Efficacy of a new refractive multifocal contact lens for presbyopia.

This prospective single-arm study aimed to evaluate the clinical efficacy and safety of a refractive multifocal contact lens for the correction of presbyopia in 22 patients. The participants underwent clinical examinations before and 1 week after wearing a refractive multifocal contact lens (OptaCon ZOOM). The primary endpoints were the corrected distance visual acuity (CDVA) and distance-corrected near visual acuity (DCNVA). Defocus curve, contrast sensitivity, and ocular surface disease index (OSDI) were analyzed. A slit-lamp examination was performed for safety analysis. Contact lens comfort and patient satisfaction were assessed using a questionnaire. No significant difference in CDVA was observed before and 1 week after refractive multifocal contact lens use (p = 0.127), whereas DCNVA was significantly improved after 1 week (p < 0.001). The contrast sensitivity was not significantly affected at any spatial frequency under mesopic or photopic conditions. OSDI was significantly increased (p = 0.023). The patient-reported satisfaction scores were 96.2, 91.9, and 85.0 out of 100 at far, intermediate, and near distances, respectively. No significant adverse events were observed. Refractive multifocal contact lenses improved near vision while maintaining distance vision in presbyopic patients, without compromising contrast sensitivity. The study results suggest that OptaCon ZOOM can be considered safe and effective for the correction of presbyopia.

Relationship between vestibular loss and the risk of dementia using the 2002-2019 national insurance service survey in South Korea.

This retrospective cross-sectional study assessed older adults aged between 40 and 80 years, registered in the Korean National Health Insurance Service database from 2002 to 2019 to investigate the association between vestibular loss and the risk of dementia. The population was divided into three groups (general, vestibular loss, and hearing loss). The hazard ratios (HRs) of dementia in the vestibular and hearing loss groups were calculated using national population data. In total, 2,347,610 individuals were identified (general: 2,145,609, vestibular loss: 60,525, hearing loss: 141,476). Mean ages were 53.29 years, 58.26 years, and 58.52 years, respectively. Dementia occurred in 127,081 (IR = 4.91 per 1000 person-years), 7705 (IR = 10.79 per 1000 person-years), and 16,116 (IR = 9.63 per 1000 person-years) patients. The vestibular and hearing loss groups had hazard ratios for dementia of 1.084 (95% CI, 1.059-1.110) and 1.074 (95% CI, 1.056-1.092), respectively, compared with the general group. The results of the current study suggest that vestibular loss increases the risk of developing dementia. Therefore, similar to hearing loss, vestibular loss should be considered a risk factor for dementia, and treatments such as adequate vestibular rehabilitation may reduce this risk.

Development and application of an in vitro assay to assess target-independent B-cell activation by targeted TLR7 immune agonists.

Targeted immune agonist (TIA) comprising a TLR7 agonist conjugated to tumor-targeting antibodies have been shown to induce potent anti-tumor responses in various preclinical models. However, the clinical proof-of-concept of a TIA has been hampered by systemic dose-limiting immune-related toxicities, including rapid induction of anti-drug antibodies in patients. We have developed ELISPOT-based assay to measure activation of antibody-secreting cells (ASCs), intended to simulate the interaction between TIA and peripheral B cells as a tool to pre-clinically de-risk tumor target-independent peripheral B-cell activation by TIA. This method has proven to be robust and has fast turn-around time to evaluate the induction of spontaneous B-cell activation by TIA in a tumor target- and FcγR-independent manner. This novel ASC assay platform may serve as a preclinical tool to de-risk TIAs that can potentially induce immune-related adverse effects in the clinic.

Prediction of Hearing Prognosis After Intact Canal Wall Mastoidectomy With Tympanoplasty Using Artificial Intelligence.

OBJECTIVE: To evaluate the performance of a machine learning model and the effects of major prognostic factors on hearing outcomes following intact canal wall (ICW) mastoidectomy with tympanoplasty. STUDY DESIGN: Retrospective cross-sectional study. SETTING: Tertiary hospital. METHODS: A total of 484 patients with chronic otitis media who underwent ICW tympanomastoidectomy between January 2007 and December 2020 were included in this study. Successful hearing outcomes were defined by a postoperative air-bone gap (ABG) of ≤20 dB and preoperative air conduction (AC)-postoperative AC value of ≥15 dB according to the Korean Otological Society guidelines for outcome reporting after chronic otitis media surgery. The light gradient boosting machine (LightGBM) and multilayer perceptron (MLP) models were tested as artificial intelligence models and compared using logistic regression. The main outcome assessed was the successful hearing outcome after surgery, measured using the area under the receiver operating characteristic curve (AUROC). RESULTS: In the analysis using the postoperative ABG criterion, the LightGBM exhibited a significantly higher AUROC compared to those of the baseline model (mean, 0.811). According to the difference between preoperative and postoperative AC, the MLP showed a significantly higher AUROC than those of the baseline model (mean, 0.795). CONCLUSION: This study analyzed multiple factors that could affect the hearing outcome using different artificial intelligence models and found that preoperative hearing status was the most important factor. Our findings provide additional information regarding postoperative hearing for clinicians.

