Refractive Error Change and Overminus Lens Therapy for Childhood Intermittent Exotropia.

Importance: Increased myopic shift was found to be associated with 1 year of overminus spectacle treatment for children with intermittent exotropia (IXT). Persistence of myopic shift after discontinuing overminus spectacles is unknown. Objective: To compare refractive error change over 3 years in children with IXT originally treated with overminus vs nonoverminus spectacles. Design, Setting, and Participants: This study was an 18-month extension of the Trial of Overminus Spectacle Therapy for Intermittent Exotropia cohort, which previously randomized children aged 3 to 10 years with IXT and baseline spherical equivalent refractive error (SER) between -6.00 diopters (D) and 1.00 D to overminus spectacles (-2.50 D for 12 months, -1.25 D for 3 months, and nonoverminus for 3 months) or nonoverminus spectacles. Children were recruited from 56 sites from July 2010 to February 2022. Data were analyzed from February 2022 to January 2024. Interventions: After trial completion at 18 months, participants were followed up at 24 and 36 months. Treatment was at investigator discretion from 18 to 36 months. Main Outcomes and Measures: Change in SER (cycloplegic retinoscopy) from baseline to 36 months. Results: Of 386 children in the Trial of Overminus Spectacle Therapy for Intermittent Exotropia, 223 (57.8%) consented to 18 months of additional follow-up, including 124 of 196 (63.3%) in the overminus treatment group and 99 of 190 (52.1%) in the nonoverminus treatment group. Of 205 children who completed 36-month follow-up, 116 (56.6%) were female, and the mean (SD) age at randomization was 6.2 (2.1) years. Mean (SD) SER change from baseline to 36 months was greater in the overminus group (-0.74 [1.00] D) compared with the nonoverminus group (-0.44 [0.85] D; adjusted difference, -0.36 D; 95% CI, -0.59 to -0.12; P = .003), with 30 of 112 (26.8%) in the overminus group having more than 1 D of myopic shift compared with 14 of 91 (15%) in the nonoverminus group (risk ratio, 1.8; 95% CI, 1.0-3.0). From 12 to 36 months, mean (SD) myopic shift was -0.34 (0.67) D and -0.36 (0.66) D in the overminus and nonoverminus groups, respectively (adjusted difference, -0.001 D; 95% CI, -0.18 to 0.18; P = .99). Conclusions and Relevance: The greater myopic shift observed after 1 year of -2.50-D overminus lens treatment remained at 3 years. Both groups had similar myopic shift during the 2-year period after treatment weaning and cessation. The risk of myopic shift should be discussed with parents when considering overminus lens treatment. Trial Registration: ClinicalTrials.gov Identifier: NCT02807350.

Screening of Candidate Inflammatory Markers of Epithelial Cells in Hepatocellular Carcinoma Based on Integration Analysis of TCGA/ICGC Databases and Single-cell Sequencing.

BACKGROUND: Hepatocellular Carcinoma (HCC) is closely linked to inflammatory reactions, with chronic liver diseases acting as major risk factors. In the inflammatory microenvironment, repeated damage and repair of liver cells lead to genetic mutations, abnormal proliferation, and tumorigenesis. OBJECTIVE: This study aimed to investigate the expression profile of specific cell clusters under inflammatory stimulation in HCC and identify potential therapeutic drugs. METHODS: Comprehensive analysis of HCC transcriptome data and single-cell sequencing data from TCGA, ICGC, and GEO databases was conducted to explore the specific molecular mechanisms of epithelial cells. Virtual screening of natural compounds in the ZINC database and in vitro cell experiments were performed to identify drugs that regulate the expression of inflammatory factors in epithelial cells. RESULTS: Analysis of the single-cell dataset revealed cell clusters closely associated with HCC, notably Epithelial cells, Hepatocytes, MSC, and iPS cells, with Epithelial cells playing a pivotal role in HCC development. Further investigation of TCGA data unveiled 83 differentially expressed genes (DEGs) related to inflammatory responses in HCC. Intersection analysis of DEGs in epithelial cells and HCC DEGs identified 12 common DEGs, including ADRM1, ATP2B1, FZD5, GPC3, KIF1B, KLF6, LY6E, MET, NAMPT, SERPINE1, SPHK1, and SRI. Prognostic analysis revealed that CCL7, GPR132, ITGB8, PTAFR, SELL, and VIP were influential in the survival prognosis of HCC. A prognostic model based on the expression levels of these genes demonstrated an increased risk of HCC associated with higher differential expression of inflammatory response genes. Additionally, molecular dynamics simulations indicated that compounds NADH and Deferoxamine formed stable docking models with the inflammatory protein VIP, suggesting their potential as candidates for targeted therapy. CONCLUSION: Inflammatory factors CCL7, GPR132, ITGB8, PTAFR, SELL, and VIP influence the inflammatory cascade response in HCC epithelial cells, and their expression correlates with the survival prognosis of HCC patients. Interfering with VIP expression effectively suppresses proliferation, migration, and invasion of HCC cells, as well as inhibiting the occurrence of inflammatory cascade reactions, thus slowing down the progression of hepatocellular carcinoma. Furthermore, compounds NADH and Deferoxamine have the potential to target and bind to the inflammatory protein VIP, highlighting their relevance in potential HCC treatment.

