Efficacy of orthokeratology lens with the modified small treatment zone on myopia progression and visual quality: a randomized clinical trial.

BACKGROUND: To evaluate the long-term effectiveness of orthokeratology (ortho-K) lenses with small treatment zone (STZ) or conventional treatment zone (CTZ) in controlling axial elongation in children with myopia as well as the impact on visual quality. We also sought to determine the effect of retinal visual signal quality on axial elongation. METHODS: This is a prospective randomized controlled study. A total of 140 participants (age ranging from 8 to 12 years) were randomly assigned to wear either STZ or CTZ ortho-K lenses. STZ ortho-K lenses design was achieved by changing the depth of reverse zone and the sagitta height of the optical zone. Using the IOL-Master 500, axial length (AL) was measured at baseline and after 6, 12 and 18 months of ortho-K treatment. Spherical aberration (SA) and corneal topographic parameters were obtained by the Pentacam anterior segment analyzer at baseline and the 1-month follow-up visit, and optical qualities were assessed by optical quality analysis system-II (OQAS-II) at baseline and after 1 month of lens wearing. Optical quality parameters mainly included the modulation transfer function (MTF) cutoff, Strehl ratio (SR), objective scattering index (OSI), and predicted visual acuity (PVA). RESULTS: A total of 131 participants completed the study, including 68 in the STZ group and 63 in the CTZ group. The STZ group had significantly reduced AL elongation compared to the CTZ group after treatment (12 months: 0.07 ± 0.11 mm vs. 0.14 ± 0.12 mm, P = 0.002; 18 months: 0.17 ± 0.15 mm vs. 0.26 ± 0.16 mm, P = 0.002). The topography in the STZ group showed a smaller treatment zone (TZ) diameter (2.50 ± 0.23 mm vs. 2.77 ± 0.18 mm, P < 0.001), a wider defocus ring width (2.45 ± 0.28 mm vs. 2.30 ± 0.30 mm, P = 0.006), and larger values of total amount of defocus (119.38 ± 63.71 D·mm2 vs. 91.40 ± 40.83 D·mm2, P = 0.003) and total SA (0.37 ± 0.25 µm vs. 0.25 ± 0.29 µm, P = 0.015), compared with the CTZ group. Objective visual quality decreased in both groups (P < 0.001). This was evidenced by a greater decrease in MTF cutoff (- 14.24 ± 10.48 vs. - 10.74 ± 9.46, P = 0.047) and SR values (- 0.09 ± 0.07 vs. - 0.06 ± 0.07, P = 0.026), and an increase in OSI value (0.84 ± 0.72 vs. 0.58 ± 0.53, P = 0.019). PVA9% decreased significantly in the STZ group but not the CTZ group. A statistically significant negative correlation was found between the changes in total SA and MTF cutoff values (r = - 0.202, P = 0.025). AL changes were associated with sex, change of MTF cutoff value, increment of total SA and TZ area. CONCLUSIONS: Compared with CTZ ortho-K lenses, STZ ortho-K lenses significantly inhibited axial elongation in children with myopia while moderately reducing their objective visual quality. Axial elongation was affected by retinal visual quality, and it may be a possible mechanism for ortho-K slowing myopia progression. Trial registration This trial is registered at Chinese Clinical Trial Registry on November 5, 2019 with trial registration number: ChiCTR1900027218. https://www.chictr.org.cn/showproj.html?proj=45380.

Progression Patterns and Risk Factors of Axial Elongation in Young Adults with Non-Pathologic High Myopia: Three-year Large Longitudinal Cohort Follow-up.

