Faculty Bibliography

Peptidoglycan (PG), the primary load-bearing component of bacterial cell envelopes, is a bio-derived material whose mechanical and hydration properties are central to microbial viability and their environmental responsiveness. PG has been increasingly recognized as a scalable water-responsive (WR) material, capable of converting chemical potential gradients from ambient changes in relative humidity (RH) directly into mechanical work. In this study, we leverage stress-induced PG remodeling pathways in a BB-3 Escherichia coli (E. coli) strain to modulate the architecture of its PG sacculus for enhanced WR performance. Under arabinose-deprived conditions (-Ara), BB-3 PG exhibits a twofold increase in the ratio of crosslinked-to-linear muropeptide stems and a threefold rise in the relative abundance of ③-③ (mDap-mDap) linkages relative to an arabinose-rich (+Ara) control. When responding to RH changes between 10% and 90% RH, these molecular-level modifications translated into a fivefold increase in WR actuation energy density (623.0 kJ/m³) with rapid response times on the order of seconds (τ_d: 1.8 s, τ_h: 0.7 s). The remodeled PG also displays a significant increase in stiffness (E: 8.9 GPa at 10% RH) and an 8% greater uptake of water, driving the PG matrix to generate twofold higher WR strain (ε: 30.2%). The observed increases in water retention and WR behavior of E. coli PG may also carry intriguing evolutionary implications, reflecting adaptive strategies microbes take to restructure PG layers and survive under microenvironmental nutrient scarcity. STATEMENT OF SIGNIFICANCE: Current testing of water responsive (WR) engineered living materials (ELMs) has largely overlooked bacterial species other than Bacillus subtilis. Our work addresses this gap by demonstrating that the peptidoglycan (PG) sacculus of Escherichia coli also exhibits robust WR properties. Through leveraging a combination of genetic and environmental factors during the organism's growth phase, we demonstrate that these properties can be rationally improved to yield enhanced actuator materials. By establishing a connection between PG crosslinking architecture and emergent mechanical and hydration dynamics, we present a promising approach to engineer dynamic and sustainable ELMs that can be employed as active components in high-performance actuators.

OBJECTIVES/OBJECTIVE:To explore the evolution of the grief experience following Sudden Unexpected Death in Epilepsy (SUDEP) and identify factors that assist the bereaved in coping with their loss. METHODS:A survey formulated by a multidisciplinary team gathered information gathered information on decedent and respondent demographics, epilepsy details, circumstances surrounding death, postmortem experiences, descriptions of grief overtime (from 3 months to > 10 years post death), insights into coping strategies and recommendations for assisting the bereaved. RESULTS:A total of 206 participants completed the survey (predominantly middle-aged white females who were parents of the deceased). Most respondents (69.2 %) were unaware of SUDEP prior to the death and strongly desired to have had prior information. Negative impacts on relationships and mental health were highest at three months post-loss but gradually improved over time; feelings of sadness persisted while anger and guilt decreased, and acceptance increased. Interactions with understanding peers, supportive family or friends, and professional counseling were identified as most helpful, alongside clear communication and support from medical professionals and advocacy groups. CONCLUSIONS:This study highlights the profound and evolving nature of grief following SUDEP, describes the importance of SUDEP disclosure as part of comprehensive epilepsy care, and illustrates the need for ongoing and dynamic support for the bereaved. Interpretation of the findings is limited as the respondents were predominantly middle-aged white females who were parents of the deceased.

INTRODUCTION/BACKGROUND:Multiple sclerosis (MS) is a chronic, immune-mediated neurological disease, leading to significant morbidity. Over 25 disease-modifying therapies (DMTs) are approved for MS; however, older patients may benefit less from high-efficacy DMTs. We compared the risk of severe infections (SIs) and annualized relapse rate (ARR) by age (< 45 and ≥ 45 years) between diroximel fumarate (DRF) and anti-CD20 monoclonal antibodies (mAbs) in patients with MS. METHODS:This retrospective study utilized the Komodo Health Claims database to identify patients treated with DRF or anti-CD20 agents. Patients were propensity score matched 1:1 on baseline characteristics and stratified by age (younger: < 45 years; older: ≥ 45 years). Infection-related encounters were identified by diagnosis codes; SIs required hospitalization or intravenous antibiotics. MS relapses were based on inpatient or outpatient claims and associated treatments. RESULTS:Between 2016 and 2025, 2894 propensity score-matched patients with MS who initiated DRF (n = 1447) or anti-CD20s (n = 1447) were included. DRF-treated patients had a lower proportion of SIs at 12 and 24 months compared with anti-CD20-treated patients (p ≤ 0.002 at 24 months). Younger DRF-treated patients had significantly fewer SIs (p = 0.005), while older DRF-treated patients had lower non-SI rates. COVID-19-related SIs were also significantly lower in DRF-treated patients (p < 0.001). ARRs were similar between the two groups. CONCLUSION/CONCLUSIONS:DRF-treated patients with MS had a significantly lower risk of SI compared with anti-CD20-treated patients, with no difference in ARR. More real-world studies are needed to understand the efficacy and safety of DMTs in the setting of de-escalation in aging patients with MS.

