Eye Adult Changes in Thought (Eye ACT) Study: Design and Report on the Inaugural Cohort.

Background: Conflicting research on retinal biomarkers of Alzheimer's disease and related dementias (AD/ADRD) is likely related to limited sample sizes, study design, and protocol differences. Objective: The prospective Eye Adult Changes in Thought (Eye ACT) seeks to address these gaps. Methods: Eye ACT participants are recruited from ACT, an ongoing cohort of dementia-free, older adults followed biennially until AD/ADRD, and undergo visual function and retinal imaging assessment either in clinic or at home. Results: 330 participants were recruited as of 03/2023. Compared to ACT participants not in Eye ACT (N = 1868), Eye ACT participants (N = 330) are younger (mean age: 70.3 versus 71.2, p = 0.014), newer to ACT (median ACT visits since baseline: 3 versus 4, p < 0.001), have more years of education (17.7 versus 16.2, p < 0.001) and had lower rates of visual impairment (12% versus 22%, p < 0.001). Compared to those seen in clinic (N = 300), Eye ACT participants seen at home (N = 30) are older (77.2 versus 74.9, p = 0.015), more frequently female (60% versus 49%, p = 0.026), and have significantly worse visual acuity (71.1 versus 78.9 Early Treatment Diabetic Retinopathy Study letters, p < 0.001) and contrast sensitivity (-1.9 versus -2.1 mean log units at 3 cycles per degree, p = 0.002). Cognitive scores and retinal imaging measurements are similar between the two groups. Conclusions: Participants assessed at home had significantly worse visual function than those seen in clinic. By including these participants, Eye ACT provides a unique longitudinal cohort for evaluating potential retinal biomarkers of dementia.

Comparison of Orthosis Management Failure Rates for Mallet Injuries.

Purpose: A closed mallet injury is a common finger injury involving terminal extensor tendon avulsion from its insertion on the distal phalanx. Nonsurgical treatment with continuous extension orthosis fabrication is the preferred treatment. Our purpose was to report the failure rates of orthotic management by digit and investigate other factors that contribute to failure. Methods: This was a retrospective chart review of all patients with an isolated mallet finger injury managed at our institution from 2011 to 2019. Patient demographics, details of management, and treatment outcomes were collected. Failure rates were compared for all digits, specifically comparing the little finger versus all other digits. A categorical variable analysis was performed to identify risk factors for failure of orthosis management. Results: Out of 1,331 identified patients, 328 met the inclusion criteria. There was no statistically significant difference of failure rate between digits. There was a trend toward the little finger failing at a higher rate (n = 131, 40%) than the other digits individually (P = .08) and combined (n = 95, 29%; P = .06). An older age at injury was associated with failure. The median patient age with failure was 54 years, versus the median patient age with nonfailure of 48 years (P < .01). The failure rate was higher in tendinous versus bony mallet injuries (n = 131, 40% vs n = 66, 20%, respectively; P < .01). The orthotic type was associated with the failure rate, and failure was highest in patients treated with Stack orthoses (n = 183, 56%; P = .01). Conclusions: There was no significant difference in the orthotic management failure rate by digit for a mallet injury. Statistically significant risk factors for failure are increasing age, a tendinous injury, and the orthotic type. Further evaluation with a larger cohort is warranted to increase the statistical power of the findings. Type of study/level of evidence: Therapeutic III.

Identification of Human Toll-like Receptor 2-Agonistic Activity in Dihydropyridine-Quinolone Carboxamides.

Using a multiplexed, reporter gene-based, high-throughput screen, we identified 9-fluoro-7-hydroxy-3-methyl-5-oxo-N-(pyridin-3-ylmethyl)-2,3-dihydro-1H,5H-pyrido[3,2,1-ij]quinoline-6-carboxamide as a TLR2 agonist. Preliminary structure-activity relationship studies on the carboxamide moiety led to the identification of analogues that induce chemokines and cytokines in a TLR2-dependent manner. These results represent new leads for the development of vaccine adjuvants.

Hyaluronic Acid Conjugates of TLR7/8 Agonists for Targeted Delivery to Secondary Lymphoid Tissue.