PURPOSE: To investigate the progression patterns and risk factors of axial elongation in young adults with non-pathologic high myopia. DESIGN: Prospective, clinical observational cohort study with 2- to 4-year follow-up. METHODS: A total of 1043 eyes of 563 participants (3515 medical records) aged 18 to 50 years with non-pathologic high myopia (axial length [AL] ≥ 26 mm; myopic maculopathy < diffuse chorioretinal atrophy; without posterior staphyloma) were included from 1546 participants (6318 medical records). Annual axial elongation was calculated via linear mixed-effect models. The associated risk factors of axial elongation were determined by ordinal logistic regression analysis, with generalized estimate equations for eliminating an interocular correlation bias. RESULTS: Based on 5359 times of AL measurements, the annual axial elongation of participants (mean [SD] age 31.39 [9.22] years) was 0.03 mm/year (95% confidence interval [CI], 0.03-0.04, P < 0.001) during a 30.23 (6.06) months' follow-up. Severe (> 0.1 mm/year), moderate (0.05-0.09 mm/year), mild (0-0.049 mm/year), and nil (≤ 0 mm/year) elongation was observed in 122 (11.7%), 211 (20.2%), 417 (40.0%), and 293 (28.1%) eyes. The following risk factors were significantly associated with axial elongation: baseline AL≥ 28 mm (odds ratio [OR], 4.23; 95%CI, 2.95-6.06; P < 0.001); age < 40 years (OR, 1.64; 95%CI, 1.18-2.28; P = 0.003); axial asymmetry (OR, 2.04; 95%CI, 1.26-3.29; P = 0.003), and women (OR, 1.52; 95%CI, 1.13-2.2.05; P = 0.006). Using anti-glaucoma medications was a protective factor (OR, 0.46; 95%CI, 0.27-0.79; P = 0.005), which slowed 75% of axial elongation from 0.04 (0.06) to 0.01 (0.06) mm/y (P < 0.001). CONCLUSIONS: Axial elongation continued in young adults with non-pathologic myopia. Risk factors included longer baseline AL and axial asymmetry, younger age, and woman. Topical use of anti-glaucoma medications may be useful to reduce ongoing axial elongation.

Intraocular amphiregulin and axial elongation in non-human adolescent primates.

The purpose of the experimental interventional study was to examine the influence of intraocularly applied amphiregulin, a member of the epidermal growth factor (EGF) family, on axial length in young non-human primates. It included three non-human primates (Macaca mulatta), aged 4-6 years. The left eyes received three intravitreal injections of amphiregulin (400ng/50 µl) in intervals of 4 weeks, while the right eyes received three intravitreal injections of phosphate buffered solution (50 µl) at the same time points. Ocular biometry was performed in weekly intervals. At baseline, the left eyes (study eyes) were shorter than the right (control) eyes (20.69 ± 0.21 mm versus 20.79 ± 0.24 mm; P < 0.001), with an inter-eye axial length (AL) difference (left minus right eye) of -0.10 ± 0.23 mm. Inter-eye AL difference increased (P < 0.001) to 0.15 ± 0.18 mm at study end, at 12 weeks after baseline. Axial elongation during the study was higher (P < 0.001) in the left eyes (20.69 ± 0.21 mm to 21.05 ± 0.29 mm or 0.36 ± 0.30 mm) than in the right eyes (20.79 ± 0.24 mm to 20.90 ± 0.31 mm or 0.11 ± 0.17 mm). In a parallel manner, inter-eye difference in vitreous cavity depth combined with lens thickness (left eye minus right eye) increased from -0.04 ± 0.17 mm at baseline to -0.02 ± 0.21 mm (P = 0.02), 0.04 ± 0.10 mm (P = 0.002), and to 0.42 ± 0.67 mm (P < 0.001) at 5, 6, and 12 weeks after baseline, respectively. The results suggest that intravitreally applied amphiregulin as EGF family member led to an increase in axial length in adolescent non-human primates. It supports the hypothesis of amphiregulin as EGF family member being involved in the process of axial elongation.

Distinct molecular profile of the chick organizer as a stem zone during axial elongation.

The vertebrate organizer plays a crucial role in building the main (antero-posterior) axis of the embryo: it neuralizes the surrounding ectoderm, and is the site of emigration for cells making axial and paraxial mesendoderm during elongation. The chick organizer becomes a stem zone at the onset of elongation; it stops recruiting cells from the neighbouring ectoderm and generates all its derivatives from the small number of resident cells it contains at the end of gastrulation stages. Nothing is known about the molecular identity of this stem zone. Here, we specifically labelled long-term resident cells of the organizer and compared their RNA-seq profile to that of the neighbouring cell populations. Screening by reverse transcription-polymerase chain reaction and in situ hybridization identified four genes (WIF1, PTGDS, ThPO and UCKL1) that are upregulated only in the organizer region when it becomes a stem zone and remain expressed there during axial elongation. In experiments specifically labelling the resident cells of the mature organizer, we show that only these cells express these genes. These findings molecularly define the organizer as a stem zone and offer a key to understanding how this zone is set up, the molecular control of its cells' behaviour and the evolution of axial growth zones.

Effects of orthokeratology on corneal reshaping and the delaying of axial eye growth in children.

