citations

Abstract Colony-stimulating factor 1 receptor-related adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (CSF1R-ALSP) is a rare, fatal, autosomal-dominant neurodegenerative disorder caused by pathogenic CSF1R variants and characterized by progressive cognitive, neuropsychiatric, and motor dysfunction, white matter lesions on brain imaging, and white matter demyelination, swollen axons, and pigmented glial cells on pathology. Limited data regarding clinical, biofluid or radiological biomarkers of disease severity are available, and no clinical trial endpoints have yet been validated. The objectives of this first-of-its-kind, prospective, observational natural history study were to characterize the clinical trajectory of CSF1R-ALSP and to identify and evaluate key biomarkers and clinical endpoints indicative of disease severity and progression. ILLUMINATE (NCT05020743) was a multicentre, noninterventional natural history study of adults with CSF1R-ALSP and prodromal carriers of CSF1R variants. Participants were followed for up to 36 months, with clinical assessments, fluid biomarkers and volumetric MRI assessments of brain atrophy collected at screening and every 6 months. This study was terminated early (4 June 2025). The analyses reported here include data collected through 19 February 2025. Of 53 participants, 19 were prodromal and 34 were symptomatic (11 of whom had a history of haematopoietic stem cell transplant and 23 who did not). Mean participant age was 47.8 (standard deviation, 4.5) years, and 36.4% were female. Prodromal participants remained relatively stable over 36 months, with little change in neurological function, neurodegeneration biomarkers or radiological disease burden. Impaired neurological function, MRI characteristics of CSF1R-ALSP, and elevated NfL (neurofilament light chain; neurodegeneration biomarker) and GFAP (glial fibrillary acidic protein; astrogliosis biomarker) levels were more pronounced at baseline and often showed progression over time among symptomatic participants who had not previously received haematopoietic stem cell transplant compared with participants who had previously received haematopoietic stem cell transplant. Significant correlations were observed at baseline and longitudinally between MRI measures of brain atrophy and clinical outcome measures. Based on the fluid biomarkers, MRI measures, and clinical outcome assessments evaluated here, active neurodegeneration, widespread changes visualized on brain MRI, and impaired cognitive and motor function were observed in symptomatic patients with CSF1R-ALSP. The neurological impairment can be assessed using the Montreal Cognitive Assessment and Cortical Basal ganglia Functional Scale. Our data suggest that quantification of brain atrophy using MRI volumetry is a potential biomarker of disease severity and progression in CSF1R-ALSP. It is hoped that this report will contribute to the understanding of disease progression in CSF1R-ALSP and inform future drug development.

Variability in novel inflammatory markers (HBP and SAA) post-surgery could indicate ongoing perioperative inflammation. This pilot cohort study collected blood from 99 patients undergoing elective cardiac surgery at baseline, 24 hours, 7 days, and 3 months post-surgery. Inflammatory markers (HBP, SAA, PCT, CRP, IL-6) were measured with a point-of-care device. Demographic and clinical data were extracted from health records. Serum SAA increased significantly in the acute postoperative phase (M e [IQR];SAA baseline =81.1[87] vs SAA 24hr= 232.65[88.02];U[72]=2343,p<0.0001), remained elevated at 7 days (Me 7d =252.6[88.56];U[57]=1484,p<0.0001) and were still more pronounced than baseline at t 3m (Me 3m =118.44[101.52];U[38]=448,p=0.0008). HBP showed a significant rise at seven days (HBP baseline =45[26;89] vs HBP 7d =121[69.75;224.5]; U[56]=805,p<0.0001) then returned to near baseline by t 3m (Me 3m =32.5[15.75;98.5]). Traditional inflammatory markers PCT, CRP, and IL-6 demonstrated a rapid increase at t 24h and plateaued at t 7d . None of the biomarkers showed variability at baseline or postoperatively with preoperative status or postoperative complications. Cluster analysis of the inflammatory markers at 24 hours (t 24h ) identified distinct subgroups. Cluster #1-patients with a modest increase in all markers; Cluster#2 characterized with a robust increase in IL-6; Cluster #3 showed increase in CRP and decline in HBP; Cluster #4 showed a modest increase in IL-6 and decline in HBP; Cluster #5 represented a decline in both CRP and SAA. Patients in these clusters differ with respect to age, pre-existing peripheral artery disease, and borderline differences in perioperative acetaminophen use. SAA and HBP remain elevated longer than IL-6, CRP, and PCT after surgery, suggesting that inflammation may persist beyond 3 months.