Immunogens carried in lymphatic fluid drain via afferent vessels into regional lymph nodes and facilitate the efficient induction of appropriate immune responses. The lymphatic system possesses receptors recognizing hyaluronic acid (HA). Covalent conjugates of small-molecule TLR7/8 agonists with HA are entirely devoid of immunostimulatory activity in vitro. In murine models of immunization, however, such conjugates traffic to lymph nodes, where they are "unmasked", releasing the small molecule TLR7/8 agonist from the carrier polysaccharide. The resulting focal immunostimulation is manifested in potent adjuvantic effects with negligible systemic exposure. The efficient delivery of immunogens has been a major challenge in the development of subunit vaccines, and enhancing targeted delivery of immunogens to secondary lymphoid organs might be a promising approach for improving vaccine efficacy, as well as safety.

Identification of High-Potency Human TLR8 and Dual TLR7/TLR8 Agonists in Pyrimidine-2,4-diamines.

The induction of toll-like receptor 7 (TLR7)-dependent type I interferons (IFN-α/ß) from plasmacytoid dendritic cells as well as the production of TLR8-dependent type II interferon (IFN-γ), TNF-α, and IL-12 in myeloid dendritic cells are of importance in generating T helper-1 biased adaptive immune responses. In an effort to identify novel dual TLR7/TLR8-active compounds, we undertook structure-activity relationship studies in pyrimidine 2,4-diamines, focusing on substituents at C5. Several analogues substituted with aminopropyl appendages at C5 displayed dominant TLR8-agonistic activity. N4-Butyl-6-methyl-5-(3-morpholinopropyl)pyrimidine-2,4-diamine was found to be a very potent dual TLR7/TLR8 agonist. Employing novel cytokine reporter cell assays, we verified that potency at TLR7 correlates with IFN-α/ß production in human blood, whereas IFN-γ and TNF-α induction is largely TLR8-dependent. Dual TLR7/TLR8 agonists markedly upregulate CD80 expression in multiple dendritic cell subsets, providing insight into the immunological basis for the superior adjuvantic properties of such innate immune stimuli.

Cell migration during heart regeneration in zebrafish.

Zebrafish possess the remarkable ability to regenerate injured hearts as adults, which contrasts the very limited ability in mammals. Although very limited, mammalian hearts do in fact have measurable levels of cardiomyocyte regeneration. Therefore, elucidating mechanisms of zebrafish heart regeneration would provide information of naturally occurring regeneration to potentially apply to mammalian studies, in addition to addressing this biologically interesting phenomenon in itself. Studies over the past 13 years have identified processes and mechanisms of heart regeneration in zebrafish. After heart injury, pre-existing cardiomyocytes dedifferentiate, enter the cell cycle, and repair the injured myocardium. This process requires interaction with epicardial cells, endocardial cells, and vascular endothelial cells. Epicardial cells envelope the heart, while endocardial cells make up the inner lining of the heart. They provide paracrine signals to cardiomyocytes to regenerate the injured myocardium, which is vascularized during heart regeneration. In addition, accumulating results suggest that local migration of these major cardiac cell types have roles in heart regeneration. In this review, we summarize the characteristics of various heart injury methods used in the research community and regeneration of the major cardiac cell types. Then, we discuss local migration of these cardiac cell types and immune cells during heart regeneration. Developmental Dynamics 245:774-787, 2016. © 2016 Wiley Periodicals, Inc.

Angiosarcoma metastatic to the orbit.

A 61-year-old woman developed metastatic angiosarcoma in her left orbit. Diagnosis was confirmed with an incisional orbital biopsy and special markers. Treatment and palliation involved the use of multiple cycles of paclitaxcel, doxorubicin, and ifosfamide along with adjuvant radiotherapy. The measured outcome was tumor mass reduction and mortality. Angiosarcoma was confirmed with histologic analysis. The patient responded to the chemotherapy with reduction of the tumor mass. However, the disease progressed off the medications. She finally died. However, she survived longer than the patient in the only other similar case report. Chemotherapy may be a useful palliative adjunct in the control of metastatic orbital angiosarcoma. Chemotherapy is unlikely to be curative but useful and an adjunct to surgery and radiation therapy.