Purpose: To investigate the inhibition of myopia progression and axial elongation in children wearing orthokeratology (OK) lenses, as well as to evaluate the status of corneal reshaping, this study explores the relationship between changes in central corneal curvature (K-value) and e-value induced by OK lenses and axial elongation. Methods: In this study, it is planned to select children aged 8-15 who wear orthokeratology lenses at the Pediatric Ophthalmology and Strabismus Clinic of the Second Affiliated Hospital of Dalian Medical University. All children will undergo slit lamp examination, visual acuity assessment, computerized refraction, intraocular pressure measurement, biometry, and corneal topography examination before lens wear and at 1 month, 3 months, and 6 months after lens wear in the pediatric ophthalmology clinic. Based on age (lower age group (8 < age ≤12 years); higher age group (12 < age ≤15 years)) and baseline equivalent spherical (SE) value (mild myopia group (-1.00 D < SE ≤ -3.25D); moderate myopia group (-3.25 D < SE ≤ -6.00 D)), four groups will be formed by pairing these factors. Suitable data will be selected according to inclusion and exclusion criteria, and different groups will be included. Data will be organized, and statistical analysis will be performed using SPSS software to obtain the results. The expected results will be discussed and analyzed. Results: After wearing OK lenses, all four groups achieved good visual acuity at follow-up. At 6 months, there were no significant differences in visual acuity among the four groups (P = 0.149, >0.05). There were no significant differences in refractive error among the four groups (P = 0.066, >0.05). Baseline axial length differed significantly among the four groups (P = 0.000, <0.001), with the LM group having longer axial length than the LL group (P < 0.001, paired samples t-test), and the HM group having longer axial length than the HL group (P < 0.001, paired samples t-test). However, there were no significant differences in axial length change compared to baseline among the groups at 1 month, 3 months, and 6 months (P 1 = 0.053; P 3 = 0.557; P 6 = 0.329, >0.05). Significant differences were observed in corneal flat K-value change compared to baseline among the four groups at 1 month, 3 months, and 6 months (P 1 = 0.001, P 3 = 0.001, P 6 = 0.004, <0.05). There were no significant differences in e-value change among the groups at 1 and 3 months (P 1 = 0.205, P 3 = 0.252, >0.05), but significant differences were found in e-value change compared to baseline at 6 months (P 6 = 0.010, <0.05). Multiple regression analysis with changes in central corneal flat K-value and e-value as independent variables and axial elongation as the dependent variable showed a correlation between e-value change at 6 months and axial elongation (P = 0.004, <0.05), indicating a negative correlation. Conclusion: Orthokeratology (OK) lenses effectively improve myopic children's vision by reshaping the cornea, leading to reduced central corneal curvature and flattening of its anterior surface. The effectiveness of OK lenses is not significantly affected by age or initial myopia severity. Children of varying ages and myopia levels experience similar levels of axial length control with OK lens wear. Changes in corneal shape due to OK lenses affect axial elongation, with greater changes in corneal morphology associated with smaller increases in axial length.

Choroidal thinning in myopia is associated with axial elongation and severity of myopic maculopathy.

High myopia can lead to pathologic myopia and visual impairment, whereas its causes are unclear. We retrospectively researched high myopia cases from patient records to investigate the association between axial elongation and myopic maculopathy. Sixty-four eyes were examined in patients who visited the department between July 2017 and June 2018, had an axial length of 26 mm or more, underwent fundus photography, and had their axial length measured twice or more. The average axial length was 28.29 ± 1.69 mm (mean ± standard deviation). The average age was 58.3 ± 14.4 years old. Myopic maculopathy was categorized as mild (grades 0 and 1) and severe (grades 2, 3, and 4). The severe group had longer axial lengths than the mild group (P < 0.05). Moreover, the severe group exhibited thinner choroidal thickness than the mild group (P < 0.05). When subjects were grouped by axial elongation over median value within a year, the elongation group showed thinner central choroidal thickness than the non-elongation group (142.1 ± 91.9 vs. 82.9 ± 69.8, P < 0.05). In conclusion, in patients with high myopia, the severity of maculopathy correlated with choroidal thickness and axial length. Thinner choroidal thickness was associated with axial elongation based on the baseline axial length.

BPA Exposure Affects Mouse Gastruloids Axial Elongation by Perturbing the Wnt/ß-Catenin Pathway.