OBJECTIVE:This study aimed to understand the factors limiting access to medications for the preventive treatment of migraine and to improve access to evidence-based preventive care. BACKGROUND:For decades, the effective use of medication for the preventive treatment of migraine was limited by slow onset, slow and complex dose titration schedules, modest benefits, drug interactions, frequent side effects, and very low long-term adherence. The calcitonin gene-related peptide (CGRP) targeted preventive medications mitigate some of these limitations and demonstrated substantial therapeutic benefits in a significant proportion of adults with migraine. The American Headache Society considers these medications among the first-line options for migraine prevention, although access to them remains limited. The American Migraine Foundation hosted a single-day, multidisciplinary expert panel discussion to identify barriers to optimal preventive care and developed recommendations to address them. METHODS:Participants identified and prioritized barriers and used a modified nominal group technique to achieve consensus on them. A series of moderated discussions in plenary and breakout sessions was used to create possible solutions. Modified nominal group technique was also employed to achieve consensus on the priorities among these barriers and to achieve whole-group consensus on the recommendations. Ethical issues that inform access were discussed. RESULTS:Participants included eight neurologists and board-certified headache specialists, six representatives of reimbursement decision-makers, six employees of life sciences companies, four patient advocates with lived experience with migraine, and a medical ethicist. Among those who have consulted healthcare professionals and received a diagnosis of migraine, we identified four main barriers to accessing preventive treatment: restrictive prior authorization requirements, the perceived lack of real-world evidence and treatment guidelines, the need for clinician education, and the need for patient education. Consensus recommendations for eliminating barriers centered on using new evidence to evaluate policies that restrict the selection of first-line therapies, initiating/improving collaboration among stakeholders, sharing of data and best practices, and increased training. Participants agreed to explore novel definitions of the value of preventive treatment and to establish the Migraine Prevention Network to facilitate ongoing cooperation and collective action. However, due to financial limitations, staffing changes, and time constraints, post-meeting discussions led to a shift from establishing a broad Migraine Prevention Network to forming smaller task forces focused on the top-priority barriers (real-world evidence and The Patient Playbook) identified through collaborative voting among American Headache Society, American Migraine Foundation, and industry stakeholders. CONCLUSIONS:Adults with migraine face multiple barriers in accessing novel migraine-specific, CGRP-targeted preventive treatment. Stakeholders in the delivery of care, including clinicians, reimbursement decision-makers, life sciences companies, and patient and clinician advocates, may be able to overcome many of these barriers and improve access by working with and on behalf of patients.

Acute symptomatic seizures are a well recognized symptom of myelin oligodendrocyte antibody-associated disease (MOGAD), but long-term seizure outcomes and risk of epilepsy are understudied. In a retrospective cohort of 135 consecutive patients meeting consensus criteria for MOGAD without a prior diagnosis of epilepsy or concurrent NMDA-R Ab positivity, 19 developed seizures after MOGAD onset (16 %). Of these 19 patients, 7 patients (37 % of those with seizures, and 5 % of the total cohort). experienced one or more seizure recurrence during MOGAD remission (i.e. outside of an acute attack). Five of the 7 patients with recurrent seizures remained on antiseizure medication (ASM) (four on monotherapy and one on two ASMs) at last follow-up (median duration of follow up: 92 months). We discuss phenotypes of recurrent seizures in patients with MOGAD in the context of the conceptual framework of acute symptomatic seizures versus autoimmune encephalitis associated epilepsy (AEAE).

