Faculty Bibliography

Haptic technology is a critical component of human-computer interfaces. Traditional haptic actuators are often unable to provide the broad frequency range and latency that is required in many advanced applications. To address this problem, we propose a new type of tactor based on macro-fiber composites (MFCs), composites of piezoelectric fibers. We propose a physics-based model for the actuation of the tactors, calibrated and validated through experiments. As our tactors are intended for haptic applications, we consider the role of skin on their response, an aspect seldom analyzed in the literature. In our experiments, we simulate the presence of the skin with a rubber membrane in contact with the tactor, with varying pre-stretch, mimicking different indentations of the tactor on the skin. The MFC-based tactor can always generate vibration amplitudes higher than skin discrimination thresholds, over the range of frequencies of interest for haptics, with a latency much smaller than traditional actuators. We theoretically investigate the effect of the skin on tactor vibrations, highlighting the individual roles of skin stiffness and damping and their combined effect across a series of pre-stretches. Our tactor shows promise in haptic applications, including assistive technologies and real-time feedback systems for training, safety, and monitoring.

Staphylococcus aureus (S. aureus) is a serious global pathogen that causes a diverse range of invasive diseases. S. aureus utilizes a family of pore-forming toxins, known as bi-component leukocidins, to evade the host immune response and promote infection. Among these is LukAB (leukocidin A/leukocidin B), a toxin that assembles into an octameric β-barrel pore in the target cell membrane, resulting in host cell death. The established cellular receptor for LukAB is CD11b of the Mac-1 complex. Here, we show that hydrogen voltage-gated channel 1 is also required for the cytotoxicity of all major LukAB variants. We demonstrate that while each receptor is sufficient to recruit LukAB to the plasma membrane, both receptors are required for maximal lytic activity. Why LukAB requires two receptors, and how each of these receptors contributes to pore-formation remains unknown. To begin to resolve this, we performed an alanine scanning mutagenesis screen to identify mutations that allow LukAB to maintain cytotoxicity without CD11b. We discovered 30 mutations primarily localized in the stem domains of LukA and LukB that enable LukAB to exhibit full cytotoxicity in the absence of CD11b. Using crosslinking, electron microscopy, and hydroxyl radical protein footprinting, we show these mutations increase the solvent accessibility of the stem domain, priming LukAB for oligomerization. Together, our data support a model in which CD11b binding unlatches the membrane penetrating stem domains of LukAB, and this change in flexibility promotes toxin oligomerization.

BACKGROUND:Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder with largely unknown pathogenesis and no effective cure. It is believed that several, not mutually exclusive mechanisms contribute to the pathogenesis and progression of this disease, including, among others, elevated oxidative stress, excitotoxicity, increased neuroinflammation, and protein aggregation. Receptor for advanced glycation end products (RAGE) is a part of immunoglobulin superfamily; it is believed to participate in ALS pathogenesis. OBJECTIVES/OBJECTIVE:Our previous studies on ALS demonstrated that RAGE is likely one of the key players in ALS, acting on its own and in tandem with its oxidative stress and pro-inflammatory ligands, such as advanced glycation end products (AGEs) or advanced oxidation protein products (AOPPs). In this study, based on our previous results, we aimed to establish blood levels of soluble RAGE, AGE and AOPP in ALS patients. MATERIAL AND METHODS/METHODS:Forty-six coded and anonymized surplus plasma samples from ALS patients and non-neurological control were used in the study. The plasma levels of RAGE, AGE and AOPP were measured using enzyme-linked immunosorbent assay (ELISA) commercially available kits. Statistical evaluation of data was performed using one-way non-parametric analysis of variance (ANOVA) with Kruskal-Wallis post hoc test. RESULTS:Our results revealed a decline in soluble RAGE level, concurrent with an increase in the levels of AGEs and AOPPs in blood samples from ALS patients, signifying a loss of neuroprotective form of RAGE and a simultaneous increase in AGE and AOPP production and uptake at the early stage of the disease. CONCLUSIONS:The results obtained from our study indicate that further longitudinal study of RAGE, AGE and AOPP levels would be beneficial, outlining the dynamics between RAGE and its ligand levels as the disease progresses, and making them valuable diagnostic tools and potential therapeutic targets.