Mammalian embryos are very vulnerable to environmental toxicants (ETs) exposure. Bisphenol A (BPA), one of the most diffused ETs, exerts endocrine-disrupting effects through estro-gen-mimicking and hormone-like properties, with detrimental health effects, including on reproduction. However, its impact during the peri-implantation stages is still unclear. This study, using gastruloids as a 3D stem cell-based in vitro model of embryonic development, showed that BPA exposure arrests their axial elongation when present during the Wnt/ß-catenin pathway activation period by ß-catenin protein reduction. Gastruloid reshaping might have been impeded by the downregulation of Snail, Slug and Twist, known to suppress E-cadherin expression and to activate the N-cadherin gene, and by the low expression of the N-cadherin protein. Also, the lack of gastruloids elongation might be related to altered exit of BPA-exposed cells from the pluripotency condition and their following differentiation. In conclusion, here we show that the inhibition of gastruloids' axial elongation by BPA might be the result of the concomitant Wnt/ß-catenin perturbation, reduced N-cadherin expression and Oct4, T/Bra and Cdx2 altered patter expression, which all together concur in the impaired development of mouse gastruloids.

Novel Lenslet-ARray-Integrated Spectacle Lenses for Myopia Control: A 1-Year Randomized, Double-Masked, Controlled Trial.

PURPOSE: To investigate the myopia control efficacy of novel Lenslet-ARray-Integrated (LARI) spectacle lenses with positive power lenslets (PLARI) and negative power lenslets (NLARI) worn for 1 year in myopic children. DESIGN: Randomized, double-masked, controlled clinical trial. PARTICIPANTS: A total of 240 children 6 to 12 years of age with spherical equivalent refraction (SER) between -4.00 and -1.00 diopters (D), astigmatism of ≤ 1.50 D, and anisometropia of ≤ 1.00 D. METHODS: Participants were assigned randomly in a 1:1:1 ratio to PLARI, NLARI, and control (single-vision [SV]) groups. Cycloplegic autorefraction and axial length were measured at baseline and 6-month intervals after lens wear. MAIN OUTCOME MEASURES: Changes in SER, axial elongation (AE), and differences between groups. RESULTS: After 1 year, SER changes and AE in the PLARI and NLARI groups were significantly less than those in the SV group (SER: -0.30 ± 0.48 D, -0.21 ± 0.35 D, and -0.66 ± 0.40 D, respectively; AE: 0.19 ± 0.20 mm, 0.17 ± 0.14 mm, 0.34 ± 0.18 mm, respectively; all P < 0.001). No significant differences were found in SER changes and AE between PLARI and NLARI groups (P = 0.54 and P = 1.00, respectively). Younger age was associated with more rapid SER increase and larger AE in the SV group (r = 0.40 [P < 0.001] and r = -0.59 [P < 0.001], respectively) and PLARI group (r = 0.46 [P < 0.001] and r = -0.52 [P < 0.001], respectively), but not in the NLARI group (r = -0.002 [P = 0.98] and r = -0.08 [P = 0.48], respectively). CONCLUSIONS: Compared with the SV group, both PLARI and NARI groups showed significantly slower myopia progression in terms of SER and AE. Faster myopia progression, in terms of both SER and AE, was associated with younger age in the SV and PLARI groups but not the NLARI group. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Anisomyopia and orthokeratology for myopia control - Axial elongation and relative peripheral refraction.

PURPOSE: To investigate axial elongation (AE) and changes in relative peripheral refraction (RPR) in anisomyopic children undergoing orthokeratology (ortho-k). METHODS: Bilateral anisomyopic children, 7-12 years of age, were treated with ortho-k. Axial length (AL) and RPR, from 30° nasal (N30°) to 30° temporal (T30°), were measured at baseline and every 6 months over the study period. AE, changes in RPR and changes in the interocular AL difference were determined over time. RESULTS: Twenty-six of the 33 subjects completed the 2-year study. The AE of the higher myopic (HM) eyes (at least 1.50 D more myopia than the other eye) (0.26 ± 0.29 mm) was significantly smaller than for the less myopic (LM) eyes (0.50 ± 0.27 mm; p = 0.003), leading to a reduction in the interocular difference in AL (p = 0.001). Baseline RPR measurements in the HM eyes were relatively more hyperopic at T30°, N20° and N30° (p ≤ 0.02) and greater myopic shifts were observed at T20° (p < 0.001), T30° (p < 0.001), N20° (p = 0.02) and N30° (p = 0.01) after lens wear. After 2 years of ortho-k lens wear, temporal-nasal asymmetry increased significantly, being more myopic at the temporal locations in both eyes (p < 0.001), while AE was associated with the change in RPR at N20° (ß = 0.134, p = 0.01). The interocular difference in AE was also positively associated with the interocular difference in RPR change at N30° (ß = 0.111, p = 0.02). CONCLUSIONS: Ortho-k slowed AE in bilateral anisomyopia, with slower growth in the HM eyes leading to a reduction in interocular AL differences. After ortho-k, RPR changed from hyperopia to myopia, with greater changes induced in the HM eyes, and slower AE was associated with a more myopic shift in RPR, especially in the nasal field of both eyes.

