A systematic review of goal attainment scaling implementation practices by caregivers in randomized controlled trials.

BACKGROUND: Goal attainment scaling (GAS), an established individualized, patient-centred outcome measure, is used to capture the patient's voice. Although first introduced ~60 years ago, there are few published guidelines for implementing GAS, and almost none for its use when caregivers GAS is implemented with caregiver input. We conducted a systematic review of studies that implemented GAS with caregiver input; and examined variations in GAS implementation, analysis, and reporting. METHODS: Literature was retrieved from Medline, Embase, Cochrane, PsycInfo and CINAHL databases. We included randomized controlled trials (published between 1968 and November 2022) that used GAS as an outcome measure and involved caregiver input during goal setting. RESULTS: Of the 2610 studies imported for screening, 21 met the inclusion criteria. Most studies employed GAS as a primary outcome. The majority (76%) had children as study participants. The most common disorders represented were cerebral palsy, developmental disorders, and dementia/Alzheimer's disease. The traditional five-point GAS scale, with levels from -2 to +2, was most often implemented, with -1 level typically being the baseline. However, most studies omitted essential GAS details from their reports including the number of goals set, number of attainment levels and whether any training was given to GAS facilitators. CONCLUSIONS: GAS with caregiver input has been used in a limited number of randomized controlled trials, primarily in pediatric patients and adults with dementia. There is a variability in GAS implementation and many crucial details related to the specifics of GAS implementation are omitted from reports, which may limit reproducibility. Here we propose catalog that may be utilized when reporting research results pertaining to GAS with caregivers to enhance the application of this patient-centered outcome measure.

Quantitative Foveal Structural Metrics as Predictors of Visual Acuity in Human Albinism.

Purpose: To assess the degree to which quantitative foveal structural measurements account for variation in best-corrected visual acuity (BCVA) in human albinism. Methods: BCVA was measured and spectral domain optical coherence tomography (SD-OCT) images were acquired for 74 individuals with albinism. Categorical foveal hypoplasia grades were assessed using the Leicester Grading System for Foveal Hypoplasia. Foveal anatomical specialization (foveal versus parafoveal value) was quantified for inner retinal layer (IRL) thickness, outer segment (OS) length, and outer nuclear layer (ONL) thickness. These metrics, participant sex, and age were used to build a multiple linear regression of BCVA. This combined linear model's predictive properties were compared to those of categorical foveal hypoplasia grading. Results: The cohort included three participants with type 1a foveal hypoplasia, 23 participants with type 1b, 33 with type 2, ten with type 3, and five with type 4. BCVA ranged from 0.08 to 1.00 logMAR (mean ± SD: 0.53 ± 0.21). IRL ratio, OS ratio, and ONL ratio were measured in all participants and decreased with increasing severity of foveal hypoplasia. The best-fit combined linear model included all three quantitative metrics and participant age expressed as a binary variable (divided into 0-18 years and 19 years or older; adjusted R2 = 0.500). This model predicted BCVA more accurately than a categorical foveal hypoplasia model (adjusted R2 = 0.352). Conclusions: A quantitative model of foveal specialization accounts for more variance in BCVA in albinism than categorical foveal hypoplasia grading. Other factors, such as optical aberrations and eye movements, may account for the remaining unexplained variance.

Updates in Genetic Screening for the General Obstetrician.

The number of prenatal genetic screening options, including aneuploidy screening and carrier screening, has drastically increased with rapid advancements in DNA sequencing technologies. Noninvasive prenatal screening analyzing cell-free DNA has quickly been integrated into routine prenatal care as it is the most sensitive and specific screening method for pregnancies at increased and average risk of fetal aneuploidy. The aim of this article is to outline current recommendations for cell-free DNA screening and carrier screening, important aspects of pretest and posttest counseling for obstetric providers, and which patients should be referred to a genetic specialist.

Electroretinogram abnormalities in FKRP-related limb-girdle muscular dystrophy (LGMDR9).

