Phototherapy is a light-triggered treatment for tumor ablation and growth inhibition via photodynamic therapy (PDT) and photothermal therapy (PTT). Despite extensive studies in this area, a major challenge is the lack of selective and effective phototherapy agents that can specifically accumulate in tumors to reach a therapeutic concentration. Although recent attempts have produced photosensitizers complexed with photothermal nanomaterials, the tedious preparation steps and poor tumor efficiency of therapy still hampers the broad utilization of these nanocarriers. Herein, we developed a CD44 targeted photoacoustic (PA) nanophototherapy agent by conjugating Indocyanine Green (ICG) to hyaluronic acid nanoparticles (HANPs) encapsulated with single-walled carbon nanotubes (SWCNTs), resulting in a theranostic nanocomplex of ICG-HANP/SWCNTs (IHANPT). We fully characterized its physical features as well as PA imaging and photothermal and photodynamic therapy properties in vitro and in vivo. Systemic delivery of IHANPT theranostic nanoparticles led to the accumulation of the targeted nanoparticles in tumors in a human cancer xenograft model in nude mice. PA imaging confirmed targeted delivery of the IHANPT nanoparticles into tumors (T/M ratio = 5.19 ± 0.3). The effect of phototherapy was demonstrated by low-power laser irradiation (808 nm, 0.8 W/cm2) to induce efficient photodynamic effect from ICG dye. The photothermal effect from the ICG and SWCNTs rapidly raised the tumor temperature to 55.4 ± 1.8 °C. As the result, significant tumor growth inhibition and marked induction of tumor cell death and necrosis were observed in the tumors in the tumors. There were no apparent systemic and local toxic effects found in the mice. The dynamic thermal stability of IHANPT was studied to ensure that PTT does not affect ICG-dependent PDT in phototherapy. Therefore, our results highlight imaging property and therapeutic effect of the novel IHANPT theranostic nanoparticle for CD44 targeted and PA image-guided dual PTT and PDT cancer therapy.
by
Edelle Field-Fote;
Daniel Pinto;
Allen W Heinemann;
Shuo-Hsiu Chang;
Susan Charlifue;
Catherine L Furbish;
Arun Jayaraman;
Candace Tefertiller;
Heather B Taylor;
Dustin D French
Background: Few, if any estimates of cost-effectiveness for locomotor training strategies following spinal cord injury (SCI) are available. The purpose of this study was to estimate the cost-effectiveness of locomotor training strategies following spinal cord injury (overground robotic locomotor training versus conventional locomotor training) by injury status (complete versus incomplete) using a practice-based cohort. Methods: A probabilistic cost-effectiveness analysis was conducted using a prospective, practice-based cohort from four participating Spinal Cord Injury Model System sites. Conventional locomotor training strategies (conventional training) were compared to overground robotic locomotor training (overground robotic training). Conventional locomotor training included treadmill-based training with body weight support, overground training, and stationary robotic systems. The outcome measures included the calculation of quality adjusted life years (QALYs) using the EQ-5D and therapy costs. We estimate cost-effectiveness using the incremental cost utility ratio and present results on the cost-effectiveness plane and on cost-effectiveness acceptability curves. Results: Participants in the prospective, practice-based cohort with complete EQ-5D data (n = 99) qualified for the analysis. Both conventional training and overground robotic training experienced an improvement in QALYs. Only people with incomplete SCI improved with conventional locomotor training, 0.045 (SD 0.28), and only people with complete SCI improved with overground robotic training, 0.097 (SD 0.20). Costs were lower for conventional training, $1758 (SD $1697) versus overground robotic training $3952 (SD $3989), and lower for those with incomplete versus complete injury. Conventional overground training was more effective and cost less than robotic therapy for people with incomplete SCI. Overground robotic training was more effective and cost more than conventional training for people with complete SCI. The incremental cost utility ratio for overground robotic training for people with complete spinal cord injury was $12,353/QALY. Conclusions: The most cost-effective locomotor training strategy for people with SCI differed based on injury completeness. Conventional training was more cost-effective than overground robotic training for people with incomplete SCI. Overground robotic training was more cost-effective than conventional training for people with complete SCI. The effect estimates may be subject to limitations associated with small sample sizes and practice-based evidence methodology. These estimates provide a baseline for future research.