Differential proliferation regulates multi-tissue morphogenesis during embryonic axial extension: integrating viscous modeling and experimental approaches.

A major challenge in biology is to understand how mechanical interactions and cellular behavior affect the shapes of tissues and embryo morphology. The extension of the neural tube and paraxial mesoderm, which form the spinal cord and musculoskeletal system, respectively, results in the elongated shape of the vertebrate embryonic body. Despite our understanding of how each of these tissues elongates independently of the others, the morphogenetic consequences of their simultaneous growth and mechanical interactions are still unclear. Our study investigates how differential growth, tissue biophysical properties and mechanical interactions affect embryonic morphogenesis during axial extension using a 2D multi-tissue continuum-based mathematical model. Our model captures the dynamics observed in vivo by time-lapse imaging of bird embryos, and reveals the underestimated influence of differential tissue proliferation rates. We confirmed this prediction in quail embryos by showing that decreasing the rate of cell proliferation in the paraxial mesoderm affects long-term tissue dynamics, and shaping of both the paraxial mesoderm and the neighboring neural tube. Overall, our work provides a new theoretical platform upon which to consider the long-term consequences of tissue differential growth and mechanical interactions on morphogenesis.

The expanding roles of Nr6a1 in development and evolution.

The Nuclear Receptor (NR) family of transcriptional regulators possess the ability to sense signalling molecules and directly couple that to a transcriptional response. While this large class of proteins are united by sequence and structural homology, individual NR functional output varies greatly depending on their expression, ligand selectivity and DNA binding sequence specificity. Many NRs have remained somewhat enigmatic, with the absence of a defined ligand categorising them as orphan nuclear receptors. One example is Nuclear Receptor subfamily 6 group A member 1 (Nr6a1), an orphan nuclear receptor that has no close evolutionary homologs and thus is alone in subfamily 6. Nonetheless, Nr6a1 has emerged as an important player in the regulation of key pluripotency and developmental genes, as functionally critical for mid-gestational developmental progression and as a possible molecular target for driving evolutionary change in animal body plan. Here, we review the current knowledge on this enigmatic nuclear receptor and how it impacts development and evolution.

TBXT dose sensitivity and the decoupling of nascent mesoderm specification from EMT progression in 2D human gastruloids.

In the nascent mesoderm, TBXT expression must be precisely regulated to ensure that cells exit the primitive streak and pattern the anterior-posterior axis, but how varying dosage informs morphogenesis is not well understood. In this study, we define the transcriptional consequences of TBXT dosage reduction during early human gastrulation using human induced pluripotent stem cell models of gastrulation and mesoderm differentiation. Multi-omic single-nucleus RNA and single-nucleus ATAC sequencing of 2D gastruloids comprising wild-type, TBXT heterozygous or TBXT null human induced pluripotent stem cells reveal that varying TBXT dosage does not compromise the ability of a cell to differentiate into nascent mesoderm, but instead directly influences the temporal progression of the epithelial-to-mesenchymal transition with wild type transitioning first, followed by TBXT heterozygous and then TBXT null. By differentiating cells into nascent mesoderm in a monolayer format, we further illustrate that TBXT dosage directly impacts the persistence of junctional proteins and cell-cell adhesions. These results demonstrate that epithelial-to-mesenchymal transition progression can be decoupled from the acquisition of mesodermal identity in the early gastrula and shed light on the mechanisms underlying human embryogenesis.

Robust axis elongation by Nodal-dependent restriction of BMP signaling.

Embryogenesis results from the coordinated activities of different signaling pathways controlling cell fate specification and morphogenesis. In vertebrate gastrulation, both Nodal and BMP signaling play key roles in germ layer specification and morphogenesis, yet their interplay to coordinate embryo patterning with morphogenesis is still insufficiently understood. Here, we took a reductionist approach using zebrafish embryonic explants to study the coordination of Nodal and BMP signaling for embryo patterning and morphogenesis. We show that Nodal signaling triggers explant elongation by inducing mesendodermal progenitors but also suppressing BMP signaling activity at the site of mesendoderm induction. Consistent with this, ectopic BMP signaling in the mesendoderm blocks cell alignment and oriented mesendoderm intercalations, key processes during explant elongation. Translating these ex vivo observations to the intact embryo showed that, similar to explants, Nodal signaling suppresses the effect of BMP signaling on cell intercalations in the dorsal domain, thus allowing robust embryonic axis elongation. These findings suggest a dual function of Nodal signaling in embryonic axis elongation by both inducing mesendoderm and suppressing BMP effects in the dorsal portion of the mesendoderm.