BACKGROUND: Dystroglycanopathies are a heterogeneous group of membrane-related muscular dystrophies. The dystroglycanopathy phenotype includes a spectrum of severity ranging from severe congenital muscular dystrophy to adult-onset limb-girdle muscular dystrophy (LGMD). LGMDR9 is a dystroglycanopathy caused by mutations in the FKRP gene. Previous studies have characterized electroretinogram findings of dystroglycanopathy mouse models but have not been reported in humans. PURPOSE: This study set out to characterize the electroretinogram in eight participants with LGMDR9. METHODS: Eight participants were recruited from an ongoing dystroglycanopathy natural history study at the University of Iowa (NCT00313677). Inclusion criteria for the current study were children and adults > 6 years old with confirmed LGMDR9. Age similar controls were identified from our electrophysiology service normative control database. Full-field electroretinograms were recorded using ISCEV standards. Six of the eight participants underwent light-adapted ON/OFF testing. RESULTS: The electronegative electroretinogram was not seen in any participants with LGMDR9. An unusual sawtooth pattern in the 30 Hz flicker with faster rise than descent was noted in all 8 participants. Our cases showed a decreased b-wave amplitude in light-adapted ON responses (p = 0.011) and decreased d-wave amplitude in light-adapted OFF responses (p = 0.015). Decreased b-wave amplitude in light-adapted 3.0 testing (p = 0.015) and decreased flicker ERG amplitudes were also detected (p = 0.0018). Additionally, compared to controls, participants with LGMDR9 had decreased a-wave amplitudes on dark-adapted 10 testing (p = 0.026). CONCLUSIONS: Abnormal ON/OFF bipolar cell responses and sawtooth 30 Hz flicker waveforms on full-field electroretinogram may be specific for LGMDR9. If confirmed in a larger population and if related to disease stage, these tests are potential biomarkers which could be useful as endpoints in clinical treatment trials.

Patterns of Symptom Tracking by Caregivers and Patients With Dementia and Mild Cognitive Impairment: Cross-sectional Study.

BACKGROUND: Individuals with dementia and mild cognitive impairment (MCI) experience a wide variety of symptoms and challenges that trouble them. To address this heterogeneity, numerous standardized tests are used for diagnosis and prognosis. myGoalNav Dementia is a web-based tool that allows individuals with impairments and their caregivers to identify and track outcomes of greatest importance to them, which may be a less arbitrary and more sensitive way of capturing meaningful change. OBJECTIVE: We aim to explore the most frequent and important symptoms and challenges reported by caregivers and people with dementia and MCI and how this varies according to disease severity. METHODS: This cross-sectional study involved 3909 web-based myGoalNav users (mostly caregivers of people with dementia or MCI) who completed symptom profiles between 2006 and 2019. To make a symptom profile, users selected their most personally meaningful or troublesome dementia-related symptoms to track over time. Users were also asked to rank their chosen symptoms from least to most important, which we called the symptom potency. As the stage of disease for these web-based users was unknown, we applied a supervised staging algorithm, previously trained on clinician-derived data, to classify each profile into 1 of 4 stages: MCI and mild, moderate, and severe dementia. Across these stages, we compared symptom tracking frequency, symptom potency, and the relationship between frequency and potency. RESULTS: Applying the staging algorithm to the 3909 user profiles resulted in 917 (23.46%) MCI, 1596 (40.83%) mild dementia, 514 (13.15%) moderate dementia, and 882 (22.56%) severe dementia profiles. We found that the most frequent symptoms in MCI and mild dementia profiles were similar and comprised early hallmarks of dementia (eg, recent memory and language difficulty). As the stage increased to moderate and severe, the most frequent symptoms were characteristic of loss of independent function (eg, incontinence) and behavioral problems (eg, aggression). The most potent symptoms were similar between stages and generally reflected disruptions in everyday life (eg, problems with hobbies or games, travel, and looking after grandchildren). Symptom frequency was negatively correlated with potency at all stages, and the strength of this relationship increased with increasing disease severity. CONCLUSIONS: Our results emphasize the importance of patient-centricity in MCI and dementia studies and illustrate the valuable real-world evidence that can be collected with digital tools. Here, the most frequent symptoms across the stages reflected our understanding of the typical disease progression. However, the symptoms that were ranked as most personally important by users were generally among the least frequently selected. Through individualization, patient-centered instruments such as myGoalNav can complement standardized measures by capturing these infrequent but potent outcomes.

Clinical albinism score, presence of nystagmus and optic nerves defects are correlated with visual outcome in patients with oculocutaneous albinism.