Insufficient stem antetorsion and lower cup abduction is a combined risk factor for posterior hip dislocation in patients undergoing THA for femoral neck fractures: a retrospective analysis.

BACKGROUND: The role of acetabular and femoral component positions with respect to the risk of post-operative instability and dislocation remains debated. In this study, we aimed to identify potential risk factors for early dislocation following primary total hip arthroplasty (THA) for displaced intracapsular femoral neck fractures (FNF) using radiological measurements. METHODS: We retrospectively analyzed data for patients who underwent cementless primary THA for FNF using a posterolateral approach between January 2018 and December 2021. Follow-up duration, age, sex, affected side, and mean time from THA to dislocation were recorded. Leg-length inequality, abductor lever arm, vertical and horizontal femoral offsets, vertical and horizontal hip centers of rotation, abduction, anteversion of the acetabulum and femoral prosthesis, and combined anteversion were measured. RESULTS: The study sample included 17 men and 34 women, with 21 and 30 patients undergoing left- and right-hip operations, respectively. The mean patient age was 70.18 ± 7.64 years, and the mean follow-up duration was 27.73 ± 13.52 months. The mean time between THA and dislocation was 1.58 ± 0.79 months. Seven patients (13.73%) sustained posterior dislocation of the hip. The abduction angle (36.05 ± 6.82° vs. 45.68 ± 8.78°) (p = 0.008) and anteversion of the femoral prosthesis (8.26 ± 4.47° vs. 19.47 ± 9.01°) (p = 0.002) were significantly lower in the dislocation group than in the control group. There were no significant differences in other parameters. CONCLUSIONS: Insufficient stem antetorsion combined with lower abduction angle of the acetabular component were associated with a high risk of dislocation, especially in patients with deep flexion or internal rotation of the flexed hip joint and knees, or in patients with a stiff spine or anterior pelvic tilt, impingement may then occur in the neck of the prosthesis and cup component, ultimately resulting in posterior dislocation. These findings could remind surgeons to avoid simultaneous occurrence of both in THA surgery. These results provide new insight into risk factors for hip dislocation in patients undergoing primary THA for FNF and may aid in reducing the risk of instability and dislocation. LEVEL OF EVIDENCE: Prospective comparative study Level II.

Eight-Year Outcomes of Bilateral Lateral Rectus Recessions versus Unilateral Recession-Resection in Childhood Basic-Type Intermittent Exotropia.

