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Abstract Background Cognitive decline in Alzheimer’s disease (AD) is associated with hyperphosphorylated tau (pTau) propagation between neurons along synaptically connected networks, in part via extracellular vesicles (EVs). EV biogenesis is triggered by ceramide enrichment at the plasma membrane from neutral sphingomyelinase2 (nSMase2)-mediated cleavage of sphingomyelin. We report, for the first time, that human tau expression elevates brain ceramides and nSMase2 activity. Methods To determine the therapeutic benefit of inhibiting this elevation, we evaluated PDDC, the first potent, selective, orally bioavailable, and brain-penetrable nSMase2 inhibitor in the transgenic PS19 AD mouse model. Additionally, we directly evaluated the effect of PDDC on tau propagation in a mouse model where an adeno-associated virus (AAV) encoding P301L/S320F double mutant human tau was stereotaxically-injected unilaterally into the hippocampus. The contralateral transfer of the double mutant human tau to the dentate gyrus was monitored. We examined ceramide levels, histopathological changes, and pTau content within EVs isolated from the mouse plasma. Results Similar to human AD, the PS19 mice exhibited increased brain ceramide levels and nSMase2 activity; both were completely normalized by PDDC treatment. The PS19 mice also exhibited elevated tau immunostaining, thinning of hippocampal neuronal cell layers, increased mossy fiber synaptophysin immunostaining, and glial activation, all of which were pathologic features of human AD. PDDC treatment reduced these changes. The plasma of PDDC-treated PS19 mice had reduced levels of neuronal- and microglial-derived EVs, the former carrying lower pTau levels, compared to untreated mice. In the tau propagation model, PDDC normalized the tau-induced increase in brain ceramides and significantly reduced the amount of tau propagation to the contralateral side. Conclusions PDDC is a first-in-class therapeutic candidate that normalizes elevated brain ceramides and nSMase2 activity, leading to the slowing of tau spread in AD mice.

Alzheimer’s disease (AD) is characterized by the progressive accumulation of amyloid-β and hyperphosphorylated tau (pTau), which can spread throughout the brain via extracellular vesicles (EVs). Membrane ceramide enrichment regulated by the enzyme neutral sphingomyelinase 2 (nSMase2) is a critical component of at least one EV biogenesis pathway. Our group recently identified 2,6-Dimethoxy-4-(5-Phenyl-4-Thiophen-2-yl-1H-Imidazol-2-yl)-Phenol (DPTIP), the most potent (30 nM) and selective inhibitor of nSMase2 reported to date. However, DPTIP exhibits poor oral pharmacokinetics (PK), modest brain penetration, and rapid clearance, limiting its clinical translation. To enhance its PK properties, we conjugated DPTIP to a hydroxyl-PAMAM dendrimer delivery system, creating dendrimer-DPTIP (D-DPTIP). In an acute brain injury model, orally administered D-DPTIP significantly reduced the intra-striatal IL-1β-induced increase in plasma EVs up to 72 h post-dose, while oral DPTIP had a limited effect. In a mouse tau propagation model, where a mutant hTau (P301L/S320F) containing adeno-associated virus was unilaterally seeded into the hippocampus, oral D-DPTIP (dosed 3× weekly) significantly inhibited brain nSMase2 activity and blocked the spread of pTau to the contralateral hippocampus. These data demonstrate that dendrimer conjugation of DPTIP improves its PK properties, resulting in significant inhibition of EV propagation of pTau in mice. Dendrimer-based delivery of DPTIP has the potential to be an exciting new therapeutic for AD.