Purpose: To correlate clinical features, molecular genetic findings, and visual acuity in a cohort of patients clinically diagnosed with oculocutaneous albinism.Design: Retrospective chart reviewMethods: 58 charts met the inclusion criteria. Clinical examination, ancillary testing, and molecular genetic diagnoses were extracted. A novel clinical albinism score (CAS) was developed.Results: A least one likely pathogenic mutation was found in 44/58 (75.9%) patients. Mutations in the OCA1 gene were the most common (52.3%), followed by OCA2 (34%), OCA4 (2.3%), OA1 (6.8%), and HPS (4.5%). Thirty-four percentage of patients had a complete genotype, 41% had one mutation found and 24% had negative genetic testing. CAS was statistically significantly higher in patients with complete genotype, versus patients with one or no mutations found (p < .01). Better visual acuity was associated with lower CAS and fewer disease-causing mutations (p < .01). Foveal defects and iris transillumination were associated with a higher number of mutations (p < .01). Patients with nystagmus or anomalous optic nerves had worse visual acuity than those who did not (p < .01, p < .05).Conclusions: Patients with a complete genotype were more likely to have higher CAS. Vision loss correlated with complete phenotype and higher CAS, the presence of nystagmus and anomalous optic nerves. Patients with features of albinism in whom an incomplete genotype was found had better vision than those with complete genotype, suggesting a mild occult mutation or modifier variant. Genetic diagnosis is vital for complete diagnosis, counseling, and family planning.

The Clinician's Interview-Based Impression of Change (Plus caregiver input) and goal attainment in two dementia drug trials: Clinical meaningfulness and the initial treatment response.

INTRODUCTION: The Clinician's Interview-Based Impression of Change Plus caregiver input (CIBIC-Plus) has been widely used in dementia drug trials to evaluate cognition, behavior, and function. New trials of symptomatic drugs forecast renewed interest in this measure. METHODS: To test its clinical meaningfulness, we examined how CIBIC-Plus performed in two cholinesterase inhibitor trials compared to goal attainment scaling Scale (GAS) scores, a patient-reported outcome measure. RESULTS: Net goal attainment was seen for all but one GAS domains in subjects who improved on the CIBIC-Plus. Subjects who improved initially on CIBIC-Plus scores were likely to remain improved across all other outcomes for each trial's duration, except for Disability Assessment for Dementia scores. DISCUSSION: The initial response to treatment, as assessed by CIBIC-Plus, remained stable for most outcome measures. Even small CIBIC-Plus improvement changes are associated with clinically meaningful change as assessed by GAS. Other tests detect decline better than improvement.

Development of a symptom menu to facilitate Goal Attainment Scaling in adults with Down syndrome-associated Alzheimer's disease: a qualitative study to identify meaningful symptoms.

BACKGROUND: As life expectancy of people with Down syndrome (DS) increases, so does the risk of Alzheimer's disease (AD). Identifying symptoms and tracking disease progression is especially challenging whenever levels of function vary before the onset of dementia. Goal Attainment Scaling (GAS), an individualized patient-reported outcome, can aid in monitoring disease progression and treatment effectiveness in adults with DS. Here, with clinical input, a validated dementia symptom menu was revised to facilitate GAS in adults living with Down Syndrome-associated Alzheimer's disease (DS-AD). METHODS: Four clinicians with expertise in DS-AD and ten caregivers of adults living with DS-AD participated in semi-structured interviews to review the menu. Each participant reviewed 9-15 goal areas to assess their clarity and comprehensiveness. Responses were systematically and independently coded by two researchers as 'clear', 'modify', 'remove' or 'new'. Caregivers were encouraged to suggest additional items and recommend changes to clarify items. RESULTS: Median caregiver age was 65 years (range 54-77). Most were female (9/10) with ≥15 years of education (10/10). Adults with DS-AD had a median age of 58 years (range 52-61) and either a formal diagnosis (6/10) or clinical suspicion (4/10) of dementia. The initial symptom menu consisted of 67 symptoms each with 2-12 descriptors (589 total). The clinicians' adaptation yielded 58 symptoms each with 4-17 descriptors (580 total). Of these 580 descriptors, caregivers identified 37 (6%) as unclear; these were reworded, and one goal area (4 descriptors) was removed. A further 47 descriptors and one goal area were added to include caregiver-identified concepts. The final menu contained 58 goal areas, each with 7-17 descriptors (623 total). CONCLUSIONS: A comprehensive symptom menu for adults living with DS-AD was developed to facilitate GAS. Incorporating expert clinician opinion and input from caregivers of adults with DS-AD identified meaningful items that incorporate patient/caregiver perspectives.

Use of Patient-Reported Symptoms from an Online Symptom Tracking Tool for Dementia Severity Staging: Development and Validation of a Machine Learning Approach.

