Development and Characterization of a Photocrosslinkable, Chitosan-Based, Nerve Growth Factor-Eluting Hydrogel for the Ocular Surface.

Purpose: Recombinant human nerve growth factor (rhNGF; cenegermin-bkbj, OXERVATE) is the first and only U.S. Food and Drug Administration-approved treatment for moderate to severe neurotrophic keratopathy. The aim of this study was to determine the feasibility of incorporating a version of rhNGF in a mucoadhesive hydrogel capable of sustained drug release to the ocular surface. Methods: Hydrogels loaded with rhNGF were synthesized by conjugating chitosan with azidobenzoic acid (Az-Ch), adding rhNGF, and exposing the solution to ultraviolet (UV) radiation to induce photocrosslinking. Az-Ch hydrogels were evaluated for physical properties and rhNGF release profiles. Cytocompatbility of Az-Ch was assessed using immortalized human corneal limbal epithelial (HCLE) cells. TF1 erythroleukemic cell proliferation and HCLE cell proliferation and migration were used to assess the bioactivity of rhNGF released from Az-Ch hydrogels. Results: Az-Ch formed hydrogels in <10 seconds of UV exposure and demonstrated high optical transparency (75-85 T%). Az-Ch hydrogels exhibited good cytocompatibility with no demonstratable effect on HCLE cell morphology or viability. rhNGF was released gradually over 24 hours from Az-Ch hydrogels and retained its ability to induce TF1 cell proliferation. No significant difference was observed between rhNGF released from Az-Ch and freshly prepared rhNGF solutions on HCLE cell proliferation or percent wound closure after 12 hours; however, both were significantly better than control (P < 0.01). Conclusions: rhNGF-loaded Az-Ch hydrogels exhibited favorable physical, optical, and drug-release properties, as well as retained drug bioactivity. This drug delivery system has the potential to be further developed for in vivo and translational clinical applications. Translational Relevance: Az-Ch hydrogels may be used to enhance rhNGF therapy in patients with NK.

Contact lenses as novel tear fluid sampling vehicles for total RNA isolation, precipitation, and amplification.

The tear fluid is a readily accessible, potential source for biomarkers of disease and could be used to monitor the ocular response to contact lens (CL) wear or ophthalmic pathologies treated by therapeutic CLs. However, the tear fluid remains largely unexplored as a biomarker source for RNA-based molecular analyses. Using a rabbit model, this study sought to determine whether RNA could be collected from commercial CLs and whether the duration of CL wear would impact RNA recovery. The results were referenced to standardized strips of filtered paper (e.g., Shirmer Strips) placed in the inferior fornix. By performing total RNA isolation, precipitation, and amplification with commercial kits and RT-PCR methods, CLs were found to have no significant differences in RNA concentration and purity compared to Schirmer Strips. The study also identified genes that could be used to normalize RNA levels between tear samples. Of the potential control genes or housekeeping genes, GAPDH was the most stable. This study, which to our knowledge has never been done before, provides a methodology for the detection of RNA and gene expression changes from tear fluid that could be used to monitor or study eye diseases.

Patients' Preferences for Sphingosine-1-Phosphate Receptor Modulators in Multiple Sclerosis Based on Clinical Management Considerations: A Choice Experiment.

