Faculty Bibliography

Protein folding dynamics emerge from subtle changes in intramolecular interactions, where hydration shapes free energy landscapes and influences conformational ensembles and supramolecular assembly. While these shape-shifting principles have been primarily explored in well-behaved systems with sharp transitions, their applicability to multidomain protein assemblies, particularly those containing partially folded or disordered regions, remains unclear. Here, we investigate how a single leucine-to-alanine mutation modulates the hierarchical interplay between folding, micelle formation, and macroscopic biomaterial behavior using two diblock protein block copolymers (BCPs): CE and C_L44AE. In solution, both BCPs exhibit spectral features consistent with their C/C_L44A monoblocks, with CE showing α-helical features and C_L44AE more disordered ones. Upon dehydration, however, both systems display increased structural order, with CE favoring β-sheets and C_L44AE adopting α-helical content. At the mesoscale, both BCPs assemble into amphiphilic micelles, but CE forms smaller, densely packed micelles, whereas C_L44AE generates larger micelles that template film networks of varying pore size depending on their packing density. These differences lead to distinct solvation behavior, with C_L44AE exhibiting greater uptake of predominantly mobile water, approximately twice that of CE, culminating in an actuation energy density of 2,043 kJ/m³, the highest reported for protein BCPs to date. Despite this increased uptake, C_L44AE shows reduced mechanical relaxation and a rougher DSC/TGA thermogram, indicative of a broader conformational ensemble compared to CE. Comparisons to monoblocks (C, C_L44A, E) and previously reported triblocks (CEC, C_L44AEC_L44A) further highlight the importance of asymmetric diblock architectures in promoting hydration-sensitive assemblies, laying the rational design groundwork for future high-performance, water-responsive protein biomaterials.

OBJECTIVE:This study was undertaken to examine acute and chronic electroencephalographic (EEG) and seizure characteristics in new onset refractory status epilepticus (NORSE). METHODS:Multicenter inpatient and follow-up clinical and EEG data were analyzed using International League Against Epilepsy definitions and American Clinical Neurophysiology Society (ACNS) EEG terminology. RESULTS:Forty-four patients were included from the Yale NORSE/FIRES Biorepository (median age = 29 years, 33 female, 38 cryptogenic). Nine hundred twenty inpatient EEG days were reviewed (median = 13.5 days/patient). Presenting status epilepticus (SE) types included 24 convulsive SE (CSE), five focal-motor (FMSE), and 15 nonconvulsive (NCSE). Of 39 patients with post discharge follow-up (median = 14.7 months), 61.5% (n = 24) had seizures and required more antiseizure medications than seizure-free patients (median = 4 vs. 1, p < .001). Inpatient EEG captured epileptiform discharges in all and periodic discharges in 38 patients. Seizures were captured in 38 patients: 33 electrographic (11 only electrographic) and 27 electroclinical. Total seizure burden ranged 6.5-29 615.0 min (median = 50.7). Seizures fulfilling ACNS EEG criteria for SE were captured in 20 patients; two had CSE and the remainder NCSE with coma, nine of whom also had FMSE. Inpatient seizure days (median = 50.0 vs. 15.5%, p = .004) and seizure burden (median = 42.9 vs. 0 min, p = .009) were higher in the first half of monitored days. Interictal findings were equally present and did not predict postdischarge seizures, whereas electroclinical seizures (90.9% vs. 45.5%, p = .037), seizure burden (median = 116.8 vs. 32.5 min, p = .045), and proportion of seizure days (36.3% vs. 20.0%, p = .037) did. Among 12 patients with follow-up EEGs (median = 19.6 months post onset), posterior-dominant rhythm (PDR) returned in nine; five had periodic discharges, and three had seizure captured. SIGNIFICANCE/CONCLUSIONS:Seizures are most commonly convulsive upon presentation and nonconvulsive or clinically subtle throughout the inpatient course in NORSE. Inpatient seizures, but not interictal abnormalities, occur earlier in the inpatient course and presence of electroclinical seizures, seizure burden, and proportion of seizure days but not interictal findings are associated with postdischarge seizures. Although return of PDR reflects neurological recovery, seizure persistence and EEG abnormalities post-NORSE are common.