Physicochemical characterization and functionality comparison of Humira®(adalimumab), Remicade®(infliximab) and Simponi Aria®(golimumab).

FDA-approved anti-TNFα biopharmaceuticals are successful in treating a range of autoimmune diseases. However, not all anti-TNFα products are identical in their patient outcomes, suggesting that there may be product-specific differences stemming from protein structural differences, doses and routes of administration. In this work, we focus only on structural and functional differences across three full-length anti-TNFα mAbs (Humira®, Remicade®, and Simponi Aria®) to better understand the implications of such differences on the products' efficacy. For structural characterization, we quantified N-glycans using mass spectrometry and fluorescence labeling. From these studies, we observed that Remicade® had the highest percent of afucosylated glycans (15.5 ± 1.3 %) and the largest number of unique glycans, 28. While Humira® had the fewest unique glycans, 15, and 11.4 ± 0.8 % of afucosylated, high-mannose glycans. For the functional studies we tested TNFα binding via ELISA, FcγRIIIa binding via AlphaLISA and effector function using an ADCC bioreporter assay. Humira® had a significantly lower EC50 (1.9 ± 0.1 pM) for ELISA and IC50 (10.5 ± 1.1 nM) for AlphaLISA, suggesting that Humira® has higher TNFα and FcγRIIIa binding affinity than Remicade® and Simponi Aria®. Humira® was also the most potent in the bioreporter assay with an EC50 value of 0.55 ± 0.03 nM compared to Remicade® (0.64 ± 0.04 nM) and Simponi Aria® (0.67 ± 0.03 nM). This comparison is significant as it highlights functional differences between mAbs with shared mechanisms of action when examined in a single laboratory and under one set of conditions.

Phospholipids impact the protective effects of HDL-mimetic nanodiscs against lipopolysaccharide-induced inflammation.

Aim: The impacts of synthetic high-density lipoprotein (sHDL) phospholipid components on anti-sepsis effects were investigated. Methods: sHDL composed with ApoA-I mimetic peptide (22A) and different phosphatidylcholines were prepared and characterized. Anti-inflammatory effects were investigated in vitro and in vivo on lipopolysaccharide (LPS)-induced inflammation models. Results: sHDLs composed with 1,2-dimyristoyl-sn-glycero-3-phosphocholine (22A-DMPC) most effectively neutralizes LPS, inhibits toll-like receptor 4 recruitment into lipid rafts, suppresses nuclear factor κB signaling and promotes activating transcription factor 3 activating. The lethal endotoxemia animal model showed the protective effects of 22A-DMPC. Conclusion: Phospholipid components affect the stability and fluidity of nanodiscs, impacting the anti-septic efficacy of sHDLs. 22A-DMPC presents the strongest LPS binding and anti-inflammatory effects in vitro and in vivo, suggesting a potential sepsis treatment.

Sepsis is triggered by endotoxins released by bacteria. These endotoxins trigger an exaggerated inflammatory response, leading to widespread inflammation and organ damage. Synthetic high-density lipoprotein (sHDL) is a potential treatment of sepsis by neutralizing endotoxins and regulating inflammatory responses. The phospholipid components of sHDL may affect the effectiveness of sHDL against sepsis. In this study, we prepared sHDLs with different phospholipids and compared their anti-septic effects on cells and in animal models. We found that sHDL made from DMPC presented the best anti-septic effects, possibly because DMPC-sHDL had the best fluidity at body temperature.

High-Density Lipoprotein in Lupus: Disease Biomarkers and Potential Therapeutic Strategy.

Systemic lupus erythematosus (SLE) patients exhibit accelerated development of atherosclerosis and increased incidents of cardiovascular disease (CVD) that cannot be explained by traditional risk factors alone. Accumulating evidence suggests that reduced levels of high-density lipoproteins (HDLs), along with altered HDL composition and function, may contribute to the accelerated atherosclerosis in SLE patients. Normally, HDLs play various atheroprotective roles through facilitating cholesterol efflux, inhibiting vascular inflammation, and scavenging oxidative species. However, systemic inflammation, oxidative stress, and autoimmunity in SLE patients induce changes in HDL size distribution and proteomic and lipidomic signatures. These compositional changes in HDLs result in the formation of proinflammatory, dysfunctional HDL. These lupus-altered HDLs have impaired antiatherogenic function with reduced cholesterol efflux capacities, impaired antioxidation abilities, and diminished antiinflammatory properties. In fact, dysfunctional HDL may promote atherogenesis by inducing inflammation. Thus, dysfunctional HDLs could be an important biomarker of accelerated atherosclerosis in lupus. Additionally, HDL-targeted therapies, especially infusion of reconstituted HDLs, may serve as a potential therapeutic intervention for SLE patients with CVD.