BACKGROUND: SymptomGuide Dementia (DGI Clinical Inc) is a publicly available online symptom tracking tool to support caregivers of persons living with dementia. The value of such data are enhanced when the specific dementia stage is identified. OBJECTIVE: We aimed to develop a supervised machine learning algorithm to classify dementia stages based on tracked symptoms. METHODS: We employed clinical data from 717 people from 3 sources: (1) a memory clinic; (2) long-term care; and (3) an open-label trial of donepezil in vascular and mixed dementia (VASPECT). Symptoms were captured with SymptomGuide Dementia. A clinician classified participants into 4 groups using either the Functional Assessment Staging Test or the Global Deterioration Scale as mild cognitive impairment, mild dementia, moderate dementia, or severe dementia. Individualized symptom profiles from the pooled data were used to train machine learning models to predict dementia severity. Models trained with 6 different machine learning algorithms were compared using nested cross-validation to identify the best performing model. Model performance was assessed using measures of balanced accuracy, precision, recall, Cohen κ, area under the receiver operating characteristic curve (AUROC), and area under the precision-recall curve (AUPRC). The best performing algorithm was used to train a model optimized for balanced accuracy. RESULTS: The study population was mostly female (424/717, 59.1%), older adults (mean 77.3 years, SD 10.6, range 40-100) with mild to moderate dementia (332/717, 46.3%). Age, duration of symptoms, 37 unique dementia symptoms, and 10 symptom-derived variables were used to distinguish dementia stages. A model trained with a support vector machine learning algorithm using a one-versus-rest approach showed the best performance. The correct dementia stage was identified with 83% balanced accuracy (Cohen κ=0.81, AUPRC 0.91, AUROC 0.96). The best performance was seen when classifying severe dementia (AUROC 0.99). CONCLUSIONS: A supervised machine learning algorithm exhibited excellent performance in identifying dementia stages based on dementia symptoms reported in an online environment. This novel dementia staging algorithm can be used to describe dementia stage based on user-reported symptoms. This type of symptom recording offers real-world data that reflect important symptoms in people with dementia.

Assessing Ganglion Cell Layer Topography in Human Albinism Using Optical Coherence Tomography.

Purpose: To test whether ganglion cell layer (GCL) and inner plexiform layer (IPL) topography is altered in albinism. Methods: Optical coherence tomography scans were analyzed in 30 participants with albinism and 25 control participants. Horizontal and vertical line scans were acquired at the fovea, then strip registered and averaged. The Duke Optical Coherence Tomography Retinal Analysis Program was used to automatically segment the combined GCL and IPL and total retinal thickness, followed by program-assisted manual segmentation of the boundary between the GCL and IPL. Layer thickness and area under the curve (AUC) were calculated within 2.5 mm of the fovea. Nasal-temporal and superior-inferior asymmetry were calculated as an AUC ratio in each quadrant. Results: GCL and IPL topography varied between participants. The summed AUC in all quadrants was similar between groups for both the GCL (P = 0.84) and IPL (P = 0.08). Both groups showed nasal-temporal asymmetry in the GCL, but only participants with albinism had nasal-temporal asymmetry in the IPL. Nasal-temporal asymmetry was greater in albinism for both the GCL (P < 0.0001) and the IPL (P = 0.0006). The GCL usually comprised a greater percentage of the combined GCL and IPL in controls than in albinism. Conclusions: The GCL and IPL have greater structural variability than previously reported. GCL and IPL topography are significantly altered in albinism, which suggests differences in the spatial distribution of retinal ganglion cells. This finding provides insight into foveal development and structure-function relationships in foveal hypoplasia.

The Symptoms Targeted for Monitoring in a Web-Based Tracking Tool by Caregivers of People With Dementia and Agitation: Cross-Sectional Study.