BACKGROUND: Several sphingosine-1-phosphate receptor (S1PR) modulators are available in the US for treating relapsing forms of multiple sclerosis (RMS). Given that these S1PR modulators have similar efficacy and safety, patients may consider the clinical management characteristics of the S1PR modulators when deciding among treatments. However, none of the S1PR modulators is clearly superior in every aspect of clinical management, and for some treatments, clinical management varies based on a patient's comorbid health conditions (e.g., heart conditions [HC]). OBJECTIVES: This study aimed to determine which S1PR modulator patients with relapsing-remitting multiple sclerosis (RRMS) would prefer based on clinical management considerations, and to estimate how different clinical management considerations might drive these preferences. Preferences were explored separately for patients with and without comorbid HC. METHODS: A multicriteria decision analysis was conducted on S1PR modulators approved to treat RMS: fingolimod, ozanimod, siponimod, and ponesimod. Clinical management preferences of patients with RRMS were elicited in a discrete choice experiment (DCE) in which participants repeatedly chose between hypothetical S1PR modulator profiles based on their clinical management attributes. Attributes included first-dose observations, genotyping, liver function tests, eye examinations, drug-drug interactions, interactions with antidepressants, interactions with foods high in tyramine, and immune system recovery time. Preferences were estimated separately for patients with HC and without HC (noHC). Marginal utilities were calculated from the DCE data for each attribute and level using a mixed logit model. In the multicriteria decision analysis, partial value scores were created by applying the marginal utilities for each attribute and level to the real-world profiles of S1PR modulators. Partial value scores were summed to determine an overall clinical management value score for each S1PR modulator. RESULTS: Four hundred patients with RRMS completed the DCE. Ponesimod had the highest overall value score for patients both without (n = 341) and with (n = 59) HC (noHC: 5.1; HC: 4.0), followed by siponimod (noHC: 4.9; HC: 3.3), fingolimod (noHC: 3.4; HC: 2.8), and ozanimod (noHC: 0.9; HC: 0.8). Overall, immune system recovery time contributed the highest partial value scores (noHC: up to 1.9 points; HC: up to 1.2 points), followed by the number of drug-drug interactions (noHC: up to 1.2 points; HC: up to 1.7 points). CONCLUSIONS: When considering the clinical management of S1PR modulators, the average patient with RRMS is expected to choose a treatment with shorter immune system recovery time and fewer interactions with other drugs. Patients both with and without heart conditions are likely to prefer the clinical management profile of ponesimod over those of siponimod, fingolimod, and ozanimod. This information can help inform recommendations for treating RRMS and facilitate shared decision making between patients and their doctors.

ENSEMBLE PLUS: final results of shorter ocrelizumab infusion from a randomized controlled trial.

INTRODUCTION: Ocrelizumab is an approved intravenously administered anti-CD20 antibody for multiple sclerosis (MS). The safety profile and patient preference for conventional versus shorter ocrelizumab infusions were investigated in the ENSEMBLE PLUS study. METHODS: ENSEMBLE PLUS was a randomized, double-blind substudy to the single-arm ENSEMBLE study (NCT03085810), comparing outcomes in patients with early-stage relapsing-remitting MS receiving ocrelizumab 600 mg over the approved 3.5-h (conventional) versus 2-h (shorter) infusion. The primary endpoint was the proportion of patients with infusion-related reactions (IRRs) following the first randomized dose (RD); the secondary endpoint included IRR frequency at subsequent RDs. RESULTS: At first RD, the number of patients with an IRR in the conventional (101/373; 27.1%) versus shorter (107/372; 28.8%) infusion group was similar (difference, stratified estimates [95% CI]: 1.9% [- 4.4, 8.2]). Most IRRs (conventional: 99.4%; shorter: 97.7%) were mild/moderate. IRR frequency decreased over the course of RDs; three patients discontinued from the shorter infusion arm but continued with conventional infusion. Overall, > 98% of IRRs resolved without sequelae in both groups. Pre-randomization throat irritation was predictive of future throat irritation as an IRR symptom. Adverse events (AEs) and serious AEs were consistent with the known ocrelizumab safety profile. On completion of ENSEMBLE PLUS, most patients chose to remain on (95%) or switch to (80%) shorter infusion. CONCLUSION: ENSEMBLE PLUS demonstrates the safety and tolerability of shorter ocrelizumab infusions. Most patients remained on/switched to shorter infusion after unblinding; IRRs did not strongly influence patient decisions. CLINICAL TRIALS REGISTRATION: Substudy of ENSEMBLE (NCT03085810). REGISTRATION: March 21, 2017.

Is reproductive development adaptively calibrated to early experience? Evidence from a national sample of females.