Multifaceted assessment of rituximab biosimilarity: The impact of glycan microheterogeneity on Fc function.

Biosimilars are poised to reduce prices and increase patient access to expensive, but highly effective biologic products. However, questions still remain about the degree of similarity and scarcity of information on biosimilar products from outside of the US/EU in the public domain. Thus, as an independent entity, we performed a comparative analysis between the innovator, Rituxan® (manufactured by Genentech/Roche), and a Russian rituximab biosimilar, Acellbia® (manufactured by Biocad). We evaluated biosimilarity of these two products by a variety of state-of-the-art analytical mass spectrometry techniques, including tandem MS mapping, HX-MS, IM-MS, and intact MS. Both were found to be generally similar regarding primary and higher order structure, though differences were identified in terms of glycoform distribution levels of C-terminal Lys, N-terminal pyroGlu, charge variants and soluble aggregates. Notably, we confirmed that the biosimilar had a higher level of afucosylated glycans, resulting in a stronger FcγIIIa binding affinity and increased ADCC activity. Taken together, our work provides a comprehensive comparison of Rituxan® and Acellbia®.

Phospholipid Component Defines Pharmacokinetic and Pharmacodynamic Properties of Synthetic High-Density Lipoproteins.

Synthetic high-density lipoprotein (sHDL) nanoparticles composed of apolipoprotein A-I mimetic peptide and phospholipids have been shown to reduce atherosclerosis in animal models. Cholesterol is mobilized from atheroma macrophages by sHDL into the blood compartment and delivered to the liver for elimination. Historically, sHDL drug discovery efforts were focused on optimizing peptide sequences for interaction with cholesterol cellular transporters rather than understanding how both sHDL components, peptide and lipid, influence its pharmacokinetic and pharmacodynamic profiles. We designed two sets of sHDL having either identical phospholipid but variable peptide sequences with different plasma stability or identical peptide and phospholipids with variable fatty acid chain length and saturation. We found that sHDL prepared with proteolytically stable 22A-P peptide had 2-fold longer circulation half-time relative to the less stable 22A peptide. Yet, longer half-life did not translate into any improvement in cholesterol mobilization. In contrast, sHDL with variable phospholipid compositions showed significant differences in phospholipid PK, with distearoyl phosphatidylcholine-based sHDL demonstrating the longest half-life of 6.0 hours relative to 1.0 hour for palmitoyl-oleoyl phosphatidylcholine-based sHDL. This increase in half-life corresponded to an approx. 6.5-fold increase in the area under the curve for the mobilized cholesterol. Therefore, the phospholipid component in sHDL plays a major role in cholesterol mobilization in vivo and should not be overlooked in the design of future sHDL. SIGNIFICANCE STATEMENT: The phospholipid composition in sHDL plays a critical role in determining half-life and cholesterol mobilization in vivo.

Inkjet-printed micro-calibration standards for ultraquantitative Raman spectral cytometry.

Herein we report the development of a cytometric analysis platform for measuring the contents of individual cells in absolute (picogram) scales; this study represents the first report of Raman-based quantitation of the absolute mass - or the total amount - of multiple endogenous biomolecules within single-cells. To enable ultraquantitative calibration, we engineered single-cell-sized micro-calibration standards of known composition by inkjet-printer deposition of biomolecular components in microarrays across the surface of silicon chips. We demonstrate clinical feasibility by characterizing the compositional phenotype of human skin fibroblast and porcine alveolar macrophage cell populations in the respective contexts of Niemann-Pick disease and drug-induced phospholipidosis: two types of lipid storage disorders. We envision this microanalytical platform as the foundation for many future biomedical applications, ranging from diagnostic assays to pathological analysis to advanced pharmaco/toxicokinetic research studies.

Use of roller compaction and fines recycling process in the preparation of erlotinib hydrochloride tablets.