PURPOSE: To report 8-year outcomes from a randomized controlled trial (RCT) comparing bilateral lateral rectus muscle recession (BLRc) with unilateral recession-resection (R&R) for childhood intermittent exotropia (IXT). DESIGN: Eight-year follow-up of RCT cohort. PARTICIPANTS: Of 197 randomized participants, 123 agreed to continue follow-up after the 3-year outcome visit (baseline age, 3-< 11 years; basic-type IXT, 15-40 prism diopters [Δ] by prism and alternate cover test [PACT]; baseline stereoacuity, ≤ 400 arcsec; no prior surgery). METHODS: After the RCT primary outcome at 3 years, annual follow-up from 4 through 8 years with treatment at investigator discretion. MAIN OUTCOME MEASURES: Suboptimal surgical outcome by 8 years after randomization, defined as any of the following at any visit: exotropia of 10 Δ or more by simultaneous prism cover test (SPCT) at distance or near, constant esotropia (ET) of 6 Δ or more by SPCT at distance or near, loss of near stereoacuity by 0.6 log arcsec or more from baseline, or reoperation. Secondary outcomes included (1) reoperation by 8 years and (2) complete or near-complete resolution at 8 years, defined as exodeviation of less than 10 Δ by SPCT and PACT at distance and near and 10 Δ or more reduction from baseline by PACT at distance and near, ET of less than 6 Δ at distance and near, no decrease in stereoacuity by 0.6 log arcsec or more from baseline, and no reoperation or nonsurgical treatment for IXT. RESULTS: The Kaplan-Meier cumulative probability of suboptimal surgical outcome through 8 years was 68% (55 events among 101 at risk) for BLRc and 53% (42 events among 96 at risk) for R&R (difference, 15%; 95% confidence interval [CI], -2% to 32%; P = 0.08). Complete or near-complete resolution at 8 years occurred in 15% (7/46) for BLRc and 37% (16/43) for R&R (difference, -22%; 95% CI, -44% to -0.1%; P = 0.049). The cumulative probability of reoperation was 30% for BLRc and 11% for R&R (difference, 19%; 95% CI, 2%-36%; P = 0.049). CONCLUSIONS: Despite no significant difference for the primary outcome, the 95% CI did not exclude a moderate benefit of R&R, which together with secondary outcomes suggests that unilateral R&R followed by usual care may yield better long-term outcomes than BLRc followed by usual care for basic-type childhood IXT using these surgical doses. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

A Pilot Randomized Clinical Trial of Base-in Relieving Prism Spectacle Treatment of Intermittent Exotropia.

SIGNIFICANCE: This pilot randomized trial, the first to evaluate a specific base-in relieving prism treatment strategy for childhood intermittent exotropia, did not support proceeding to a full-scale clinical trial. Defining and measuring prism adaptation in children with intermittent exotropia are challenging and need further study. PURPOSE: This study aimed to determine whether to proceed to a full-scale trial of relieving base-in prism spectacles versus refractive correction alone for children with intermittent exotropia. METHODS: Children 3 years old to those younger than 13 years with distance intermittent exotropia control score of ≥2 points on the Intermittent Exotropia Office Control Scale (Strabismus 2006;14:147-150; 0 [phoria] to 5 [constant]), ≥1 episode of spontaneous exotropia, and 16 to 35∆ by prism-and-alternate-cover test, who did not fully prism adapt on a 30-minute in-office prism-adaptation test were randomized to base-in relieving prism (40% of the larger of distance and near exodeviations) or nonprism spectacles for 8 weeks. A priori criteria to conduct a full-scale trial were defined for the adjusted treatment group difference in mean distance control: "proceed" (≥0.75 points favoring prism), "uncertain" (>0 to <0.75 points favoring prism), or "do not proceed" (≥0 points favoring nonprism). RESULTS: Fifty-seven children (mean age, 6.6 ± 2.2 years; mean baseline distance control, 3.5 points) received prism (n = 28) or nonprism (n = 29) spectacles. At 8 weeks, mean control values were 3.6 and 3.3 points in prism (n = 25) and nonprism (n = 25) groups, respectively, with an adjusted difference of 0.3 points (95% confidence interval, -0.5 to 1.1 points) favoring nonprism (meeting our a priori "do not proceed" criterion). CONCLUSIONS: Base-in prism spectacles, equal to 40% of the larger of the exodeviations at distance or near, worn for 8 weeks by 3- to 12-year-old children with intermittent exotropia did not yield better distance control than refractive correction alone, with the confidence interval indicating that a favorable effect of 0.75 points or larger is unlikely. There was insufficient evidence to warrant a full-scale randomized trial.

Complications Occurring Through 5 Years Following Primary Intraocular Lens Implantation for Pediatric Cataract.