Moderate traumatic brain injury (TBI) is a prevalent entity with a wide, dynamic, and heterogeneous injury spectrum. It has its own characteristics. However, it does not receive enough attention, as evidenced by the scarce representation in the literature and the absence of specific guidelines. Its changing epidemiological profile allows us to predict an increase in its incidence in the future, especially in the fragile population. Moderate TBI is not adequately categorized, and the risk of neuroworsening is elevated. The mortality of moderate TBI is not negligible and its functional outcomes are poor. Non-invasive neuromonitoring tools may have a key role in the initial evaluation and categorization of moderate TBI. Moderate TBI has cloudy, dark, and sunny aspects. To analyze these aspects and to propose management strategies constitute the main objective of this narrative review.

Abstract Genetic studies have significantly advanced our understanding of tauopathies, yet the genetic aetiology of Pick’s disease, a rare 3-Repeat tauopathy, remains unclear. The MAPT p.A152T variant has been identified as a risk factor for Alzheimer’s disease and progressive supranuclear palsy, but its role in Pick’s disease is unknown. In this study, we examined the prevalence of MAPT p.A152T in the largest series of neuropathologically confirmed Pick’s disease cases to date (n = 401). Through genotyping, we identified a single mutation carrier in the Pick’s disease cohort (minor allele frequency = 0.12%). We previously reported MAPT p.A152T at a 0.20% frequency in healthy controls (n = 2456), suggesting that it does not associate with 3-Repeat tauopathy risk. To further investigate the effect of the variant on MAPT transcript expression, we used bulk RNA sequencing in Alzheimer’s disease and progressive supranuclear palsy A152T mutation carriers. We did not detect significant differences in 4-Repeat tau levels, though preliminary trends may indicate more nuanced effects that need to be examined with long-read sequencing in a larger series. Overall, our study suggests that MAPT p.A152T does not increase Pick’s disease risk and may instead be linked to 4-Repeat or mixed tau pathologies, warranting further functional investigation.

ABSTRACT Background Olfactory neuroblastoma (ONB) exhibits variable recurrence patterns, with significant late recurrences occurring years after treatment. We investigated cutoff periods to define late recurrence and identified predictors that distinguish patients at risk of late recurrence from those considered cured. Methods From a multi‐institutional cohort of 219 ONB patients treated at nine centers, we analyzed 77 patients with documented recurrence. Using a 48‐month cutoff to define early (< 48 months) versus late (≥ 48 months) recurrence, we evaluated 35 clinical, anatomic, and treatment variables using Firth penalized logistic regression across three comparisons: (1) late versus early recurrence timing, (2) late recurrence versus no recurrence, and (3) early recurrence versus no recurrence. Results Thirty‐four of the 77 (44.2%) recurrences were classified as late. Among the 77 patients who recurred, smaller tumor volume (OR 0.243, p = 0.035) and lower novel Dulguerov staging (OR 0.802, p = 0.038) were associated with late, rather than early recurrence. When patients with late recurrence were compared to those who remained disease‐free, radiographic skull base bone involvement was the strongest independent predictor (OR 2.90, 95% CI 1.14–8.64, p = 0.025), and this effect strengthened after adjusting for tumor volume (OR 3.80, p = 0.029). Pathologic dural invasion (OR 3.29, p = 0.013), Kadish stage (OR 2.02, p = 0.026), and T‐stage (OR 1.32, p = 0.040) were also significant. Conclusions A 48‐month cutoff effectively stratifies ONB recurrence risk. Skull base bone involvement independently predicts recurrence when compared to nonrecurrent cases and uniquely persists as a risk factor for late recurrence. These findings establish skull base bone involvement as a novel biomarker for risk‐stratified surveillance protocols.