Intraocular cetuximab: Safety and effect on axial elongation in young Guinea pigs with lens-induced myopization.

This study aimed to examine the intraocular tolerability of the epidermal growth factor receptor antibody cetuximab, when applied intravitreally, and its effect on axial elongation. Guinea pigs aged 2-3 weeks were subjected to bilateral plano glasses and bilateral lens-induced myopization (LIM) as a single procedure for group I (n = 8) and group II (n = 8), respectively. In the animals of group III (n = 8), group IV (n = 8), and group V (n = 8), the right eyes of the animals, in addition to LIM, received four weekly intravitreal injections of cetuximab (Erbitux®) in doses of 6.25 µg, 12.5 µg, and 25 µg, respectively. As controls, the left eyes, in addition to LIM, received corresponding intraocular injections of phosphate-buffered saline. The animals underwent regular ophthalmoscopic examinations and biometry for axial length measurements. With increasing doses of cetuximab, the inter-eye difference in axial elongation (at study end, left eyes minus right eyes) were significantly the smallest in group I (0.00 ± 0.02 mm) and group II (-0.01 ± 0.02 mm), they were larger in group III (0.04 ± 0.04 mm) and group IV (0.10 ± 0.03 mm), and they were the largest in group V (0.11 ± 0.01 mm). The inter-eye difference in axial elongation enlarged (P < 0.001) with the number of injections applied. Retinal thickness at the posterior pole (right eyes) was significantly thicker in group V than in group II (P < 0.01). The density of apoptotic cells (visualized by TUNEL-staining) did not vary significantly between any of the groups (all P > 0.05). The results suggest that intravitreal injections of cetuximab in young guinea pigs with LIM resulted in a reduction in axial elongation in a dose-dependent and number of treatment-dependent manner. Intraocular toxic effects, such as intraocular inflammation, retinal thinning, or an increased density of apoptotic cells in the retina, were not observed in association with the intravitreally applied cetuximab.

Reduction of experimental ocular axial elongation by neuregulin-1 antibody.

Background: Since the mechanisms underlying myopic axial elongation have remained unclear, we examined the effect of neuregulin-1 (NRG-1), an epidermal growth factor family member, on myopic axial elongation. Methods: The guinea pigs aged two to three weeks were subjected to bilateral negative lens-induced axial elongation and received weekly intravitreal injections into their right eyes of NRG-1 antibody (doses: 5 µg, n = 8; 10 µg, n = 8, 20 µg, n = 9) or of NRG-1 (doses: 0.05 µg, n = 8; 0.01 µg, n = 9; 0.2 µg, n = 8), underwent only bilateral negative lens-induced axial elongation (myopia control group, n = 10), or underwent no intervention (control group, n = 10). The contralateral eyes received corresponding intravitreal phosphate-buffered solution injections. One week after the last injection, the guinea pigs were sacrificed, the eyeballs were removed, the thicknesses of the retina and sclera were histologically examined, the expression of NRG-1 and downstream signal transduction pathway members (ERK1/2 and PI3K/AKT) and the mRNA expression of NRG-1 in the retina was assessed. Results: The inter-eye difference in axial length at study end increased (p < 0.001) from the normal control group (-0.02 ± 0.09 mm) and the myopia control group (-0.01 ± 0.09 mm) to the low-dose NRG-1 antibody group (-0.11 ± 0.05 mm), medium-dose NRG-1 antibody group (-0.17 ± 0.07 mm), and high-dose NRG-1 antibody group (-0.28 ± 0.06 mm). The relative expression of NRG-1, ERK1/2, and PI3K/AKT in the retina decreased in a dose-dependent manner from the myopia control group to the NRG-1 antibody groups and the normal control group. The relative NRG-1 mRNA expression in the retina was higher (p < 0.01) in the myopic control group than in the NRG-1 antibody groups and normal control group. Scleral and retinal thickness decreased from the normal control group to the NRG-1 antibody groups to the myopic control group. After intraocular injection of NRG-1 protein, there was a slight dose-dependent increase in the difference in axial length between the right and left eye, however not statistically significantly, from the normal control group (-0.02 ± 0.09 mm) to the high-dose NRG-1 protein group (0.03 ± 0.03 mm; p = 0.12). Conclusion: Intravitreal NRG-1 antibody application was dose-dependently and time-dependently associated with a reduction in negative lens-induced axial elongation in young guinea pigs.