Importance: Lensectomy with primary intraocular lens (IOL) implantation is often used in the management of nontraumatic pediatric cataract, but long-term data evaluating the association of age and IOL location with the incidence of complications are limited. Objective: To describe the incidence of complications and additional eye surgeries through 5 years following pediatric lensectomy with primary IOL implantation and association with age at surgery and IOL location. Design, Setting, and Participants: This prospective cohort study used Pediatric Eye Disease Investigator Group cataract registry data from 61 institution- and community-based practices over 3 years (June 2012 to July 2015). Participants were children younger than 13 years without baseline glaucoma who had primary IOL implantation (345 bilateral and 264 unilateral) for nontraumatic cataract. Data analysis was performed between September 2021 and January 2023. Exposures: Lensectomy with primary IOL implantation. Main Outcome and Measures: Five-year cumulative incidence of complications by age at surgery (<2 years, 2 to <4 years, 4 to <7 years, and 7 to <13 years) and by IOL location (sulcus vs capsular bag) were estimated using Cox proportional hazards models. Results: The cohort included 609 eyes from 491 children (mean [SD] age, 5.6 [3.3] years; 261 [53%] male and 230 [47%] female). Following cataract extraction with primary IOL implantation, a frequent complication was surgery for visual axis opacification (VAO) (cumulative incidence, 32%; 95% CI, 27%-36%). Cumulative incidence was lower with anterior vitrectomy at the time of IOL placement (12%; 95% CI, 8%-16%) vs without (58%; 95% CI, 50%-65%), and the risk of undergoing surgery for VAO was associated with not performing anterior vitrectomy (hazard ratio [HR], 6.19; 95% CI, 3.70-10.34; P < .001). After adjusting for anterior vitrectomy at lens surgery, there were no differences in incidence of surgery for VAO by age at surgery (<2 years, HR, 1.35 [95% CI, 0.63-2.87], 2 to <4 years, HR, 0.86 [95% CI, 0.44-1.68], 4 to <7 years, HR, 1.06 [95% CI, 0.72-1.56]; P = .74) or by capsular bag vs sulcus IOL fixation (HR, 1.22; 95% CI, 0.36-4.17; P = .75). Cumulative incidence of glaucoma plus glaucoma suspect by 5 years was 7% (95% CI, 4%-9%), which did not differ by age after controlling for IOL location and laterality. Conclusions and Relevance: In this cohort study, a frequent complication following pediatric lensectomy with primary IOL was surgery for VAO, which was associated with primary anterior vitrectomy not being performed but was not associated with age at surgery or IOL location. The risk of glaucoma development across all ages at surgery suggests a need for long-term monitoring.

Improved control of intermittent exotropia with part-time patching.

We evaluated the effect of part-time patching versus observation on distance exodeviation control in post hoc analyses of 3- to <11-year-olds with intermittent exotropia who were assigned to either patching 3 hours/day or observation in a previously reported randomized clinical trial. The present analysis was limited to a subgroup of 306 participants who at distance fixation spontaneously manifested either a constant or intermittent exotropia or had prolonged recovery after monocular occlusion (a distance control score of 2 or worse using the 0-5 Office Control Score scale) at baseline. We assessed change in control at distance and near fixation, from baseline to 3 months and baseline to 6 months (1 month after discontinuing patching). We found greater improvement in the distance control score with patching than with observation at 3 months (mean difference, 0.4 points; 95% CI, 0.1-0.7) and 6 months (mean difference, 0.3 points; 95% CI, 0.02-0.6). These analyses suggest that part-time patching may improve distance control in children with intermittent exotropia and a control score ≥ 2; however, because this conclusion is based on post hoc subgroup analyses, further studies are needed.

EMP1 as a Potential Biomarker in Liver Fibrosis: A Bioinformatics Analysis.

Liver fibrosis is a wound-healing response to chronic injury, which may result in cirrhosis and liver failure. Studies have been carried on the mechanisms and pathogenesis of liver fibrosis. However, the potential cell-specific expressed marker genes involved in fibrotic processes remain unknown. In this study, we combined a publicly accessible single-cell transcriptome of human liver with microarray datasets to evaluate the cell-specific expression patterns of differentially expressed genes in the liver. We noticed that EMP1 (epithelial membrane protein 1) is significantly active not only in CCl4 (carbon tetrachloride)-treated mouse liver fibrosis but also in BDL (bile duct ligation)-induced liver fibrosis and even in human fibrotic liver tissues such as alcoholic hepatitis, NASH (nonalcoholic steatohepatitis), and advanced stage liver fibrosis. Furthermore, we demonstrated that EMP1 is a specific fibrotic gene expressed in HSCs (hepatic stellate cells) and endothelial cells using the Protein Atlas single-cell transcriptome RNA-sequencing clustering. Its expression was significantly elevated in fibrotic HSCs or CCl4 and NASH-induced fibroblasts. Previous research revealed that EMP1 plays a role in proliferation, migration, metastasis, and tumorigeneses in different cancers via a variety of mechanisms. Because HSC activation and proliferation are two important steps following liver injury, it would be interesting to investigate the role of EMP1 in these processes. All of this information suggested that EMP1 could be used as a novel fibrotic liver marker and a possible target in the future.