BACKGROUND AND OBJECTIVES/OBJECTIVE:Sudden unexpected death in epilepsy (SUDEP) is the leading cause of seizure-related deaths in people with epilepsy. Despite evidence that SUDEP counseling does not cause stress, improves treatment adherence, and empowers people with epilepsy and their caregivers, it remains underdiscussed. This study aimed to explore the in-depth perspectives of parents who have lost a child to SUDEP, focusing on their experiences, grief, and coping strategies, while factoring in their demographics, the clinical features of their deceased children, and their previous awareness of SUDEP, all aspects that have not been systematically investigated before. METHODS:This qualitative phenomenological study involved in-depth semistructured interviews with 51 parents of 43 children who died of SUDEP. Transcripts were analyzed using immersion/crystallization qualitative methodology with Dedoose software, using an iterative consensus-building process. Thematic analysis revealed common perspectives, grief narratives, coping strategies, and perceived needs among parents after their child's SUDEP. RESULTS:Of the 51 participating parents (mean age 54.1 ± 9.4 years, 71% female), 27 reported being unaware of SUDEP before it occurred, whereas 24 reported previous awareness of it. These groups shared similar demographics and clinical characteristics. However, "unaware" parents expressed more intense trauma and prolonged maladaptive grief, characterized by guilt, extreme anger, and medical distrust. By contrast, "aware" parents described mitigated trauma, with less guilt- and anger-ridden grief, and reduced reliance on specialized support groups. Previous SUDEP awareness provided emotional preparation, buffering the devastating reality and fostering agency and acceptance. Another theme highlighted the struggles parents faced immediately after SUDEP, particularly with law enforcement and treating physicians. Unanimously, parents emphasized the paramount importance of counseling about the known relationship between epilepsy and SUDEP. DISCUSSION/CONCLUSIONS:Previous awareness of SUDEP (or lack thereof) has complex and far-reaching effects on the subsequent parental perceived trauma, grief, and coping processes. Furthermore, emergency responders, official personnel, and treating physicians may mishandle the aftermath of SUDEP. This study's findings strongly advocate for a paradigm shift in SUDEP-related practices across multiple disciplines, including legislation. Emphasis should be placed on increasing proactive SUDEP counseling to mitigate the traumatic effect and subsequent grieving process when SUDEP occurs.

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with exposure to repetitive head impacts (RHIs), characterized by tau tangles around small blood vessels at the depths of the sulci. Currently, CTE can be diagnosed only postmortem, but can present with an array of cognitive, behavioral, mood, and motor symptoms. However, traumatic brain injury is also associated with increased risk of Alzheimer's disease (AD) and may lead to comorbid neuropathology. Characterization of the in vivo biomarkers of CTE is a necessary next step to facilitate accurate diagnoses. We examined the profile of cerebrospinal fluid (CSF) biomarkers of amyloid-β, total tau (tTau), and phospho-tau (pTau) in a cohort of former professional (PRO, n = 100) and college (COL, n = 40) football players at high risk of CTE compared to asymptomatic unexposed controls (UE, n = 43). CSF was collected under controlled conditions using collection, processing, and cryostorage kits provided by the DIAGNOSE CTE Research Project Biomarker Core, and concentrations of Aβ₄₀, Aβ₄₂, tTau, and pTau (pTau₁₈₁, pTau₂₁₇, pTau₂₃₁) were measured at the University of Gothenburg, Sweden, using immunoassays. Associations between CSF biomarker levels with football history, and diagnosis of traumatic encephalopathy syndrome (TES) were examined using linear regression, and corrected for age, education, APOE-ε4 allele status, race, and body mass index. Our analysis revealed that football exposure affected both CSF Aβ₄₀ (p = 0.039) and Aβ₄₂ (p = 0.038), particularly among those under 60 years of age in the PRO compared to the UE exposure group. Among former football players, estimates of RHI exposure were not generally associated with CSF Aβ, tTau, and pTau biomarker levels. CSF Aβ₄₀ (p = 0.0041) and Aβ₄₂ (p = 0.011) were lower in former football players with TES diagnosis compared to unexposed participants, although CSF Aβ, tTau, and pTau biomarker levels did not differ between former players with and without a TES diagnosis. Among former football players, reduced CSF Aβ₄₀ (p = 0.011) and Aβ₄₂ (p = 6e-04) were observed in those with cognitive impairment compared to those with neurobehavioral dysregulation. The findings of significant associations of reduced CSF Aβ levels with RHI in elite football players are in line with recent postmortem studies; however, the lack of relationship with CSF tTau and pTau species observed to be altered in the setting of AD suggests that the pathological features of CTE reflected in fluid biomarkers are complex and require further study. The overlapping comorbid age-dependent features of neurodegeneration that occur in those at risk for CTE suggest that tau pathology in CTE is not reliably reflected by currently available fluid biomarkers and that the use of multiple biomarkers related to the compound characteristics of CTE may be required for early detection.