Many developmental theories have not been sufficiently evaluated using designs that control for unobserved familial confounds. Our long-term goal is to determine the causal structure underlying associations between early environmental conditions and later psychosocial and health outcomes. Our overall objective in this study was to further evaluate predictions derived from applications of life history theory to female reproductive development, key among them that reproductive milestones translate early environmental risk into fertility, health, and behavioral outcomes. To this end, we used female data from the National Longitudinal Survey of Youth 1979 and structural equation modeling to conduct increasingly severe tests, beginning with covariate control and then progressing to sibling control and behavioral genetic designs. After adjusting for confounds varying between sets of siblings, we did not find evidence that age at menarche reflected components of early environment or that any focal outcomes reflected early fragmented family structure (birth to age nine). Although we detected no links between measured environment and individual differences in age at sexual debut, we did find that it reflected both shared and nonshared influences in our behavior genetic models. Interestingly, delayed sexual debut (into young adulthood) reflected identification of parents as the greatest influences and forecasted an array of fertility-related outcomes. Taken together, these findings challenge theories suggesting menarche timing is adaptively calibrated to early environment. They also highlight the need for more research using sibling control and related designs to examine the roles of environments in development. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Tolerability of subcutaneous ofatumumab with long-term exposure in relapsing multiple sclerosis.

Background: Ofatumumab is approved for treating relapsing multiple sclerosis (RMS). Examining tolerability will enable understanding of its risk-benefit profile. Objective: Report the tolerability profile of ofatumumab in RMS during treatment of up to 4 years and the effect of pre-medication. Methods: Cumulative data from the overall safety population included patients taking continuous ofatumumab or being newly switched from teriflunomide. Injection-related reactions (IRRs) by incidence and severity, and post-marketing surveillance data, with an exposure of 18,530 patient-years, were analyzed. Results: Systemic IRRs affected 24.7% of patients (487/1969) in the overall safety population; most (99.2% [483/487]) were mild (333/487) to moderate (150/487) in Common Terminology Criteria for Adverse Events severity; most systemic IRRs occurred after first injection. Local-site IRRs affected 11.8% (233/1969) and most (99.6% [232/233]) were mild/moderate. Incidence and severity of systemic and localized IRRs were similar between continuous and newly switched patients across repeated injections. Systemic IRR incidence and severity were not substantially affected by steroidal or non-steroidal pre-medication. Post-marketing surveillance identified no new tolerability issues. Conclusion: Ofatumumab is well tolerated, displays a consistent safety profile during continuous use or after switching from teriflunomide and does not require pre-medication. This enables home management of RMS with a high-efficacy treatment.

Factors Associated With Disease-Modifying Therapy Adherence and Persistence in Multiple Sclerosis: A Scoping Literature Review.

BACKGROUND: Patients with multiple sclerosis (MS) receiving disease-modifying therapies (DMT) show published adherence rates of 27.0% to 93.8% and published persistence rates of 49.7% to 96.5%. Improvements in DMT adherence and persistence are key to optimizing MS care, and enhanced understanding could improve MS disease management and identify research gaps. This scoping literature review aims to examine the nature and findings of the literature evaluating factors associated with DMT adherence and persistence in patients with MS. METHODS: Eligible articles included in the literature review were quantitative clinical studies written in English, included adherence or persistence as primary outcomes, and accounted for covariates/confounders. The articles were assessed to identify factors associated with adherence/persistence and analyzed according to DMT type (self-injectable, oral, infusion). RESULTS: Fifty-eight studies (103,450 patients) were included. Study distribution by DMT type was self-injectable only (n = 41), oral only (n = 2), infusion only (n = 1), and more than 1 type (n = 14). Older age and previous DMT use were associated with increased adherence and/or persistence. Increased alcohol consumption, DMT adverse events, higher education, and higher body mass index were negatively associated with adherence and/or persistence. Greater number and severity of relapses was associated with increased adherence but decreased persistence. CONCLUSIONS: Most studies examined factors associated with adherence and persistence to self-injectable DMTs. These factors should be evaluated further for oral and infusion DMTs. Insights into the modifiable factors associated with adherence and persistence could guide treatment decisions and help improve adherence and clinical outcomes.