Incidence of Glaucoma-Related Adverse Events in the First 5 Years After Pediatric Lensectomy.

Importance: Glaucoma can develop following cataract removal in children. Objective: To assess the cumulative incidence of glaucoma-related adverse events (defined as glaucoma or glaucoma suspect) and factors associated with risk of these adverse events in the first 5 years after lensectomy prior to 13 years of age. Design, Setting, and Participants: This cohort study used longitudinal registry data collected at enrollment and annually for 5 years from 45 institutional and 16 community sites. Participants were children aged 12 years or younger with at least 1 office visit after lensectomy from June 2012 to July 2015. Data were analyzed from February through December 2022. Exposures: Usual clinical care after lensectomy. Main Outcomes and Measures: The main outcomes were cumulative incidence of glaucoma-related adverse events and baseline factors associated with risk of these adverse events. Results: The study included 810 children (1049 eyes); 443 eyes of 321 children (55% female; mean [SD] age, 0.89 [1.97] years) were aphakic after lensectomy, and 606 eyes of 489 children (53% male; mean [SD] age, 5.65 [3.32] years) were pseudophakic. The 5-year cumulative incidence of glaucoma-related adverse events was 29% (95% CI, 25%-34%) in 443 eyes with aphakia and 7% (95% CI, 5%-9%) in 606 eyes with pseudophakia; 7% (95% CI, 5%-10%) of aphakic eyes and 3% (95% CI, 2%-5%) of pseudophakic eyes were diagnosed as glaucoma suspect. Among aphakic eyes, a higher risk for glaucoma-related adverse events was associated with 4 of 8 factors, including age less than 3 months (vs ≥3 months: adjusted hazard ratio [aHR], 2.88; 99% CI, 1.57-5.23), abnormal anterior segment (vs normal: aHR, 2.88; 99% CI, 1.56-5.30), intraoperative complications at time of lensectomy (vs none; aHR, 2.25; 99% CI, 1.04-4.87), and bilaterality (vs unilaterality: aHR, 1.88; 99% CI, 1.02-3.48). Neither of the 2 factors evaluated for pseudophakic eyes, laterality and anterior vitrectomy, were associated with risk of glaucoma-related adverse events. Conclusions and Relevance: In this cohort study, glaucoma-related adverse events were common after cataract surgery in children; age less than 3 months at surgery was associated with elevated risk of the adverse events in aphakic eyes. Children with pseudophakia, who were older at surgery, less frequently developed a glaucoma-related adverse event within 5 years of lensectomy. The findings suggest that ongoing monitoring for the development of glaucoma is needed after lensectomy at any age.

Ocular and developmental outcomes of a dosing study of bevacizumab for retinopathy of prematurity.

PURPOSE: To report 2-year ocular and developmental outcomes for infants receiving low doses of intravitreal bevacizumab for type 1 retinopathy of prematurity (ROP). METHODS: A total of 120 premature infants (mean birthweight, 687 g; mean gestational age, 24.8 weeks) with type 1 ROP were enrolled in a multicenter, phase 1 dose de-escalation study. One eye per infant received 0.25 mg, 0.125 mg, 0.063 mg, 0.031 mg, 0.016 mg, 0.008 mg, 0.004 mg, or 0.002 mg of intravitreal bevacizumab; fellow eyes when treated received one dosage level higher. At 2 years, 70 of 120 children (58%) underwent ocular examinations; 51 (43%) were assessed using the Bayley Scale of Infant and Toddler Development. RESULTS: Correlation coefficients for the association of total dosage of bevacizumab with Bayley subscales were -0.20 for cognitive (95% CI, -0.45 to 0.08), -0.15 for motor (95% CI, -0.41 to 0.14), and -0.19 for language (95% CI, -0.44 to 0.10). Fourteen children (21%) had myopia greater than -5.00 D in one or both eyes, 7 (10%) had optic nerve atrophy and/or cupping, 20 (29%) had strabismus, 8 (11%) had manifest nystagmus, and 9 (13%) had amblyopia. CONCLUSIONS: In this study cohort, there was no statistically significant correlation between dosage of bevacizumab and Bayley scores at 2 years. However, the sample size was small and the retention rate relatively low, limiting our conclusions. Rates of high myopia and ocular abnormalities do not differ from those reported after larger bevacizumab doses.