Abstract How glial cells sense and regulate neuronal hypoactivity remains poorly understood. Using in vivo imaging in anesthetized, sleeping, and behaving mice, we identified a glial purinergic signaling mechanism that converts neuronal hypoactivity into local circuit regulation. Cortical hypoactivity increased spatially confined ATP release through astrocytic pannexin-1 hemichannels, which were structurally enriched near perisomatic parvalbumin-positive boutons. Local ATP release directed microglial process movement and stabilized bulbous endings through microglial P2Y12 signaling, accompanied by localized Ca²⁺ activity in microglial processes. Disruption of astrocytic pannexin-1 or microglial P2Y12 impaired bulbous-ending stabilization and abolished rebound increases in neuronal activity during emergence from anesthesia. Similar ATP release and bulbous-ending formation were observed during chemogenetic neuronal silencing or natural sleep in freely behaving mice. These findings identify astrocyte-to-microglia purinergic signaling as a mechanism that converts neuronal hypoactivity into synapse-selective microglial regulation of circuit activity.

ABSTRACT Patients requiring permanent pacing after tricuspid valve intervention present challenges due to the need to cross tricuspid valve prostheses. We report three cases of successful dual coronary sinus (CS) lead implantation for biventricular pacing following a range of tricuspid interventions—surgical tricuspid annuloplasty, transcatheter edge‐to‐edge repair, and transcatheter tricuspid valve replacement. The approach avoided tricuspid valve traversal, was technically feasible and resulted in satisfactory pacing performance without procedural complications. Dual CS lead configurations were individualized based on CS anatomy and pacing characteristics. The degree of QRS narrowing achieved varied according to lead location and ventricular activation patterns, highlighting the importance of individualized lead placement strategies and device programming. Dual CS lead pacing may represent a viable alternative for biventricular pacing in selected patients with prior tricuspid valve interventions. Larger studies are needed to evaluate long‐term outcomes and define the optimal role of this approach among available pacing strategies in this patient population.

Study Design. Post hoc analysis of prospectively-collected data. Objective. To identify factors predicting the most (and least) satisfaction following surgery for cervical spondylotic myelopathy (CSM). Summary of Background Data. Patient satisfaction affects long-term outcomes after surgery but the preoperative factors that influence postoperative satisfaction have not been well studied in patients with CSM. Methods. We conducted a post hoc analysis of prospectively-collected data from the Quality Outcomes Database (QOD) CSM registry cohort. Baseline and surgical characteristics were compared for patients with CSM reporting the most [North American Spine Society Satisfaction Score (NASS) 1] and least (NASS 4) satisfaction 24 months postoperatively. A multivariable logistic regression model was constructed using backward stepwise elimination to determine significant predictors of most versus least satisfaction. Twenty-four-month patient-reported outcomes (PROs) were compared. Results. Overall, 1141 patients were prospectively enrolled with 948 (83.1%) reaching 24-month follow-up. Of these, 699 met prespecified inclusion criteria: 610 (87.3%) were most satisfied and 89 (12.7%) were least satisfied. Though there were mean improvements in all 24-month PROs for the most satisfied cohort ( P <0.001), there were no significant improvements in 24-month PROs for the least satisfied cohort ( P >0.05). Using multivariable logistic regression modeling, a preoperative symptom of upper extremity weakness (OR=2.5, P =0.003), subjective myelopathy (OR=2.0, P =0.04), absence of numbness complaints (OR=2.2, P =0.003), symptom duration under 12 months (OR=1.6, P =0.047), Caucasian race (OR=2.3, P =0.001), participation in activities outside of the home (OR=2.0, P =0.04), anterior approach (OR=2.3, P <0.001), and higher baseline quality of life (OR=4.0, P =0.01) were predictive of the most satisfaction. Conclusion. Compared with the least satisfied, those most satisfied following surgery for CSM more often had a preoperative symptom of arm weakness, subjective myelopathy, the absence of numbness complaints, symptom duration under 12 months, higher baseline quality of life, and participation in activities outside of the home. Compared with a posterior approach, an anterior approach was associated with the most satisfaction. Taken together, early surgical treatment--before myelopathic symptoms significantly impact one's quality of life--may be considered to optimize patient satisfaction following CSM surgery.