AIMS/UNASSIGNED:The aim of this study was to establish consensus statements on medial patellofemoral ligament (MPFL) reconstruction, anteromedialization tibial tubercle osteotomy, trochleoplasty, and rehabilitation and return to sporting activity in patients with patellar instability, using the modified Delphi process. METHODS/UNASSIGNED:This was the second part of a study dealing with these aspects of management in these patients. As in part I, a total of 60 surgeons from 11 countries contributed to the development of consensus statements based on their expertise in this area. They were assigned to one of seven working groups defined by subtopics of interest. Consensus was defined as achieving between 80% and 89% agreement, strong consensus was defined as between 90% and 99% agreement, and 100% agreement was considered unanimous. RESULTS/UNASSIGNED:Of 41 questions and statements on patellar instability, none achieved unanimous consensus, 19 achieved strong consensus, 15 achieved consensus, and seven did not achieve consensus. CONCLUSION/UNASSIGNED:Most statements reached some degree of consensus, without any achieving unanimous consensus. There was no consensus on the use of anchors in MPFL reconstruction, and the order of fixation of the graft (patella first versus femur first). There was also no consensus on the indications for trochleoplasty or its effect on the viability of the cartilage after elevation of the osteochondral flap. There was also no consensus on postoperative immobilization or weightbearing, or whether paediatric patients should avoid an early return to sport.

Post-acute neurological sequelae of COVID-19 affect millions of people worldwide, yet little data is available to guide treatment strategies for the most common symptoms. We conducted a scoping review of PubMed/Medline from 1/1/2020-4/1/2023 to identify studies addressing diagnosis and treatment of the most common post-acute neurological sequelae of COVID-19 including: cognitive impairment, sleep disorders, headache, dizziness/lightheadedness, fatigue, weakness, numbness/pain, anxiety, depression and post-traumatic stress disorder. Utilizing the available literature and international disease-specific society guidelines, we constructed symptom-based differential diagnoses, evaluation and management paradigms. This pragmatic, evidence-based consensus document may serve as a guide for a holistic approach to post-COVID neurological care and will complement future clinical trials by outlining best practices in the evaluation and treatment of post-acute neurological signs/symptoms.

RATIONALE/BACKGROUND:The International Classification of Cognitive Disorders in Epilepsy (IC-CoDE) was recently introduced as a consensus-based, empirically-driven taxonomy of cognitive disorders in epilepsy and has been effectively applied to patients with temporal lobe epilepsy (TLE). The purpose of this study was to apply the IC-CoDE to patients with frontal lobe epilepsy (FLE) using national multicenter data. METHODS:Neuropsychological data of 455 patients with FLE aged 16 years or older were available across four US-based sites. First, we examined test-specific impairment rates across sites using two impairment thresholds (1.0 and 1.5 standard deviations below the normative mean). Following the proposed IC-CoDE guidelines, patterns of domain impairment were determined based on commonly used tests within five cognitive domains (language, memory, executive functioning, attention/processing speed, and visuospatial ability) to construct phenotypes. Impairment rates and distributions across phenotypes were then compared with those found in patients with TLE for which the IC-CoDE classification was initially validated. RESULTS:The highest rates of impairment were found among tests of naming, verbal fluency, speeded sequencing and set-shifting, and complex figure copy. The following IC-CoDE phenotype distributions were observed using the two different threshold cutoffs: 23-40% cognitively intact, 24-29% single domain impairment, 13-20% bi-domain impairment, and 18-33% generalized impairment. Language was the most common single domain impairment (68% for both thresholds) followed by attention and processing speed (15-18%). Overall, patients with FLE reported higher rates of cognitive impairment compared with patients with TLE. CONCLUSIONS:These results demonstrate the applicability of the IC-CoDE to epilepsy syndromes outside of TLE. Findings indicated generally stable and reproducible phenotypes across multiple epilepsy centers in the U.S. with diverse sample characteristics and varied neuropsychological test batteries. Findings also highlight opportunities for further refinement of the IC-CoDE guidelines as the application expands.