Purpose: Our previous investigations showed that involuntary treadmill exercise is neuroprotective in a light-induced retinal degeneration mouse model, and it may act through activation of tropomyosin-related kinase B (TrkB) receptors. This study investigated whether voluntary running wheel exercise can be neuroprotective in an inheritable model of the retinal degenerative disease retinitis pigmentosa (RP), rd10 mice.
Methods: Breeding pairs of rd10 and C57BL/6J mice were given free-spinning (active) or locked (inactive) running wheels. Pups were weaned into separate cages with their parents’ respective wheel types, and visual function was tested with ERG and a virtual optokinetic system at 4, 5, and 6 weeks of age. Offspring were killed at 6 weeks of age and retinal cross-sections were prepared for photoreceptor nuclei counting. Additionally, separate cohorts of active and inactive rd10 pups were injected daily for 14 days after eye opening with a selective TrkB receptor antagonist (ANA-12) or vehicle solution and assessed as described above.
Results: Mice in the rd10 active group exhibited significant preservation of visual acuity, cone nuclei, and total photoreceptor nuclei number. Injection with ANA-12 precluded the preservation of visual acuity and photoreceptor nuclei number in rd10 mice.
Conclusions: Voluntary running partially protected against the retinal degeneration and vision loss that otherwise occurs in the rd10 mouse model of RP. This protection was prevented by injection of ANA-12, suggesting that TrkB activation mediates exercise’s preservation of the retina. Exercise may serve as an effective, clinically translational intervention against retinal degeneration.
Glaucoma is a leading cause of irreversible blindness worldwide and is characterized by progressive loss of visual function and retinal ganglion cells (RGC). Current epidemiological, clinical, and basic science evidence suggest that estrogen plays a role in the aging of the optic nerve. Menopause, a major biological life event affecting all women, coincides with a decrease in circulating sex hormones, such as estrogen. While 59% of the glaucomatous population are females, sex is not considered a risk factor for developing glaucoma. In this review, we explore whether menopause is a sex-specific risk factor for glaucoma. First, we investigate how menopause is defined as a sex-specific risk factor for other pathologies, including cardiovascular disease, osteoarthritis, and bone health. Next, we discuss clinical evidence that highlights the potential role of menopause in glaucoma. We also highlight preclinical studies that demonstrate larger vision and RGC loss following surgical menopause and how estrogen is protective in models of RGC injury. Lastly, we explore how surgical menopause and estrogen signaling are related to risk factors associated with developing glaucoma (e.g., intraocular pressure, aqueous outflow resistance, and ocular biomechanics). We hypothesize that menopause potentially sets the stage to develop glaucoma and therefore is a sex-specific risk factor for this disease. Graphical Abstract: [Figure not available: see fulltext.].
Background
To compare a near decade of follow-up, newer control cohort data, use of both the societal and third party insurer cost perspectives, and integration of unilateral/bilateral therapy on the comparative effectiveness and cost-effectiveness of intravitreal ranibizumab therapy for neovascular, age-related macular degeneration (AMD).
Methods
Value-Based Medicine®, 12-year, combined-eye model, cost-utility analysis employing MARINA and HORIZON clinical trial data. Preference-based comparative effectiveness outcomes were quantified in (1) QALY (quality-adjusted life-year) gain, and (2) percent improvement in quality-of-life, while cost-effectiveness outcomes were quantified in (3) the cost-utility ratio (CUR) and financial return-on-investment (ROI) to society.
Results
Using MARINA and HORIZON trial data and a meta-analysis control cohort after 24 months, ranibizumab therapy conferred a combined-eye patient value (quality-of-life) gain of 16.3%, versus 10.4% found in 2006. The two-year direct ophthalmic medical cost for ranibizumab therapy was $46,450, a 33.8% real dollar decrease from 2006. The societal cost perspective CUR was −$242,920/QALY, indicating a $282,517 financial return-on-investment (ROI), or 12.3%/year to society for direct ophthalmic medical costs expended. The 3rd party insurer CUR ranged from $21,199/QALY utilizing all direct, medical costs, to $69,591/QALY using direct ophthalmic medical costs.