Background: Ipilimumab disinhibits immune system activity which results in the elimination of malignant cells. An unintended consequence of ipilimumab therapy is off-target immune-related adverse events (irAEs). It has therefore been proposed that the incidence of irAEs is a manifestation of treatment effectiveness. The objective of this systematic review is to examine the relationship between irAEs and survivability among melanoma patients administered ipilimumab monotherapy., Methods: A comprehensive search was conducted across several databases which yielded a total of 2381 studies. Clinical trials and prospective studies administering ipilimumab monotherapy to melanoma patients were included. Furthermore, there was no restriction placed on publication date. After screening, five studies were included for data extraction. The primary outcome of median overall survival (OS) and the secondary outcome of OS hazard ratio were extracted from the included studies., Results: Based on qualitative analysis of the included studies, there seemed to be an association between the occurrence of non-lethal irAEs and improved survival outcomes among melanoma patients administered ipilimumab monotherapy. With that being said, the poorer survivability among patients who experienced high-grade irAEs may be the result of subsequent treatment discontinuation. Potential confounders such as corticosteroid use should be accounted for. Finally, landmark analyses may be conducted to account for immortal time bias., Conclusions: The findings from this systematic review provide evidence suggesting that the incidence of irAEs is a marker of an improved anti-tumor response., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Purpose: To assess health-related quality of life (HRQoL), vision-related quality of life (VRQoL), depression and anxiety symptoms, and social support and community integration of seniors with eye diseases and to identify important predictor variables of the outcomes., Methods: A cross-sectional survey was performed in seniors with eye diseases ( n  = 90). Demographic characteristics and questionnaire scores were summarized. Linear regression analysis with backward stepwise selection was used to predict the value of the outcomes of eye disease., Results: Preference-based HRQoL of the study patients with eye diseases during the pandemic was likely good with a mean utility value of 0.88. VRQoL and sleep quality appeared to be good as well. Depression and anxiety symptoms appeared to be low, while community integration and social support were moderate. Furthermore, the presence of retinal disease, number of nonocular comorbidities, and education appeared to have significant negative effects on social support and community integration. The presence of retinal disease and the number of nonocular comorbidities both appeared to negatively impact VRQoL. The use of a mobility aid appeared to negatively affect depressive symptoms and sleep quality., Conclusions: Overall quality of life and wellness among seniors with eye diseases appeared to be good during the COVID-19 pandemic. However, the presence of retinal disease and the number of nonocular comorbidities both appeared to negatively impact VRQoL and social support and community integration. Education appeared to impact social support and community integration negatively. The use of a mobility aid appeared to negatively affect depressive symptoms and sleep quality., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2023 Brian Edward Yu et al.)

Topic: The purpose of the current study was to systematically identify and evaluate existing patient-reported outcome measures (PROMs) for clinical glaucoma practice., Clinical Relevance: Understanding and incorporating patient preferences into decision-making is now recognized as critical for optimal resource allocation, especially in technologically advancing areas, such as minimally invasive surgeries. Patient-reported outcome measures are instruments designed to evaluate the health outcomes that are most important to patients. Despite their recognized importance, especially in the era of patient-centered care, their routine use in clinical settings remains low., Methods: A systematic literature search was conducted in 6 databases (EMBASE, MEDLINE, PsycINFO, Scopus, BIOSIS, and Web of Science) from the date of inception. Studies were included in the qualitative review if they reported measurement properties of PROMs in adult patients with glaucoma. COnsensus-based Standards for the selection of health Measurement INstruments guidelines were used to assess the included PROMs. The study protocol is registered with PROSPERO (registration number: CRD42020176064)., Results: The literature search yielded 2661 records. After deduplication, 1259 studies entered level 1 screening, and based on title and abstract review, 164 records proceeded to full-text screening. In 48 included studies, 70 instrument reports discuss 43 distinct instruments in 3 major categories: glaucoma-specific, vision-specific, and general health-related quality of life. Most used measures were glaucoma-specific (Glaucoma Quality of Life [GQL] and Glaucoma Symptom Scale [GSS]) and vision-specific (National Eye Institute Visual Function Questionnaire [NEI VFQ-25]). All 3 have sufficient validity (especially construct), with GQL and GSS having sufficient internal consistency, cross-cultural validity, and reliability, with reports suggesting high methodological quality., Conclusion: The GQL, GSS, and NEI VFQ-25 are the 3 most used questionnaires in a research setting, having considerable validation in a patient population with glaucoma. Limited reports on interpretability, responsiveness, and feasibility in all 43 identified instruments make identifying a single optimal questionnaire for clinical use challenging and highlight the need for further studies., Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article., (Copyright © 2023 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Background: Electronic medical record (EMR) adoption in primary care has grown exponentially since their introduction in the 1970s. However, without their proper use benefits cannot be achieved. This includes: 1) the complete and safe documentation of patient information; 2) improved coordination of care; 3) reduced errors and 4) more involved patients. The use of EMRs is defined by practitioners using EMRs and their features to perform daily practice functions., Objective: The purpose of this systematic review was to identify interventions aimed at improving EMR use in primary healthcare settings., Methods: Ten online databases were searched to identify studies conducted in primary healthcare settings aimed at implementing interventions to observe the use of EMRs and directly measure the use of EMR functions or outcomes effected by the use of EMR functions., Results: Of 2098 identified studies, 12 were included in the review. Results showed that interventions focused on the use of EMR functions, including referrals, electronic communication, reminders, use of clinical decision support systems and workflow management support functions, were five times more likely to show improvements in EMR use compared with controls. Interventions focused on data quality were five and a half times more likely to show improvements in EMR use compared with controls., Conclusions: Individuals in primary healthcare settings aiming to improve EMR use would benefit from implementing interventions focused on EMR feature add-ons such as clinical decision support systems and customised referral templates, and provisions of educational materials, or financial incentives targeted at improving the use of EMR functions and data quality., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: For patients with comorbid cataract and primary open-angle glaucoma (POAG), guidance is lacking as to whether cataract extraction and traditional filtering surgery should be performed as a staged or combined procedure. Achieving this guidance requires an evidence-based understanding of the effects of phacoemulsification alone on intraocular pressure (IOP) in patients with POAG. For this reason, a systematic review and meta-analysis was undertaken to synthesize evidence quantifying the effect of phacoemulsification on IOP and the required number of topical glaucoma medications in patients with cataract and POAG., Materials and Methods: Database searches were last run on August 15, 2016 to identify potentially relevant studies. Identified articles were screened for relevance and meta-analysis was used to compute postoperative mean and percentage reduction in IOP (IOPR%) as well as mean difference in topical glaucoma medications., Results: The search strategy identified 1613 records. Thirty-two studies (1826 subjects) were included in quantitative synthesis. A 12%, 14%, 15%, and 9% reduction in IOP from baseline occurred 6, 12, 24, and 36 months after phacoemulsification. A mean reduction of 0.57, 0.47, 0.38, and 0.16 medications per patient of glaucoma medication occurred 6, 12, 24, and 36 months after phacoemulsification., Conclusions: Phacoemulsification as a solo procedure does lower IOP in patients with POAG, and reduces dependency on topical glaucoma medications. These effects appear to last at least 36 months with gradual loss of the initial effect noted after 2 years. Certain populations appear to experience much greater reductions in IOP than others and future work to identify these high responding patients is needed.