This study focuses on improving the manufacturing process for a generic immediate-release tablet containing erlotinib hydrochloride by adding a fines recycling process during roller compaction. Due to the large fraction of small-sized API particles, the starting powder mixture was inconsistently fed into the roller compactor. Consequently, poorly flowing granules with a high ratio of fines were produced. A fines recycling step was, therefore, added to the existing roller compaction process to minimize the risks caused by the poor granule flow. A laboratory scale roller compactor and a tablet simulator were used to prepare granules at various process conditions. The effect of dry granulation parameters on size distribution, API distribution, powder flow, compaction properties, and dissolution profile was evaluated. The granule batch after fines recycling had markedly improved size distribution and flowability while maintaining acceptable tablet tensile strength and rapid dissolution profile. The application of the fines recycling process at commercial scale resulted in reliable dissolution performance and batch-to-batch consistency, which were further confirmed by bioequivalence to the reference product. Understanding how granule properties are impacted by the fines recycling process may enable fine-tuning of the dry granulation process for optimal product quality.

Coenzyme Q10 inhibits glutamate excitotoxicity and oxidative stress-mediated mitochondrial alteration in a mouse model of glaucoma.

PURPOSE: To test whether a diet supplemented with coenzyme Q10 (CoQ10) ameliorates glutamate excitotoxicity and oxidative stress-mediated retinal ganglion cell (RGC) degeneration by preventing mitochondrial alterations in the retina of glaucomatous DBA/2J mice. METHODS: Preglaucomatous DBA/2J and age-matched control DBA/2J-Gpnmb(+) mice were fed with CoQ10 (1%) or a control diet daily for 6 months. The RGC survival and axon preservation were measured by Brn3a and neurofilament immunohistochemistry and by conventional transmission electron microscopy. Glial fibrillary acidic protein (GFAP), superoxide dismutase-2 (SOD2), heme oxygenase-1 (HO1), N-methyl-d-aspartate receptor (NR) 1 and 2A, and Bax and phosphorylated Bad (pBad) protein expression was measured by Western blot analysis. Apoptotic cell death was assessed by TUNEL staining. Mitochondrial DNA (mtDNA) content and mitochondrial transcription factor A (Tfam)/oxidative phosphorylation (OXPHOS) complex IV protein expression were measured by real-time PCR and Western blot analysis. RESULTS: Coenzyme Q10 promoted RGC survival by approximately 29% and preserved the axons in the optic nerve head (ONH), as well as inhibited astroglial activation by decreasing GFAP expression in the retina and ONH of glaucomatous DBA/2J mice. Intriguingly, CoQ10 significantly blocked the upregulation of NR1 and NR2A, as well as of SOD2 and HO1 protein expression in the retina of glaucomatous DBA/2J mice. In addition, CoQ10 significantly prevented apoptotic cell death by decreasing Bax protein expression or by increasing pBad protein expression. More importantly, CoQ10 preserved mtDNA content and Tfam/OXPHOS complex IV protein expression in the retina of glaucomatous DBA/2J mice. CONCLUSIONS: Our findings suggest that CoQ10 may be a promising therapeutic strategy for ameliorating glutamate excitotoxicity and oxidative stress in glaucomatous neurodegeneration.

Coenzyme Q10 ameliorates oxidative stress and prevents mitochondrial alteration in ischemic retinal injury.

Coenzyme Q10 (CoQ10) acts by scavenging reactive oxygen species for protecting neuronal cells against oxidative stress in neurodegenerative diseases. We tested whether a diet supplemented with CoQ10 ameliorates oxidative stress and mitochondrial alteration, as well as promotes retinal ganglion cell (RGC) survival in ischemic retina induced by intraocular pressure elevation. A CoQ10 significantly promoted RGC survival at 2 weeks after ischemia. Superoxide dismutase 2 (SOD2) and heme oxygenase-1 (HO-1) expression were significantly increased at 12 h after ischemic injury. In contrast, the CoQ10 significantly prevented the upregulation of SOD2 and HO-1 protein expression in ischemic retina. In addition, the CoQ10 significantly blocked activation of astroglial and microglial cells in ischemic retina. Interestingly, the CoQ10 blocked apoptosis by decreasing caspase-3 protein expression in ischemic retina. Bax and phosphorylated Bad (pBad) protein expression were significantly increased in ischemic retina at 12 h. Interestingly, while CoQ10 significantly decreased Bax protein expression in ischemic retina, CoQ10 showed greater increase of pBad protein expression. Of interest, ischemic injury significantly increased mitochondrial transcription factor A (Tfam) protein expression in the retina at 12 h, however, CoQ10 significantly preserved Tfam protein expression in ischemic retina. Interestingly, there were no differences in mitochondrial DNA content among control- or CoQ10-treated groups. Our findings demonstrate that CoQ10 protects RGCs against oxidative stress by modulating the Bax/Bad-mediated mitochondrial apoptotic pathway as well as prevents mitochondrial alteration by preserving Tfam protein expression in ischemic retina. Our results suggest that CoQ10 may provide neuroprotection against oxidative stress-mediated mitochondrial alterations in ischemic retinal injury.