Analysis of Pregnancy Outcomes Following Exposure to Intramuscular Interferon Beta-1a: The AVONEX® Pregnancy Exposure Registry.

BACKGROUND AND OBJECTIVES: There is a lack of well-controlled US studies of intramuscular (IM) interferon beta (IFNß)-1a use in pregnant women with multiple sclerosis; however, in the European Medicines Agency region, IFNß formulations may be considered during pregnancy if clinically needed based on data from European Union cohort registries. The AVONEX Pregnancy Exposure Registry was established to prospectively study the effects of IM IFNß-1a on the risk of birth defects and spontaneous pregnancy loss in a US population. METHODS: Pregnant women with multiple sclerosis exposed to IM IFNß-1a within ~ 1 week of conception or during the first trimester were included. Participants were followed until there was a pregnancy outcome, live-born infants were followed until age 8-12 weeks. Data were collected on IM IFNß-1a exposure, demographics, patient characteristics, medical history, and pregnancy outcomes, including live births (with or without birth defect), spontaneous abortions/miscarriages and fetal death/stillbirth, elective abortions (with and without birth defect), and ectopic pregnancies. A population-based birth defect surveillance program, the Metropolitan Atlanta Congenital Defects Program (MACDP), served as the primary external control group for evaluating the risk of birth defects. RESULTS: Three-hundred and two patients with a median (range) age of 31.0 (16-48) years and a median (range) gestational age at the time of enrollment of 10.1 (4-39) weeks were evaluable. Most patients (n = 278/302; 92%) reported IM IFNß-1a exposure in the week before conception and most (n = 293/302; 97%) discontinued treatment before the end of the first trimester. Of 306 pregnancy outcomes, there were 272 live births, 28 spontaneous abortions of 266 pregnancies enrolled before 22 weeks' gestation (rate 10.5%; 95% confidence interval 7.2-15.0), five elective abortions, and one stillbirth. There were 17 adjudicator-confirmed major birth defects of 272 live births (rate 6.3%; 95% confidence interval 3.8-10.0); the pattern of birth defects observed was not suggestive of a relationship to prenatal IM IFNß-1a exposure. CONCLUSIONS: This large US registry study suggests IM IFNß-1a exposure during early pregnancy was not clinically associated with adverse pregnancy outcomes in women with multiple sclerosis. These findings help inform clinicians and patients in weighing the risks and benefits of IM IFNß-1a use during pregnancy. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov: NCT00168714, 15 September, 2005.

The Relationship between Nursing Leadership and Patient Readmission Rate: A Systematic Review.

BACKGROUND: Nurse leaders play a fundamental role in improving patient quality care delivery, thus improving patient clinical outcomes. PURPOSE: This systematic review examined the knowledge to date of nursing leadership on reducing patient readmission rates. METHODS: A literature review was conducted using seven electronic databases: Medline Ovid, PubMed, Cumulative Index to Nursing and Allied Health (CINAHL) Plus, Emerald, PsycINFO, ABI/INFORM collection, and EBSCO, with the addition of references for relevant papers reviewed. FINDINGS: The search resulted in a total of 15 articles. Findings revealed that leadership practices of nurses have an impact on reducing patient readmission rates. CONCLUSIONS: The results suggest a need for further rigorous studies investigating the mechanism of how nursing leadership relates to patient readmission rates and how to translate this into practice across diverse cultures.

Patient and nurse preference for Sensoready autoinjector pen versus other autoinjectors in multiple sclerosis: results from a pilot multicenter survey.