Knockdown of PKMYT1 is associated with autophagy inhibition and apoptosis induction and suppresses tumor progression in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is a cancerous tumor that ranks as the third leading cause of cancer death across the globe. Protein kinase membrane-associated tyrosine/threonine kinase 1 (PKMYT1) is overexpressed in many cancer types, including HCC, but the potential mechanism and biological function of PKMYT1 are not fully understood. MATERIALS AND METHODS: The expression level of PKMYT1 was detected in human HCC tissues and adjacent tissues. We then established HCC cell lines with PKMYT1 knockdown and observed proliferation, migration, autophagy, apoptosis in cell lines and tumor growth in a nude mouse model. To investigate the underlying mechanism by which PKMYT1 regulates autophagy and apoptosis, RNA sequencing was performed in HCC-LM3 cells with and without PKMYT1 knockdown. RESULTS: Here, we observed that human HCC tissues had higher expression of PKMYT1 than adjacent tissues. Overexpression of PKMYT1 was closely associated with poor prognosis in HCC patients. PKMYT1 knockdown inhibited the proliferative potential and migration of HCC cell lines. We also found that downregulation of PKMYT1 inhibited autophagy and induced apoptosis. RNA sequencing analysis showed that the MAPK and PI3K-AKT pathways, which have been reported to affect autophagy and apoptosis, may be regulated after PKMYT1 knockdown by KEGG pathway enrichment analysis. Furthermore, we identified that knockdown of PKMYT1 attenuated the phosphorylation levels of p38 MAPK, ERK and PI3K/Akt/mTOR, which might mediate autophagy inhibition and apoptosis induction via these signaling pathways to inhibit the development of HCC. CONCLUSION: Our study suggests that PKMYT1 functions as an oncogene and may be a new target for HCC treatment.

Impact of hepatectomy and postoperative adjuvant transarterial chemoembolization on serum tumor markers and prognosis in intermediate-stage hepatocellular carcinoma.

BACKGROUND: Primary hepatocellular carcinoma (HCC) is a common malignant tumour, and its early symptoms are often not obvious, resulting in many patients experiencing middle- to late-stage disease at the time of diagnosis. The optimal time for surgery is often missed for these patients, and those who do undergo surgery have unsatisfactory long-term outcomes and a high recurrence rate within five years. Therefore, postoperative follow-up treatments, such as transhepatic arterial chemoembolization (TACE), have become critical to improving survival and reducing recurrence rates. AIM: To validate the prophylactic role of TACE after hepatic resection and to assess its impact on patient prognosis. METHODS: This study investigated the efficacy of TACE in patients with intermediate-stage HCC after hepatectomy. When the post-treatment results of the observation group and the control group were compared, it was found that the inclusion of TACE significantly improved the clinical efficacy, reduced the levels of tumour markers and did not aggravate the damage to liver function. Thus, this may be an effective and comprehensive treatment strategy for patients with intermediate-stage HCC that helps to improve their quality of life and survival time. RESULTS: When the baseline data were analysed, no statistical differences were found between the two groups in terms of gender, age, hepatitis B virus, cirrhosis, Child-Pugh grading, number of tumours, maximum tumour diameter and degree of tumour differentiation. The assessment of clinical efficacy showed that the post-treatment overall remission rate of the observation group was significantly higher than that of the control group. In terms of changes in tumour markers, the alpha-fetoprotein and carcinoembryonic antigen levels in the patients in the observation group decreased more significantly after treatment compared with those in the control group. When post-treatment changes in liver function indicators were analysed, no statistical differences were found in the total bilirubin, alanine aminotransferase and aspartate aminotransferase levels between the two groups. CONCLUSION: In patients with intermediate-stage HCC, post-hepatectomy TACE significantly improved clinical outcomes, reduced tumour-marker levels and may have improved the prognosis by removing residual lesions. Thus, this may be an effective and comprehensive treatment strategy for patients with intermediate-stage HCC.