Autonomous robotic-assisted surgery (RAS) has emerged as a promising objective in biomedical technology, further enhanced by miniaturization toward microrobotic-assisted surgery (μ-RAS). This reduction in scale promises minimally invasive, partially or fully automated surgical procedures, with the potential to reduce patient recovery times, lower medical costs, and enable previously unavailable procedural options. This perspective highlights the specific advances in RAS that potentially map to the microscale (μ-RAS), organized across five surgical domains: endovascular, endoluminal, laparoscopic, ophthalmic, and orthopedic. We examine both clinical demands and technological advances in surgical robotics and identify the key innovations required for progress across these surgical fields. Our contribution is distinct in combining the perspectives of both surgical experts and bioengineering innovators, outlining a roadmap for the advancement and eventual integration of autonomous RAS and μ-RAS into mainstream surgical practice.

Importance Anhydramnios from fetal kidney failure causes lethal pulmonary hypoplasia. Serial amnioinfusions have shown promise in mitigating pulmonary disease from bilateral renal agenesis, but efficacy and safety for other causes of fetal kidney failure are unproven. Objective To assess the efficacy of serial amnioinfusions initiated before 26 weeks’ gestation to mitigate lethal pulmonary hypoplasia in cases of anhydramnios due to fetal kidney failure. Design, Setting, and Participants Prospective, nonrandomized clinical trial conducted at 13 US fetal therapy centers from December 2018 to February 2025. Outcomes for maternal-fetal pairs with anhydramnios before 22 weeks’ gestation due to fetal kidney failure without bilateral renal agenesis are reported; data collection for surviving infants continued until February 13, 2026. Exposure Thirty-two participants underwent serial amnioinfusions with isotonic fluid beginning before 26 weeks’ gestation. Main Outcomes and Measures The primary end point was neonatal survival for 14 days or longer with dialysis access placement. Secondary outcome measures of survival to discharge home and kidney transplant are reported. Results Twenty-nine of 32 participants (91%) had a live birth, with a median (IQR) gestational age at delivery of 34 weeks 1 day (31 weeks 5 days to 34 weeks 6 days). All participants delivered before 37 weeks’ gestation. No unexpected serious maternal adverse events occurred, and the most common maternal complications were preterm prelabor rupture of membranes in 19 participants (56%) and chorioamniotic separation in 10 (29%). The primary outcome occurred in 19 (65.5%) of 29 live-born neonates (95% CI, 45.7%-82.1%). Factors associated with survival to the primary outcome included receiving more amnioinfusions (median [IQR], 14 [9-18] in survivors vs 7 [4-11] in nonsurvivors; P = .01), longer time interval from first amnioinfusion to preterm prelabor rupture of membranes (63.5 [60.5-74.5] days in survivors vs 29.0 [22.0-56.0] days in nonsurvivors; P = .01), gestational age greater than 32 weeks (79% of survivors vs 38% of nonsurvivors; P = .03), and higher birth weight (2029 [1770-2250] g in survivors vs 1635 [1185-1915] g in nonsurvivors; P = .01). Fourteen live-born infants (48%) survived to hospital discharge at a median (IQR) age of 4.7 (3.4-5.7) months. Of the 11 infants surviving to date, 7 (64%) have undergone kidney transplant between ages 2 years to 5 years. Conclusions and Relevance Serial amnioinfusions mitigated lethal pulmonary hypoplasia in neonates with anhydramnios due to fetal kidney failure. Significant neonatal morbidity and mortality independent of early lung function was noted. Factors associated with survival were consistent with the Renal Anhydramnios Fetal Therapy trial’s bilateral renal agenesis cohort, suggesting common mechanistic pathways for mitigating pulmonary hypoplasia. Trial Registration ClinicalTrials.gov Identifier: NCT03101891