BACKGROUND: Sensoready® autoinjector pen facilitates self-administration of subcutaneous ofatumumab injections at home. We aim to investigate patient and nurse preference for using Sensoready® versus comparator autoinjectors in multiple sclerosis (MS). METHODS: A pilot survey was conducted in Germany followed by in-field interviews across United States, Germany, France, and Italy. The survey recruited 80 MS patients and 50 MS nurses. Respondents were interviewed for 45-min on qualitative open-ended and quantitative close-ended survey consisting of 31 questions for patients and 41 for nurses. Ratings were measured on Likert scale from 1 (not at all important) to 10 (extremely important). RESULTS: "Easy to perform self-injection with the pen" and "Patient able to use independently" (both, mean overall score 9.4) were the most important attributes for both patients and nurses. Sensoready® scored high across most important attributes for both patients and nurses (p < 0.05). Sensoready® was preferred over comparator devices across majority of the important attributes (84%; p < 0.05), especially ease of use of the pen (mean overall score 9.4). Sensoready® was preferred over their current device by 9/10 nurses and 8/10 patients if they had to choose a treatment based on the device alone. CONCLUSION: Both MS patients and nurses preferred the Sensoready® (ofatumumab) over comparator autoinjectors for their treatment, mostly driven by ease of administration.

A Functional Single-Nucleotide Polymorphism Upstream of the Collagen Type III Gene Is Associated with Catastrophic Fracture Risk in Thoroughbred Horses.

Fractures caused by bone overloading are a leading cause of euthanasia in Thoroughbred racehorses. The risk of fatal fracture has been shown to be influenced by both environmental and genetic factors but, to date, no specific genetic mechanisms underpinning fractures have been identified. In this study, we utilised a genome-wide polygenic risk score to establish an in vitro cell system to study bone gene regulation in horses at high and low genetic risk of fracture. Candidate gene expression analysis revealed differential expression of COL3A1 and STAT1 genes in osteoblasts derived from high- and low-risk horses. Whole-genome sequencing of two fracture cases and two control horses revealed a single-nucleotide polymorphism (SNP) upstream of COL3A1 that was confirmed in a larger cohort to be significantly associated with fractures. Bioinformatics tools predicted that this SNP may impact the binding of the transcription factor SOX11. Gene modulation demonstrated SOX11 is upstream of COL3A1, and the region binds to nuclear proteins. Furthermore, luciferase assays demonstrated that the region containing the SNP has promoter activity. However, the specific effect of the SNP depends on the broader genetic background of the cells and suggests other factors may also be involved in regulating COL3A1 expression. In conclusion, we have identified a novel SNP that is significantly associated with fracture risk and provide new insights into the regulation of the COL3A1 gene.

Topical Sustained Delivery of Miltefosine Via Drug-Eluting Contact Lenses to Treat Acanthamoeba Keratitis.

This study aimed to develop a miltefosine-eluting contact lens (MLF-CL) device that would allow sustained and localized miltefosine release for the treatment of Acanthamoeba keratitis. MLF-CLs were produced in three different miltefosine doses by solvent-casting a thin miltefosine-polymer film around the periphery of a methafilcon hydrogel, which was then lathed into a contact lens. During seven days of in vitro testing, all three formulations demonstrated sustained release from the lens at theoretically therapeutic levels. Based on the physicochemical characterization of MLF-CLs, MLF-CL's physical properties are not significantly different from commercial contact lenses in terms of light transmittance, water content and wettability. MLF-CLs possessed a slight reduction in compression modulus that was attributed to the inclusion of polymer-drug films but still remain within the optimal range of soft contact lenses. In cytotoxicity studies, MLF-CL indicated up to 91% viability, which decreased proportionally as miltefosine loading increased. A three-day biocompatibility test on New Zealand White rabbits revealed no impact of MLF-CLs on the corneal tissue. The MLF-CLs provided sustained in vitro release of miltefosine for a week while maintaining comparable physical features to a commercial contact lens. MLF-CL has a promising potential to be used as a successful treatment method for Acanthamoeba keratitis.

Multicenter, prospective feasibility study of Nano-Pulse Stimulation™ technology for the treatment of both nodular and superficial low-risk basal cell carcinoma.