BACKGROUND:Parkinson's disease management is often complicated by motor fluctuations and dyskinesia. Although deep brain stimulation addresses these symptoms, its use is limited by invasiveness, potential device failure, and the need for ongoing maintenance. Magnetic resonance-guided focused ultrasound (MRgFUS) provides incisionless, image-guided ablation as an alternative. However, the benefits and harms of staged, bilateral MRgFUS pallidothalamic tractotomy have not been evaluated systematically in prospective multicentre studies. METHODS:In this prospective, multicentre, single-arm study, adults with idiopathic, levodopa-responsive Parkinson's disease and motor complications (Movement Disorders Society Unified Parkinson's Disease Rating Scale [MDS-UPDRS] part IV item 4.2 or 4.4 score ≥2) were enrolled at nine investigational centres (six in the USA, two in Spain, and one in Taiwan). Participants underwent unilateral MRgFUS pallidothalamic tractotomy to the symptom-dominant side. Contralateral pallidothalamic tractotomy followed a minimum of 6 months later for participants meeting prespecified criteria. The primary efficacy endpoint was percent change from baseline to 3 months after the second procedure in the summed MDS-UPDRS part III off-medication upper and lower extremity (ULE) motor scores. Safety outcomes were incidence, severity, and persistence of treatment-related adverse events in the 12 months after each procedure. Safety and efficacy of unilateral treatment were evaluated in the unilateral intention-to-treat (ITT) and safety populations, defined as all patients receiving one or more sonications during the first procedure. The primary outcome and safety of bilateral treatment were evaluated in the bilateral modified ITT (mITT) and safety populations, which required one or more sonications during the second procedure, a baseline motor assessment, and at least one post-bilateral motor assessment. This trial is registered at ClinicalTrials.gov, NCT04728295 and is active, not recruiting. FINDINGS/RESULTS:Between July 12, 2021, and Nov 1, 2023, 54 patients received unilateral treatment and 40 proceeded to bilateral treatment (63 [67%] were male and 31 [33%] were female) and were included in the primary analysis; 36 completed 12-month follow-up after the second procedure. Median bilateral ULE motor scores decreased from 33·0 points (IQR 28·0-40·5) at baseline to 21·0 points (15·0-25·5) at month 3 post-bilateral treatment, a median within-patient change of 10·5 points (5·7-20·0), representing a 32% (18-52) improvement (p<0·0001). Benefits became apparent within 1 month of the first procedure and lasted through to 12 months after the second procedure. Treatment-related adverse events occurred in 21 (39%) of 54 patients after unilateral treatment; one (2%) had a persistent moderate adverse event at 6 months. After bilateral treatment, 22 (55%) of 40 patients had treatment-related adverse events; ten (25%) had persistent moderate or severe adverse events at 12 months, mainly affecting speech, gait, and balance. One (3%) patient developed severe persistent anarthria. INTERPRETATION/CONCLUSIONS:Unilateral MRgFUS pallidothalamic tractotomy demonstrated safety and efficacy for Parkinson's disease motor complications; however, bilateral treatment offered small motor gains while increasing persistent moderate or severe adverse events. Post-bilateral treatment complications in speech, gait, and balance are consistent with historical data for bilateral ablative procedures for movement disorders. Although unilateral MRgFUS pallidothalamic tractotomy was beneficial in our study, bilateral procedures demand rigorous patient selection and counselling regarding cumulative risks. FUNDING/BACKGROUND:Insightec.

INTRODUCTION/UNASSIGNED:Since the establishment of Pain Medicine (PM) as an ACGME-recognized subspecialty in 1992, the field has undergone significant transformation. These changes brought increasing diversity in applicants` primary specialties, and the introduction of a myriad of emerging treatment paradigms. In this study, we aimed to evaluate the expectations, experiences, and perspectives of three target groups-PM trainees, program directors (PDs), and employers-to guide the evolution of PM education. METHODS/UNASSIGNED:This study employed an integrated survey approach to comprehensively evaluate PM fellowship training. Surveys were distributed through professional societies, verified forums, and direct outreach over separate 3-month periods in 2023 for PD and trainee surveys and in 2024 for the employer survey. A total of 518 respondents across PDs, employers, and trainees completed surveys; overall response rate was indeterminable due to unknown denominators, while the PD survey response rate was 69.0%. RESULTS/UNASSIGNED:The survey findings highlighted both shared and unique perspectives among the stakeholder groups. Trainees emphasized procedural volume and diversity as critical motivators for fellowship selection. Despite this focus, 70% of trainees expressed reluctance toward extending their fellowship duration, with 50% of trainees favored private practice. PDs acknowledged variability in training quality and emphasized the importance of supplemental workshops to address procedural gaps. Vast majority of PDs supported extending the fellowship duration to mitigate reliance on industry-led supplemental education. Employers underscored significant deficiencies in graduates' preparedness for independent practice, with only 7% considering fellows adequately trained under the current model. Across all groups, there was a consensus on the need for curriculum standardization and enhanced training to align with the growing complexity of PM. CONCLUSION/UNASSIGNED:This study suggests that the one-year fellowship can be re-evaluated for adequacy in preparing physicians for independent practice, particularly in advanced procedures. Alternative training pathways offer additional exposure but vary in structure and oversight.