Relationships among Clinical Factors and Patient-reported Outcome Measures in Adults with Convergence Insufficiency.

SIGNIFICANCE: When exploring relationships among clinical measures and patient-reported outcome measures in adults with convergence insufficiency, worse symptoms (Convergence Insufficiency Symptom Survey [CISS] score) seemed to be correlated with worse reading function domain score (Adult Strabismus-20 quality-of-life questionnaire). After treatment, improved symptoms were associated with improved reading function quality of life. PURPOSE: This study aimed to explore relationships between clinical measures and patient-reported outcome measures in adults undergoing treatment for symptomatic convergence insufficiency. METHODS: In a prospective multicenter observational study, we evaluated adults with symptomatic convergence insufficiency (i.e., clinical measures of near exodeviation, receded near point of convergence, reduced near positive fusional vergence; CISS score ≥21). Fifty-seven participants treated with vision therapy/exercises (n = 35) or base-in prism (n = 22) were analyzed. Spearman correlation coefficients ( R ) were used to assess associations among the three clinical measures and patient-reported outcome measures (CISS, Diplopia Questionnaire, four Adult Strabismus-20 quality-of-life domains) before treatment (baseline) and after 10 weeks and 1 year. Associations were interpreted to be present when the lower limit of the 95% confidence interval (CI) was moderate to strong ( R ≥ 0.4). RESULTS: Among multiple exploratory analyses, the only moderate to strong baseline correlation was between worse CISS and worse Adult Strabismus-20 reading function scores ( R = 0.62; 95% CI, 0.43 to 0.76). Regarding change in measures with treatment, the only moderate to strong correlations were between improved CISS and improved Adult Strabismus-20 reading function scores for prism at 10 weeks ( R = 0.78; 95% CI, 0.52 to 0.91) and 1 year ( R = 0.85; 95% CI, 0.65 to 0.94) and for vision therapy/exercises at 1 year ( R = 0.78; 95% CI, 0.57 to 0.89). CONCLUSIONS: In exploratory analyses, we found positive correlations between CISS symptom scores and reading function quality-of-life scores. The absence of correlations between symptoms and individual clinical measures is consistent with clinical experience that, in convergence insufficiency, symptoms and clinical findings can be discordant.

Low- and Very Low-Dose Bevacizumab for Retinopathy of Prematurity: Reactivations, Additional Treatments, and 12-Month Outcomes.

PURPOSE: Low-dose and very low-dose intravitreal bevacizumab (IVB) have been reported to be successful in short-term treatment of type 1 retinopathy of prematurity (ROP), down to an initial dose of 0.004 mg. We now report 12-month outcomes for these infants. DESIGN: Masked, multicenter, dose de-escalation study. PARTICIPANTS: One hundred twenty prematurely born infants with type 1 ROP. METHODS: A cohort of 120 infants with type 1 ROP in at least 1 eye from 2 sequential dose de-escalation studies of low-dose IVB (0.25 mg, 0.125 mg, 0.063 mg, and 0.031 mg) or very low-dose IVB (0.016 mg, 0.008 mg, 0.004 mg, and 0.002 mg) to the study eye; the fellow eye (if also type 1) received 1 dose level higher of IVB. After primary success or failure at 4 weeks, clinical management was at investigator discretion, including all additional treatment. MAIN OUTCOME MEASURES: Reactivation of severe ROP by 6 months corrected age, additional treatments, retinal and other ocular structural outcomes, and refractive error at 12 months corrected age. RESULTS: Sixty-two of 113 study eyes (55%) and 55 of 98 fellow eyes (56%) received additional treatment. Of the study eyes, 31 (27%) received additional ROP treatment, and 31 (27%) received prophylactic laser therapy for persistent avascular retina. No trend toward a higher risk of additional ROP treatment related to initial IVB doses was found. However, time to reactivation among study eyes was shorter in eyes that received very low-dose IVB (mean, 76.4 days) than in those that received low-dose IVB (mean, 85.7 days). At 12 months, poor retinal outcomes and anterior segment abnormalities both were uncommon (3% and 5%, respectively), optic atrophy was noted in 10%, median refraction was mildly myopic (-0.31 diopter), and strabismus was present in 29% of infants. CONCLUSIONS: Retinal structural outcomes were very good after low- and very low-dose IVB as initial treatment for type 1 ROP, although many eyes received additional treatment. The rate of reactivation of severe ROP was not associated with dose; however, a post hoc data-driven analysis suggested that reactivation was sooner with very low doses.