BACKGROUND: In people with dementia, neuropsychiatric symptoms (NPSs), especially agitation, are associated with worse quality of life and caregiver burden. As NPSs may vary with illness severity, knowledge of how people with dementia and their caregivers describe and rate the importance of agitation symptoms can improve the understanding of the clinical meaningfulness of the manifestations of agitation. The internet provides new opportunities to better understand patient experiences, as patients and caregivers increasingly look to Web-based platforms as a means of managing symptoms. OBJECTIVE: The aim of this study was to examine Web-based reports from a dementia symptom website to better understand the symptoms of agitation and explore how they are being targeted for monitoring by caregivers of people with dementia. METHODS: The Dementia Guide website hosts a Web-based database used by caregivers (97%) and people with dementia (3%). From its 61 dementia symptoms, users can select relevant symptoms that they deem important to monitor or track the effects of treatment. We employed a staging algorithm to determine if individuals had mild cognitive impairment (MCI) or mild, moderate, or severe dementia. Agitation was defined using terms consistent with the International Psychogeriatrics Association's provisional consensus definition. We compared the proportion of people with NPSs and agitation across stages of dementia severity and studied how many agitation-defining descriptors were selected, and how often they occurred, by stage. RESULTS: As of March 2017, 4121 people had used the tracking tool, of whom 2577 provided sufficient data to allow disease severity staging. NPSs were tracked by 2127/2577 (82.54%) and agitation by 1898/2577 (73.65%). The proportion in whom agitation was tracked increased with increasing cognitive impairment: 68.5% (491/717) in people with MCI, and 72.50% (754/1040), 73.3% (378/516), and 90.5% (275/304) in mild, moderate, and severe dementia, respectively (χ23=54.9; P<.001). The number of NPS and agitation descriptors selected also increased with severity (median number of NPSs=1, 2, 2, and 3 for MCI, mild, moderate, and severe dementia, respectively, Kruskal-Wallis H Test H3=250.47; P<.001; median number of agitation descriptors=1, 2, 3, and 4, H3=146.11; P<.001). CONCLUSIONS: NPSs and agitation are common targets for tracking over the course of dementia and appear more frequently with increasing disease severity. These common and distressing symptoms represent clinically meaningful targets in treating people with dementia.

Correlation between electroretinography, foveal anatomy and visual acuity in albinism.

BACKGROUND: Albinism patients have poor visual acuity in addition to hypopigmentation. Their foveal anatomy is abnormal, but correlation with function is incompletely understood. This study correlates retinal electrophysiology, visual acuity and optical coherence tomography (OCT) anatomy in albinism patients and compares with age-similar controls. METHODS: Institutional Review Board approval was obtained (IRB# 201408782). Patients were recruited from clinical practice. Inclusion criteria were at least three clinical features of albinism including iris transillumination, nystagmus, fundus hypopigmentation, or foveal hypoplasia on OCT and/or molecular genetic confirmation. Diagnosys (Lowell, Mass) full-field ERG (ffERG) and VERIS multifocal ERG (mfERG; Electro-Diagnostic Imaging, Milpitas, California) were obtained using standard International Society for Clinical Electrophysiology of Vision protocols. The mfERG protocol was a 4-min 103-hexagon protocol covering approximately 40° in diameter of central retina. Control subjects without albinism were recruited by in-hospital notices and invitations in clinic. OCT central thickness was recorded, and an OCT foveal score was calculated. Nonparametric permutation testing was utilized to determine the statistical significance. RESULTS: A total of 16 albinism patients and 19 age-similar controls were recruited. Four of 16 albinism patients had no nystagmus. Seventeen non-albinism controls had no ocular disorder other than refractive error. Two controls had infantile nystagmus with normal maculas on OCT. There was no statistically significant difference in mfERG amplitude or latency between albinism patients with or without nystagmus (lowest p = 0.68; 0.54, respectively). mfERG: 12 of 16 (75%) albinism patients had average ring 1 amplitudes within one standard deviation of controls despite having abnormal foveal anatomy on OCT. Patients averaged shorter latencies in rings 1 and 2 than controls (p = 0.005, p = 0.02). Patients averaged higher amplitudes than controls in rings 4, 5 and 6 (p = 0.03, p = 0.006, p = 0.004). There was no significant correlation between visual acuity and mfERG amplitudes in any ring (smallest p = 0.15). ffERG: Patients averaged higher amplitudes on 30 Hz flicker (p = 0.008). In all conditions, albinism patients had higher amplitude a-waves (p ≤ 0.03). B-waves were higher amplitude than controls in light-adapted 3.0 (p = 0.03). There was no statistical correlation between ffERG amplitudes and visual acuity (smallest p = 0.45). OCT: In albinism patients, thicker central macula on OCT correlated with lower mfERG amplitudes in all rings except for ring 1 (p < 0.05) and lower ffERG a-wave amplitudes on dark-adapted 0.01 (p = 0.003). Macular thickness on OCT did not correlate with visual acuity (p = 0.51); OCT foveal score did (p = 0.0004). CONCLUSIONS: Amplitude of mfERG does not correlate with visual acuity in any ring in patients with albinism. The slope of the change in amplitude from central to peripheral rings on the mferg is significantly different in albinism patients versus controls whether or not nystagmus is present. The decreased slope of change in amplitudes from center to periphery of the macula in albinism patients indicates changes in macular topography that are more important to visual deficits than the foveal depression.