Background: Nano-Pulse Stimulation™ (NPS™) therapy is a new, non-thermal bioelectric modality that applies ultrashort pulses of electric energy to trigger regulated cell death (RCD) in treated tissues. Instead of initiating necrosis by heating or freezing, NPS therapy permeabilizes intracellular organelles to activate the cell's own self-destruct pathway of programmed or regulated cell death. Unlike cryotherapeutic procedures that can both damage structural tissues and diffuse into the periphery beyond the margins of the lesion, NPS therapy only affects cells within the treated zone leaving surrounding tissue and acellular components unaffected. Methods: In this study we treated 37 basal cell carcinoma lesions on 30 subjects (NCT04918381). The treated lesions were photographed on 3-, 7-, 14-, 30- and 60-days after treatment. All subjects then underwent surgical excision for histological examination of the treated tissue. Results: 92% of the BCC lesions (34 of 37) showed complete histological clearance of BCC. Histologic analysis of the 3 cases where residual BCC was noted indicated that full energy coverage was not achieved, which could be remedied with an improved treatment guide to standardize and optimize the CellFX® procedure based on NPS technology. Conclusion: The CellFX procedure was shown to be safe and effective for the treatment of low-risk nodular and superficial BCC lesions.

Doxorubicin-Loaded Extracellular Vesicles Enhance Tumor Cell Death in Retinoblastoma.

Chemotherapy is often used to treat retinoblastoma; however, this treatment method has severe systemic adverse effects and inadequate therapeutic effectiveness. Extracellular vesicles (EVs) are important biological information carriers that mediate local and systemic cell-to-cell communication under healthy and pathological settings. These endogenous vesicles have been identified as important drug delivery vehicles for a variety of therapeutic payloads, including doxorubicin (Dox), with significant benefits over traditional techniques. In this work, EVs were employed as natural drug delivery nanoparticles to load Dox for targeted delivery to retinoblastoma human cell lines (Y-79). Two sub-types of EVs were produced from distinct breast cancer cell lines (4T1 and SKBR3) that express a marker that selectively interacts with retinoblastoma cells and were loaded with Dox, utilizing the cells' endogenous loading machinery. In vitro, we observed that delivering Dox with both EVs increased cytotoxicity while dramatically lowering the dosage of the drug. Dox-loaded EVs, on the other hand, inhibited cancer cell growth by activating caspase-3/7. Direct interaction of EV membrane moieties with retinoblastoma cell surface receptors resulted in an effective drug delivery to cancer cells. Our findings emphasize the intriguing potential of EVs as optimum methods for delivering Dox to retinoblastoma.

Advances in biomaterials for the treatment of retinoblastoma.

Retinoblastoma is the most common primary intraocular malignancy in children. Although traditional chemotherapy has shown some success in retinoblastoma management, there are several shortcomings to this approach, including inadequate pharmacokinetic parameters, multidrug resistance, low therapeutic efficiency, nonspecific targeting, and the need for adjuvant therapy, among others. The revolutionary developments in biomaterials for drug delivery have enabled breakthroughs in cancer management. Today, biomaterials are playing a crucial role in developing more efficacious retinoblastoma treatments. The key goal in the evolution of drug delivery biomaterials for retinoblastoma therapy is to resolve delivery-associated obstacles and lower nonlocal exposure while ameliorating certain adverse effects. In this review, we will first delve into the historical perspective of retinoblastoma with a focus on the classical treatments currently used in clinics to enhance patients' quality of life and survival rate. As we move along, we will discuss biomaterials for drug delivery applications. Various aspects of biomaterials for drug delivery will be dissected, including their features and recent advances. In accordance with the current advances in biomaterials, we will deliver a synopsis on the novel chemotherapeutic drug delivery strategies and evaluate these approaches to gain new insights into retinoblastoma treatment.

Extracellular Vesicles in Corneal Fibrosis/Scarring.