Conclusions
Ranibizumab therapy for neovascular AMD in 2015, considering treatment of both eyes, conferred greater patient value gain (comparative effectiveness) and improved cost-effectiveness than in 2006, as well as a large monetary return-on-investment to the Gross Domestic Product and nation’s wealth. The model herein integrates important novel features for neovascular age-related macular degeneration, vitreoretinal cost effectiveness analyses, including: (1) treatment of both eyes, (2) a long-term, untreated control cohort, and (3) the use of societal costs.
Purpose:
To evaluate spectacle adherence with impact-resistant lenses among 4-year-old children after unilateral cataract surgery in the Infant Aphakia Treatment Study.
Design:
Retrospective cohort analysis of randomized clinical trial data.
Methods:
SETTING: Multicenter. PATIENTS: One hundred and fourteen children randomized to contact lens correction or intraocular lens implantation following unilateral cataract surgery during infancy. INTERVENTION: One-week diaries completed annually and retrospective telephone interviews conducted every 3 months to age 5 years to assess spectacle adherence with impact-resistant lenses. Visual acuity was assessed by a traveling examiner at age 4.5 years. MAIN OUTCOME MEASURES: Spectacle adherence between ages 4 and 5 years.
Results:
Children with 20/40 or better vision in their treated eye were more likely to wear spectacles ≥80% of their waking hours than children with vision worse than 20/40 (66% vs 42%, P =.034). Reported adherence to spectacle wear correlated with reported patching (r = 0.30, P =.002). Spectacle adherence did not correlate with sex, type of healthcare insurance, or the refractive error in the treated or fellow eye. Seven patients with reduced vision in their treated eye reported <10% spectacle adherence.
Conclusions:
These results confirm that it is possible to achieve high levels of spectacle adherence among 4-year-old children after unilateral cataract surgery during infancy. However, children with vision worse than 20/40 in their worse eye, who needed eye protection the most, had the worst adherence.
Mutant mouse models with specific visual pathway defects offer an advantage to comprehensively investigate the role of specific pathways/neurons involved in refractive development. In this review, we will focus on recent studies using mouse models that have provided insight into retinal pathways and neurotransmitters controlling refractive development. Specifically, we will examine the contributions of rod and cone photoreceptors and the ON and OFF retinal pathways to visually driven eye growth with emphasis on dopaminergic mechanisms.
A 64-year-old man with a past medical history of liver transplantation on chronic immunosuppressive therapy presented with gradual worsening of vision over 2 months in his right eye. His recent history of Aspergillus and Nocardia pneumonia with positive bronchoalveolar lavage, in concert with vitritis and subretinal abscess, were concerning for endogenous endophthalmitis. A sputum culture and transbronchial lung biopsy stains grew Nocardia farcinica although aqueous humor sampling was negative. He was treated with four serial amikacin intravitreal injections over the course of 4 weeks. Pars plana vitrectomy for worsening macular traction and subsequent cataract surgery resulted in significant clinical and anatomic improvement of vision to 20/60 and consolidation of the subretinal abscess.