Background: Diabetic eye complications are the leading cause of visual loss among working-aged people. Pharmacy-based teleophthalmology has emerged as a possible alternative to in-person examination that may facilitate compliance with evidence-based recommendations and reduce barriers to specialized eye care. The objective of this study was to estimate the cost-effectiveness of mobile teleophthalmology screening compared with in-person examination (primary care) for the diabetic population residing in semiurban areas of southwestern Ontario., Methods: A decision tree was constructed to compare in-person examination (comparator program) versus pharmacy-based teleophthalmology (intervention program). The economic model was designed to identify patients with more than minimal diabetic retinopathy, manifested by at least 1 microaneurysm at examination (modified Airlie House classification grade of ≥ 20). Cost-effectiveness was assessed as cost per case detected (true-positive result) and cost per case correctly diagnosed (including true-positive and true-negative results)., Results: The cost per case detected was $510 with in-person examination and $478 with teleophthalmology, and the cost per case correctly diagnosed was $107 and $102 respectively. The incremental cost-effectiveness ratio was $314 per additional case detected and $73 per additional case correctly diagnosed. Use of pharmacologic dilation and health care specialists' fees were the most important cost drivers., Interpretation: The study showed that a compound teleophthalmology program in a semiurban community would be more effective but more costly than in-person examination. The findings raise the question of whether the benefits of pharmacy-based teleophthalmology in semiurban areas, where in-person examination is still available, are equivalent to those observed in remote communities. Further study is needed to investigate the impact of this program on the prevention of severe vision loss and quality of life in a semiurban setting.

Glaucoma is the leading cause of irreversible vision loss and costs the American economy $2.9 billion. Teleglaucoma remotely detects glaucoma improving access to ophthalmic care in rural areas. It helps manage glaucoma more efficiently to preserve vision and reduce healthcare costs. A cost-effectiveness analysis was conducted using healthcare provider or third-party payer perspective within rural Canada. The study population were patients at-risk of glaucoma which includes those with diabetes and/or hypertension, family history of glaucoma, adults older than 50 years, and concurrent ocular conditions in rural Alberta. Markov modelling was used to model glaucoma health states. Effectiveness was measured in Quality-Adjusted Life Years (QALYs) and costs were used in Canadian dollars. Using TreeAge Pro 2009, incremental cost-effectiveness ratios (ICER) were developed in dollars per QALYs. Deterministic and probabilistic sensitivity analyses were performed to assess the factors affecting cost-effectiveness. Teleglaucoma had a 20% increase in ophthalmologist-referral rate; it reduced patient travel times by 61 hours and physician wait times by 30% in comparison to in-person examination (standard of care). Teleglaucoma costs $872 per patient screened which was 80% less than in-person examination. Teleglaucoma had a greater incremental effectiveness providing an additional 0.12 QALY per patient examination. It was more sensitive (86.5%) and less specific (78.6%) than in-person examination. Teleglaucoma was more cost-effective than in-person examination with an ICER of-$27,460/QALY. This indicated that teleglaucoma will save $27, 460 for each additional QALY gained. Long term benefits showed teleglaucoma prevents 24% cases of glaucoma blindness after 30 years. Teleglaucoma demonstrated improved health outcomes, as well as, cost benefits. It increases access to ophthalmic care and improves healthcare service efficiency, specifically in rural areas. Teleglaucoma is more cost-effective than current in-person examination and can improve the quality of life in glaucoma patients.