Development and characterization of monoclonal antibodies to detect klotho.

Although antibodies are commercially available to allow investigation into the biology of the age-regulating protein Klotho, problems with antibody specificity and application functionality are significant barriers to progress. Chief among these limitations is the inability of current tools to allow in vivo validation of binding partners originally identified through transfection of tagged proteins. To overcome this barrier, we generated a series of hybridoma cell lines by immunizing rats with a GST-KL1 fusion protein. Purified antibodies generated from these cell lines differentially detect human or mouse Klotho protein via Western blot, immunocyto/histochemistry, and immunoprecipitation. Specificity of antibody binding to Klotho was confirmed by mass spectrometry following immunoprecipitation. With this confidence in antibody specificity, co-immunoprecipitation was utilized to validate the interaction of Klotho/FGFR and Klotho/wnt7a in mouse kidney lysates.

Evaluating the applicability of the Fokker-Planck equation in polymer translocation: a Brownian dynamics study.

Brownian dynamics (BD) simulations are used to study the translocation dynamics of a coarse-grained polymer through a cylindrical nanopore. We consider the case of short polymers, with a polymer length, N, in the range N = 21-61. The rate of translocation is controlled by a tunable friction coefficient, γ0p, for monomers inside the nanopore. In the case of unforced translocation, the mean translocation time scales with polymer length as <τ1> ∼ (N - Np)(α), where Np is the average number of monomers in the nanopore. The exponent approaches the value α = 2 when the pore friction is sufficiently high, in accord with the prediction for the case of the quasi-static regime where pore friction dominates. In the case of forced translocation, the polymer chain is stretched and compressed on the cis and trans sides, respectively, for low γ0p. However, the chain approaches conformational quasi-equilibrium for sufficiently large γ0p. In this limit the observed scaling of <τ1> with driving force and chain length supports the Fokker-Planck (FP) prediction that <τ> ∝ N/fd for sufficiently strong driving force. Monte Carlo simulations are used to calculate translocation free energy functions for the system. The free energies are used with the FP equation to calculate translocation time distributions. At sufficiently high γ0p, the predicted distributions are in excellent agreement with those calculated from the BD simulations. Thus, the FP equation provides a valid description of translocation dynamics for sufficiently high pore friction for the range of polymer lengths considered here. Increasing N will require a corresponding increase in pore friction to maintain the validity of the FP approach. Outside the regime of low N and high pore friction, the polymer is out of equilibrium, and the FP approach is not valid.

Identification of a high-mannose ICAM-1 glycoform: effects of ICAM-1 hypoglycosylation on monocyte adhesion and outside in signaling.

Endothelial adhesion molecules are critical effectors of inflammation ensuring coordinated interactions that allow leukocytes to home to sites of injury. These adhesion molecules are often extensively modified posttranslationaly by the addition of N-glycans, but if, or how, these modifications contribute to the protein function remains poorly understood. Herein we show that activated endothelial cells express two distinct N-glycoforms of intercellular adhesion molecule 1 (ICAM-1) that comprise a complex N-glycoform with α-2,6 sialic acid present at relatively high levels and a second, less abundant and previously undescribed high-mannose glycoform (HM-ICAM-1). This novel HM-ICAM-1 glycoform was also detected in human coronary artery specimens and moreover appeared to be the dominant glycoform in vivo. Production of exclusively HM-ICAM-1 in cells by α-mannosidase inhibition increased monocyte rolling and adhesion compared with mature ICAM-1 consistent with high-mannose epitopes providing leukocyte ligands. Cross-linking of ICAM-1 transmits outside-in signals that affect endothelial permeability and survival. Interestingly, cell signaling (assessed using ERK, VE-cadherin, and Akt phosphorylation) was maintained after cross-linking of HM-ICAM-1 compared with mature ICAM-1; however, interactions with the actin cytoskeleton were lost with HM-ICAM-1. These findings suggest that specific ICAM-1 N-glycoforms modulate distinct aspects of the inflammatory response and identify HM-ICAM-1 as a new therapeutic target for controlling leukocyte trafficking and endothelial inflammation.