AIMS/UNASSIGNED:The aim of this study was to establish consensus statements on the diagnosis, nonoperative management, and indications, if any, for medial patellofemoral complex (MPFC) repair in patients with patellar instability, using the modified Delphi approach. METHODS/UNASSIGNED:A total of 60 surgeons from 11 countries were invited to develop consensus statements based on their expertise in this area. They were assigned to one of seven working groups defined by subtopics of interest within patellar instability. Consensus was defined as achieving between 80% and 89% agreement, strong consensus was defined as between 90% and 99% agreement, and 100% agreement was considered to be unanimous. RESULTS/UNASSIGNED:Of 27 questions and statements on patellar instability, three achieved unanimous consensus, 14 achieved strong consensus, five achieved consensus, and five did not achieve consensus. CONCLUSION/UNASSIGNED:The statements that reached unanimous consensus were that an assessment of physeal status is critical for paediatric patients with patellar instability. There was also unanimous consensus on early mobilization and resistance training following nonoperative management once there is no apprehension. The statements that did not achieve consensus were on the importance of immobilization of the knee, the use of orthobiologics in nonoperative management, the indications for MPFC repair, and whether a vastus medialis oblique advancement should be performed.

PURPOSE OF REVIEW/OBJECTIVE:The use of immune checkpoint inhibitors (ICIs) for oncologic indications is associated with immune-related adverse events (irAEs). Patients with pre-existing autoimmune diseases are at increased risk of irAEs and have largely been excluded from clinical trials of ICIs. Therefore, there is limited data on the safety of safety of ICIs in patients with pre-existing neurologic autoimmune diseases (nAIDs) such as myasthenia gravis and multiple sclerosis. This review aims to synthesize the literature on the post-marketing experience with ICI in patients with pre-existing nAID and to discuss possible strategies for mitigating the risk of post-ICI nAID relapses. RECENT FINDINGS/RESULTS:Patients with pre-existing myasthenia gravis (MG), myositis, and paraneoplastic encephalitis appear highly susceptible to neurologic relapses of their underlying neurologic disorder following ICI initiation; these relapses can cause considerable morbidity and mortality. In patients with multiple sclerosis (MS), the risk and severity of MS relapses following ICI appears to be relatively lower compared to MG. Preliminary evidence suggests that older MS patients with no recent focal neuroinflammatory activity may be safely treated with ICI. Among the several case reports of ICI in patients with a history of Guillain-Barre syndrome (GBS), neurologic worsening was only recorded in one patient who was in the acute phase of GBS at the time of ICI start. Initiating an ICI in a patient with pre-existing nAID involves a complex risk-benefit discussion between the patient, their oncologist, and neurologist. Relevant issues to consider before ICI include the choice of disease-modifying therapy for nAID (if any) and strategies for promptly identifying and managing nAID relapses should they occur. Currently, the literature consists mainly of case reports and case series, subject to publication bias. Prospective studies of ICI in patients with nAID are needed to improve the level of evidence.

BACKGROUND/UNASSIGNED:Diroximel fumarate (DRF) is approved for adults with relapsing-remitting multiple sclerosis (RRMS) in Europe and for relapsing forms of MS in the United States. DRF and dimethyl fumarate (DMF) yield bioequivalent exposure of the active metabolite monomethyl fumarate. Prior studies indicated fewer gastrointestinal (GI)-related adverse events (AEs) with DRF compared with DMF. OBJECTIVE/UNASSIGNED:To report final outcomes from EVOLVE-MS-1. METHODS/UNASSIGNED:EVOLVE-MS-1 was an open-label, 96-week, phase 3 study assessing DRF safety, tolerability, and efficacy in patients with RRMS. The primary endpoint was safety and tolerability; efficacy endpoints were exploratory. RESULTS/UNASSIGNED:< 0.0001); adjusted annualized relapse rate was 0.13 (95% confidence interval: 0.11-0.15). CONCLUSION/UNASSIGNED:DRF was generally well tolerated over 2 years, with few discontinuations due to AEs; radiological measures indicated decreased disease activity from baseline. These outcomes support DRF as a treatment option in patients with RRMS.