Purpose: To compare methods for homogenizing the mouse whole eye or retina for RNA extraction. Methods: We tested five homogenization techniques for the whole eye and the retina. Two established shearing techniques were a version of the Potter-Elvehjem homogenizer, which uses a plastic pellet pestle in a microfuge tube, and a Dounce homogenizer. Two modern bead-beating methods used commercially manufactured devices, the Next Advance Bullet Blender and the Qiagen TissueLyser LT. The last method involved vortex mixing multiple samples simultaneously in a buffer containing a stainless-steel set screw, a novel approach. RNA was extracted from the tissue after each technique was used. Degradation of RNA was measured with the RNA integrity number (RIN score) after electrophoresis on an Agilent BioAnalyzer RNA LabChip. Nucleic acid yields were measured with ultraviolet (UV) spectroscopy in a BioTek Synergy H1 Hybrid plate reader. The purity of the nucleic acids was assessed with the mean absorbance ratio (A260/A280). The preparation time per sample was measured with a digital stopwatch. Costs of necessary consumables were calculated per ten samples. Results: The RIN scores for all homogenization methods and both tissue types ranged from 7.75±0.64 to 8.78±0.18; none were statistically significantly different. The total RNA yield per whole eye from the bead-based methods ranged from 7,700 to 9,800 ng and from 3,000 to 4,600 ng for the pellet pestle and Dounce shearing methods, respectively. The total RNA yield per retina from the bead-based methods ranged from 4,600 to 8,400 ng and from 2,200 to 7,400 ng for the pellet pestle and Dounce shearing methods, respectively. Homogenization was faster using the bead-based methods (about 15 min for ten samples) because multiple samples could be run simultaneously compared to the shearing methods that require samples be homogenized individually (about 45-60 min per ten samples). The costs in consumables for the methods tested ranged from $2.60 to $14.70 per ten samples. The major differences in overall costs come in the form of one-time equipment purchases, which can range from one hundred to thousands of dollars. The bead-based methods required less technician involvement and had less potential for sample contamination than the shearing methods. Conclusions: The purity and quality of RNA were similar across all methods for both tissue types. The novel set screw method and the two bead-based methods (bullet blender and TissueLyser) outperformed the two shearing methods (the pellet pestle and Dounce techniques) in total RNA yields for the whole eye. Although the bullet blender, TissueLyser, and set screw methods produced comparable levels of RNA yield, purity, and quality, the set screw method was less expensive. Researchers seeking the efficiency of sophisticated bead homogenization equipment without the high equipment costs might consider this novel method.
Purpose: To report the cytopathology of vitreous biopsy samples in patients with acute retinal necrosis (ARN) who underwent pars plana vitrectomy (PPV). We also describe two patients with unique clinical courses, cytopathologic findings, and immune response
Methods: A retrospective review of patients with ARN who developed retinal detachment (RD) and underwent PPV from 2011–2019 at the Emory Eye Center was performed to assess cytopathology findings of vitreous biopsy samples. Patient demographics and laboratory testing including aqueous humor PCR for viral pathogens were recorded. Additional clinical details abstracted included intravitreal injections, surgical procedures, and vitreous cytopathological reports including immunohistochemistry findings.
Results: Fourteen eyes of twelve patients with RD were reviewed. Ten eyes showed HSV DNA (71%) and 4 demonstrated VZV DNA (29%). All eyes received intravitreal antivirals (i.e. ganciclovir or foscarnet) with a median of 8.5 intravitreal injections per eye. Diagnoses prompting PPV included tractional RD in 14 eyes (100%), rhegmatogenous RD in 8 eyes (57%), vitreous hemorrhage in 4 eyes (29%) and vitreous opacity in 4 (29%). Ophthalmic pathology reports showed lymphocyte populations in 10 eyes (71%) with a CD3+ T-cell predominance in two patients where immunohistochemistry of CD3+ and CD20+ for T- and B-cell populations was performed. Observed immune cell populations included macrophages or histiocytes (11 eyes, 79%) and polymorphonuclear cells in 4 eyes (29%). Initial median VA was 2.5 (IQR 2.0–3.0) and improved to 2.0 (IQR 1.48–3.00, p=0.48) at 6-months and 1.8 (IQR 1.2–3.0, p=0.45) at 12 months follow-up.
Conclusions: Our cohort of ARN patients undergoing PPV show a spectrum of immunologic findings with the majority demonstrating a lymphocytic response. Histiocytes, macrophages, and PMNs were also observed. Cytopathologic and immunologic studies suggest that both innate and adaptive immunity are responsible for the clinical disease findings observed in ARN. The variability of the response to treatment in patients with ARN may reflect patient-to-patient differences in their antigen-specific immune response. Understanding the immunologic response associated with ARN may provide valuable information regarding the dosing and timing of treatment.