TBXT dose sensitivity and the decoupling of nascent mesoderm specification from EMT progression in 2D human gastruloids.

In the nascent mesoderm, levels of Brachyury (TBXT) expression must be precisely regulated to ensure cells exit the primitive streak and pattern the anterior-posterior axis, but how this varying dosage informs morphogenesis is not well understood. In this study, we define the transcriptional consequences of TBXT dose reduction during early human gastrulation using human induced pluripotent stem cell (hiPSC)-based models of gastrulation and mesoderm differentiation. Multiomic single-nucleus RNA and single-nucleus ATAC sequencing of 2D gastruloids comprised of WT, TBXT heterozygous (TBXT-Het), or TBXT null (TBXT-KO) hiPSCs reveal that varying TBXT dosage does not compromise a cell's ability to differentiate into nascent mesoderm, but that the loss of TBXT significantly delays the temporal progression of the epithelial to mesenchymal transition (EMT). This delay is dependent on TBXT dose, as cells heterozygous for TBXT proceed with EMT at an intermediate pace relative to WT or TBXT-KO. By differentiating iPSCs of the allelic series into nascent mesoderm in a monolayer format, we further illustrate that TBXT dose directly impacts the persistence of junctional proteins and cell-cell adhesions. These results demonstrate that EMT progression can be decoupled from the acquisition of mesodermal identity in the early gastrula and shed light on the mechanisms underlying human embryogenesis.

Comparison of two different orthokeratology lenses and defocus incorporated soft contact (DISC) lens in controlling myopia progression.

BACKGROUND: To compare axial elongation in 8-11-year-old myopes wearing orthokeratology (OK) lenses with different back optic zone diameters (BOZD), defocus incorporated soft contact (DISC) lenses, and single-vision soft contact lenses (SCLs). METHODS: A total of 122 children (aged 8-11 years) with spherical equivalent refraction (SER) between - 1.00 D and - 4.00 D were enrolled in this prospective study and randomly assigned to four groups: 5.0 mm-BOZD OK, 6.2 mm-BOZD OK, DISC, and single-vision SCLs. Children in each group were further divided into subgroups stratified by the average baseline SER: low myopic eyes (SER: - 1.00 D to - 2.50 D) and moderate myopic eyes (SER: - 2.50 D and over). Axial length (AL) was measured at baseline and after one year. RESULTS: The 5.0 mm-BOZD OK, 6.2 mm-BOZD OK, and DISC groups exhibited significantly slower AL elongation than the SCL group. The proportion of slow progressors (AL elongation ≤ 0.18 mm/year) in the first three groups was 42%, 23%, and 29%, respectively. Furthermore, one-year AL elongation was significantly smaller in the 5.0 mm-BOZD OK group compared with the 6.2 mm-BOZD OK group. Regardless of SER, children in the 5.0 mm-BOZD OK and DISC groups showed comparably slower AL elongation than those in the SCL group. However, fitting with 6.2 mm-BOZD OK lenses significantly retarded AL elongation in moderate myopic eyes, but not in low myopic eyes. CONCLUSIONS: Overall, 5.0 mm-BOZD OK lenses, 6.2 mm-BOZD OK lenses, and DISC lenses were effective in retarding AL elongation in 8-11-year-old myopes compared with single-vision SCLs, but for children with SER less than - 2.50 D, fitting with 5.0 mm-BOZD OK lenses and DISC lenses yielded better myopia control efficacy compared to wearing single-vision SCLs or 6.2 mm-BOZD OK lenses.

Variation of Orthokeratology Lens Treatment Zone (VOLTZ) Study: A 2-year randomised clinical trial.