Test-retest variability in glaucoma patients tested with C-20-1 screening-mode frequency doubling technology perimetry.

PURPOSE: To investigate test-retest variability in glaucoma patients tested with C-20-1 (screening) Frequency Doubling Technology (FDT) perimetry. METHODS: Thirty-one glaucoma patients with a range of visual field defects (17 with mild, 11 with moderate, and 3 with severe defects by AGIS classification) and experienced in standard automated perimetry but not FDT perimetry were prospectively recruited. The C-20-1 screening mode of FDT was consecutively administered three times. Concordance between tests for each patient was measured by presence and severity of defects for each test location. Learning and/or fatigue effects were also evaluated using FDT test scores in which number and severity of defects was graded. RESULTS: Agreement between FDT test locations averaged 88% for any defect, but only 51% for severity of defect. Although the mean test score increased slightly over the three tests, subjects did not demonstrate a statistically significant change in test score across the three testings (P = 0.975). Among 17 patients with early glaucoma (AGIS score 1-5), two returned a normal initial FDT test, and four returned a normal second FDT test. CONCLUSIONS: Using C-20-1 FDT, concordance between tests at a given test location was high for the presence of any defect, which would be important in glaucoma screening, but was only fair for severity of defect. Six of 17 patients with early glaucoma returned normal tests during testing. This group of glaucoma patients with perimetric experience did not demonstrate a significant learning or fatigue effect with FDT screening perimetry.

Learning effect among perimetric novices with screening C-20-1 frequency doubling technology perimetry.

PURPOSE: To investigate whether perimetric novices without glaucoma demonstrate a learning effect using screening-mode frequency doubling technology perimetry. DESIGN: Prospective observational study. METHODS: The study included 101 healthy subjects who had never undergone automated perimetry and who were administered the C-20-1 version of the frequency doubling technology. Subjects who returned an abnormal or unreliable test were retested until a normal result was obtained. RESULTS: Ninety-seven subjects (96%) returned a normal examination after one test, and 99 (98%) did so after two tests. Two subjects had abnormal initial tests, and two others had unreliable tests. These four subjects required repeat (up to four) testings to return a normal test. CONCLUSIONS: A small percentage of perimetric novices will demonstrate a learning effect using C-20-1 perimetry, but this mode has high specificity appropriate for glaucoma screening.

Comparing clock tests for dementia screening: naïve judgments vs formal systems--what is optimal?

BACKGROUND: Clock drawing tests (CDTs) vary in format, scoring, and complexity. Herein, we compared the dementia screening performance of seven CDT scoring systems and the judgements of untrained raters. METHODS: 80 clock drawings by subjects of known dementia status were selected, 20 from each of four categories (Consortium to Establish a Registry for Alzheimer's disease [CERAD] defined normal, mild, moderate, and severe abnormality). An expert rater scored all clocks using published criteria for seven systems. Additionally, 20 naïve raters judged clocks as either normal or abnormal, without formal instructions. Clocks were then classified by drawers' dementia status for comparison of dementia detection across systems. RESULTS: Naïve and formal CDT systems showed 90-100% agreement in CERAD normal, moderate and severe categories, but poor agreement (mean = 39%) for mildly impaired clocks. When CDT systems were compared for accurate dementia classification, the Mendez and CERAD systems correctly identified the greatest proportion of subjects (84-85%), and Wolf-Klein the smallest (58%). The better systems correctly identified> 70% of mildly demented individuals (CDR = 1). In contrast, medical records from patients' personal physicians correctly identified only 24% of the mildly demented. Strikingly, naïve raters' CDT judgements were as effective as five of the seven CDT systems in dementia identification. CONCLUSIONS: While the Mendez system was the most accurate overall, it was not significantly better than CERAD, which had simpler scoring rules. Untrained raters discriminated normal from abnormal clocks with acceptable accuracy for community screening purposes. Results suggest that, if used, most CDT systems would improve personal physicians' dementia recognition in difficult to detect mildly demented subjects.