Communication between cells and the microenvironment is a complex, yet crucial, element in the development and progression of varied physiological and pathological processes. Accumulating evidence in different disease models highlights roles of extracellular vesicles (EVs), either in modulating cell signaling paracrine mechanism(s) or harnessing their therapeutic moiety. Of interest, the human cornea functions as a refractive and transparent barrier that protects the intraocular elements from the external environment. Corneal trauma at the ocular surface may lead to diminished corneal clarity and detrimental effects on visual acuity. The aberrant activation of corneal stromal cells, which leads to myofibroblast differentiation and a disorganized extracellular matrix is a central biological process that may result in corneal fibrosis/scarring. In recent years, understanding the pathological and therapeutic EV mechanism(s) of action in the context of corneal biology has been a topic of increasing interest. In this review, we describe the clinical relevance of corneal fibrosis/scarring and how corneal stromal cells contribute to wound repair and their generation of the stromal haze. Furthermore, we will delve into EV characterization, their subtypes, and the pathological and therapeutic roles they play in corneal scarring/fibrosis.

Simulated Forest Immersion Therapy: Methods Development.

Shinrin-yoku, forest bathing, may provide relief from chronic and breakthrough pain in patients with axial spondyloarthritis and improve immune function through increasing NK cell numbers and activity and their downstream effectors, perforin and granulysin, after chemo- or radiation therapy in breast and prostate cancer patients. The aim of this paper is to describe the study protocol for a simulated forest immersion therapy using virtual reality and atomized phytoncides, volatile organic compounds found in forested areas designed to effect positive change for these two patient populations. The setting, including the room set up and samples with inclusion/exclusion specific to this type of intervention, is outlined. Measures and calibration procedures pertinent to determining the feasibility of simulated forest immersion therapy are presented and include: ambient and surface room temperatures and relative humidity in real time, ambient ultrafine particulate matter, ambient droplet measurement that coincides with volatile organic compounds, specific phytoncides, and virtual reality and atomization of phytoncide set up. Particular lessons learned while training and setting up the equipment are presented. Simulated forest immersion therapy is possible with attention to detail during this early phase when development of methods, equipment testing, and feasibility in deploying the intervention become operational. The expected outcome of the development of the methods for this study is the creation of a standardized approach to simulating forest therapy in a controlled laboratory space.

Bibliometric and visualized analysis of ocular drug delivery from 2001 to 2020.

OBJECTIVE: To perform a bibliometric analysis in the field of ocular drug delivery research to characterize the current international trends and to present visual representations of the past and emerging trends on ocular drug delivery research over the past decade. METHOD: In this cross-sectional study, a bibliometric analysis of data retrieved and extracted from the Web of Science Core Collection (WoSCC) database was performed to analyze evolution and theme trends on ocular drug delivery research from January 1, 2001, to December 31, 2020. A total of 4334 articles on ocular drug delivery were evaluated for specific characteristics, such as publication year, journals, authors, institutions, countries/regions, references, and keywords. Co-authorship analysis, co-occurrence analysis, co-citation analysis, and network visualization were constructed by VOSviewer. Some important subtopics identified by bibliometric characterization were further discussed and reviewed. RESULTS: From 2001 to 2020, the annual global publications increased by 746.15%, from 52 to 440. International Journal of Pharmaceutics published the most manuscripts (250 publications) and produced the highest citations (9509 citations), followed by Investigative Ophthalmology & Visual Science (202 publications) and Journal of Ocular Pharmacology and Therapeutics (136 publications). The United States (1289 publications, 31,512 citations), the University of Florida (82 publications, 2986 citations), and Chauhan, Anuj (52 publications, 2354 citations) were the most productive and impactful institution, country, and author respectively. The co-occurrence cluster analysis of the top 100 keywords form five clusters: (1) micro/nano ocular drug delivery systems; (2) the treatment of inflammation and posterior diseases; (3) macroscopic ocular drug delivery systems/devices; (4) the characteristics of drug delivery systems; (5) and the ocular drug delivery for glaucoma treatment. Diabetic macular edema, anti-VEGF, ranibizumab, bevacizumab, micelles and latanoprost, were the latest high-frequency keywords, indicating the emerging frontiers of ocular drug delivery. Further discussions into the subtopics were provided to assist researchers to determine the range of research topics and plan research direction. CONCLUSIONS: Over the last two decades there has been a progressive increase in the number of publications and citations on research related to ocular drug delivery across many countries, institutions, and authors. The present study sheds light on current trends, global collaboration patterns, basic knowledge, research hotspots, and emerging frontiers of ocular drug delivery. Novel solutions for ocular drug delivery and the treatment of inflammation and posterior diseases were the major themes over the last 20 years.