PURPOSE: To compare axial elongation (AE) and treatment zone (TZ) characteristics in children wearing 6 mm or 5 mm back optic zone diameter (BOZD) orthokeratology (ortho-k) lenses over 2 years. METHODS: Forty-five (6 to <11 years of age) myopic (-4.00 to -0.75 D) children of Chinese ethnicity were randomly assigned to use the two different lens designs (23 and 22 wore the 6 and 5 mm lenses, respectively). Data collection was performed at baseline and every 6-months after commencing lens wear. RESULTS: After 24 months, subjects wearing lenses with a 5 mm BOZD achieved smaller TZ diameter (horizontal: 2.69 ± 0.28 vs. 3.84 ± 0.39 mm; vertical: 2.65 ± 0.22 vs. 3.42 ± 0.34 mm, p < 0.001) and less AE (0.15 ± 0.21 vs. 0.35 ± 0.23, p = 0.005) compared to those using the 6 mm design, with no difference in choroidal thickness (ChT) changes (p = 0.93). A significant increase in ChT, using pooled data analysis, was noted at the 6-month (11.8 ± 19.77 µm, p < 0.001) and 12-month (12.0 ± 23.7 µm, p = 0.004) visits, compared to baseline, indicating a transient change in ChT. Significant associations were noted, using linear mixed models, between AE and the TZ diameters (p < 0.003) after adjusting for baseline data. A very weak association was found between ChT changes and AE, with the effect size close to zero. CONCLUSIONS: Smaller BOZD ortho-k lenses resulted in a smaller TZ diameter, which was associated with less AE after 2 years of treatment. The changes in ChT played a very weak role, suggesting that other factors may contribute more to the reduced AE in subjects wearing lenses having a smaller BOZD.

Assessment of myopic rebound effect after discontinuation of treatment with 0.01% atropine eye drops in Japanese school-age children.

PURPOSE: Having previously demonstrated the efficacy of 0.01% atropine eye drops for inhibiting progression of childhood myopia, we conducted additional analyses to assess post-treatment changes in myopia progression. STUDY DESIGN: Analysis of follow-up data from a previously reported randomized controlled trial METHODS: A mixed-effects model was used to compare intergroup changes in spherical equivalent (SE) and axial length (AL) at 1 month and 12 months after discontinuation of 2-year treatment with atropine or placebo in 167 school-age children. RESULTS: Follow-up measurements were available for 149 participants at 1 month after discontinuation of treatment and for 51 participants at 12 months after discontinuation. At 1 month post-treatment, differences between the atropine and placebo groups in least squares (LS) mean changes in SE and AL, respectively, from 24 months were -0.06 diopters (D) (95% CI: -0.21, 0.08; P = .39) and 0.02 mm (95% CI: -0.05, 0.08; P = .60). At 12 months post-treatment, intergroup differences (atropine vs placebo) in LS mean changes in SE and AL, respectively, were -0.13 D (95% CI: -0.35, 0.10; P = .26) and -0.02 mm (95% CI: -0.12, 0.09; P = .75). LS mean changes in SE and AL from treatment discontinuation did not differ between the groups at 1 or 12 months post-treatment. CONCLUSION: Axial elongation was significantly less in the atropine group than in the placebo group. The suppression effect obtained at 2 years was maintained after 12 months. The absence of intergroup differences in myopia progression since treatment cessation suggests that myopic rebound did not occur.

One-year results for myopia control with aspheric base curve orthokeratology lenses: A prospective randomised clinical trial.

PURPOSE: To compare the effect of orthokeratology (ortho-k) using aspheric or spherical base curve (BCA vs. BCS) contact lenses on axial elongation and the relative peripheral refraction change (RPRC) in Chinese children. METHODS: Children aged 8-12 years with myopia between -0.75 and -4.00 D and astigmatism ≤1.00 D were randomly assigned to the BCA or BCS group. Peripheral refraction was assessed at 10°, 20° and 30° along the temporal and nasal retina at baseline and at the 12-month visit. Axial length (AL) was measured under cycloplegia at baseline and at the 6- and 12-month visits. Only right eye data were analysed. Repeated-measures analysis of covariance was performed to examine the differences in axial elongation and the RPRC between the BCA and BCS groups. RESULTS: The 1-year results from 31 BCA and 32 BCS subjects were analysed. No significant between-group differences were found at baseline (p ≥ 0.28). At the 12-month visit, the BCA lens produced a greater absolute RPRC along the horizontal meridian than the BCS lens (p < 0.001). Axial elongation was slower in the BCA group (0.19 ± 0.20 mm) than in the BCS group (0.29 ± 0.14 mm; p = 0.03). Axial elongation was correlated with the RPRC at 10° (r = 0.43, p = 0.02) and 20° (r = 0.39, p = 0.03) along the temporal retina in the BCA group; however, these correlations were not observed in the BCS group. CONCLUSION: The BCA ortho-k lens could improve the efficacy of slowing axial elongation in children. The improved myopia control observed in the BCA group may be the result of a larger myopic shift in relative peripheral refraction within 20° along the temporal retina.