A 58-year-old woman presented with painless progressive bilateral blurred vision, worse in the right eye, over several days. Two months prior, she developed a diffuse pruritic rash that spared her face. On examination, she was found to have reduced visual acuity bilaterally, optic nerve edema, anterior uveitis, and scattered intraretinal and peripapillary nerve fiber layer hemorrhages. Diagnostic evaluation demonstrated optic nerve head enhancement on MRI. Her serum workup showed positive antibodies for Borrelia burgdorferi with a negative Lyme disease Western blot and positive Treponema pallidum antibodies with an rapid plasma reagin titer of 1:1,024. CSF showed normal protein, a slight elevation in nucleated cells with lymphocytic predominance, and a negative Venereal Disease Research Laboratory. We examine the differential diagnosis for bilateral optic nerve edema and uveitis and explore challenges around interpreting diagnostic testing for a neuro-ophthalmic pathology of ongoing public health interest.

Repetitive head impacts sustained during American football have been associated with neuropathological changes such as white matter shear injuries. However, the impact of specific factors, such as age of first exposure and cumulative head impact burden, on white matter integrity remains unclear. This study investigated in vivo white matter microstructural changes using diffusion tensor imaging and tract-based spatial statistics in 165 male former American football players (mean age 57.3 years, range 45-74) and 52 unexposed asymptomatic male controls (mean age 59.4 years, range 45-74) in the DIAGNOSE CTE Research Project. Compared to controls, former football players exhibited significantly higher fractional anisotropy (FA) in 1.97% of the white matter skeleton (1552 voxels; Cohen's d = 0.587) and higher tissue-corrected FA (FAt) in 1.48% of the white matter skeleton (1004 voxels; Cohen's d = 0.616). No significant differences were observed for mean diffusivity, axial diffusivity, radial diffusivity, or free water between football players and controls. Among football players, there were no significant differences in the white matter microstructure between players diagnosed with traumatic encephalopathy syndrome and those without the diagnosis. Lower FA was significantly associated with older age (P < 0.00001) and an earlier age of first exposure to tackle football (P < 0.01), while lower FAt was associated with greater cumulative head impact burden, specifically higher linear acceleration (P < 0.04) and rotational force (P < 0.02). This study highlights the influential role of exposure factors on white matter microstructure in former American football players, as well as the utility of diffusion tensor imaging to aid in characterizing the long-term effects of repetitive head impacts in contact sport athletes.

OBJECTIVE:To systematically map and synthesise the scientific literature on substance use patterns among elite athletes, encompassing recreational substances, performance-enhancing drugs (PEDs) and polysubstance use. DESIGN/METHODS:This study was a scoping review conducted in accordance with the Joanna Briggs Institute (JBI) methodological framework and reported following the Preferred Reporting Items for Systematic Review and Meta-Analysis extension for Scoping Reviews (PRISMA-ScR) guidelines. The review protocol was prospectively registered on the Open Science Framework. DATA SOURCES/METHODS:A comprehensive search was conducted in PubMed/MEDLINE, PsycINFO, Scopus and SportDiscus from inception to March 2025. ELIGIBILITY CRITERIA FOR SELECTING STUDIES/METHODS:Eligible studies were peer-reviewed original research articles examining substance use, misuse or substance use disorders among elite athletes, including collegiate, professional, Olympic, Paralympic or national-level competitors. Both recreational substances (eg, alcohol, cannabis, nicotine, prescription drugs) and PEDs were included. RESULTS:From 3292 unique records screened, 119 studies met inclusion criteria. Alcohol was the most extensively studied substance, particularly among National Collegiate Athletic Association collegiate athletes, with consistent evidence of heavy consumption in certain sports, especially those with strong social and team-based norms. PED studies revealed marked sport-specific patterns, largely informed by anti-doping surveillance data, but offered limited insight into psychosocial mechanisms. Research on other substances and polysubstance use was heterogeneous, fragmented, and methodologically variable. Across all domains, the literature was dominated by cross-sectional designs, self-reported data and Western populations. CONCLUSION/CONCLUSIONS:The existing evidence base demonstrates substantial substance-related vulnerability among elite athletes but is characterised by significant conceptual, methodological and geographical gaps. Future research should prioritise longitudinal and theory-driven designs, broader representation of professional and non-Western athletes, integration of mental health frameworks and rigorous evaluation of prevention and intervention strategies. TRIAL REGISTRATION NUMBER/BACKGROUND:The review protocol was prospectively registered on the Open Science Framework (OSF) (DOI: 10.17605/OSF.IO/3PJDN) on 8 January 2025.