A novel, sensitive, and widely accessible besifloxacin quantification method by HPLC-fluorescence: Application to an ocular pharmacokinetic study.

Besifloxacin has been embraced for the treatment of ocular bacterial infections. While LC-MS/MS has been used in investigating BSF pharmacokinetics, those costly instruments are not universally available and have complicated requirements for operation and maintenance. Additionally, pharmacokinetics of besifloxacin in dose-intense regimens are still unknown. Herein, a new quantification method was developed employing the widely accessible HPLC with fluorescence detection and applied to an ocular pharmacokinetic study with an intense regimen. Biosamples were pre-treated using protein precipitation. Chromatographic separation was achieved on a C18 column using mobile phase of 0.1% trifluoroacetic acid and acetonitrile. To address the weak fluorescence issue of besifloxacin, effects of detection parameters, elution pattern, pH of mobile phase, and reconstitution solvents were investigated. The method was fully validated per US-FDA guidelines and demonstrated precision (<13%), accuracy (91-112%), lower limit of quantification (5 ng/mL), linearity over clinically relevant concentrations (R2 > 0.999), matrix-effects (93-105%), recoveries (95-106%), and excellent selectivity. The method showed agreement with agar disk diffusion assays for in vitro screening and comparable in vivo performance to LC-MS/MS (Deming Regression, y = 1.010x + 0.123, r = 0.997; Bland-Altman analysis, mean difference was -6.3%; n = 21). Pharmacokinetic parameters suggested superior surface-retentive properties of besifloxacin. Maximum concentrations were 1412 ± 1910 and 0.15 ± 0.12 µg/mL; area under the curve was 1,637 and 1.08 µg·h/g; and half-life was 4.9 and 4.1 h; and pharmacokinetic-to-pharmacodynamic ratios were ≥ 409 and ≤ 17.8 against ocular pathogens in tears and aqueous humor, respectively. This readily available method is sensitive for biosamples and practical for routine use, facilitating besifloxacin therapy development.

Dexamethasone-Eluting Contact Lens for the Prevention of Postphotorefractive Keratectomy Scar in a New Zealand White Rabbit Model.

PURPOSE: To evaluate the safety and efficacy of an experimental dexamethasone-eluting contact lens (DCL) for the prevention of postphotorefractive keratectomy (PRK) corneal haze in a New Zealand White (NZW) rabbit model. METHODS: Both eyes of 29 NZW rabbits underwent PRK. The rabbits were randomized to one of the 5 study arms for 4 weeks: tarsorrhaphy only, tarsorrhaphy and bandage contact lens (BCL) replaced weekly, tarsorrhaphy and BCL for 1 week plus topical 0.1% dexamethasone ophthalmic solution (drops) for 4 weeks, tarsorrhaphy and BCL replaced weekly plus topical dexamethasone for 4 weeks, and tarsorrhaphy and DCL changed weekly for 4 weeks. Each week for 4 consecutive weeks postoperatively, the tarsorrhaphies were opened, the eyes underwent evaluation and imaging, and the tarsorrhaphies were replaced. Contact lenses were cultured on removal. Central corneal haze was assessed weekly with corneal densitometry. After 4 weeks, the animals were killed, and the eyes were enucleated for histopathologic analysis. RESULTS: The tarsorrhaphy only group displayed more haze with a greater change in optical densitometry from pre-op compared with the other treatment groups. There was no difference between the DCL group and the groups receiving a BCL and dexamethasone drops in densitometry or histopathology. No NZW rabbits developed clinical signs of infection, and cultures from DCLs and BCLs grew similar organisms. CONCLUSIONS: In the post-PRK rabbit model, DCLs worn weekly for 4 weeks were safe and as effective at preventing corneal haze as 0.1% dexamethasone drops applied 4 times a day for 4 weeks.