Apixaban or Warfarin and Aspirin or Placebo After Acute Coronary Syndrome or Percutaneous Coronary Intervention in Patients With Atrial Fibrillation and Prior Stroke: A Post Hoc Analysis From the AUGUSTUS Trial.

Importance: Data are limited regarding the risk of cerebrovascular ischemic events and major bleeding in patients with atrial fibrillation (AF) and recent acute coronary syndrome (ACS) and/or percutaneous coronary intervention (PCI). Objective: Determine the efficacy and safety of apixaban or vitamin K antagonists (VKA) and aspirin or placebo according to prior stroke, transient ischemic attack (TIA), or thromboembolism (TE). Design, Setting, and Participants: In this prospective, multicenter, 2-by-2 factorial, randomized clinical trial, post hoc parallel analyses were performed to compare randomized treatment regimens according to presence or absence of prior stroke/TIA/TE using Cox proportional hazards models. Patients with AF, recent ACS or PCI, and planned use of P2Y12 inhibitors for 6 months or longer were included; 33 patients with missing data about prior stroke/TIA/TE were excluded. Interventions: Apixaban (5 mg or 2.5 mg twice daily) or VKA and aspirin or placebo. Main Outcomes and Measures: Major or clinically relevant nonmajor (CRNM) bleeding. Results: Of 4581 patients included, 633 (13.8%) had prior stroke/TIA/TE. Patients with vs without prior stroke/TIA/TE were older; had higher CHA2DS2-VASC and HAS-BLED scores; and more frequently had prior bleeding, heart failure, diabetes, and prior oral anticoagulant use. Apixaban was associated with lower rates of major or CRNM bleeding and death or hospitalization than VKA in patients with (hazard ratio [HR], 0.69; 95% CI, 0.46-1.03) and without (HR, 0.68; 95% CI, 0.57-0.82) prior stroke/TIA/TE. Patients without prior stroke/TIA/TE receiving aspirin vs placebo had higher rates of bleeding; this difference appeared less substantial among patients with prior stroke/TIA/TE (P = .01 for interaction). Aspirin was associated with numerically lower rates of death or ischemic events than placebo in patients with (HR, 0.71; 95% CI, 0.42-1.20) and without (HR, 0.93; 95% CI, 0.72-1.21) prior stroke/TIA/TE (not statistically significant). Conclusions and Relevance: The safety and efficacy of apixaban compared with VKA was consistent with the AUGUSTUS findings, irrespective of prior stroke/TIA/TE. Aspirin increased major or CRNM bleeding, particularly in patients without prior stroke/TIA/TE. Although aspirin may have some benefit in patients with prior stroke, our findings support the use of apixaban and a P2Y12 inhibitor without aspirin for the majority of patients with AF and ACS and/or PCI, regardless of prior stroke/TIA/TE status. Trial Registration: ClinicalTrials.gov Identifier: NCT02415400.

Plasma Levels of Bevacizumab and Vascular Endothelial Growth Factor After Low-Dose Bevacizumab Treatment for Retinopathy of Prematurity in Infants.

Importance: Intravitreal bevacizumab effectively treats severe retinopathy of prematurity (ROP), but it enters the bloodstream and may reduce serum vascular endothelial growth factor (VEGF), potentially causing detrimental effects on developing organs in the premature infant. Objective: To evaluate the association of intravitreal bevacizumab with plasma bevacizumab and VEGF concentrations at 2 and 4 weeks after predefined, de-escalating doses of intravitreal bevacizumab were administered to infants with severe ROP. Design, Setting, and Participants: This phase 1 dose de-escalation case series study was conducted at 10 US hospitals of ophthalmology institutions from May 21, 2015, to May 7, 2019. Blood samples were collected 2 and 4 weeks after intravitreal bevacizumab injection. Participants included 83 premature infants with type 1 ROP in 1 or both eyes and no previous ROP treatment. Data were analyzed from April 2017 to August 2021. Interventions: Study eyes received a single bevacizumab injection of 0.250 mg, 0.125 mg, 0.063 mg, 0.031 mg, 0.016 mg, 0.008 mg, 0.004 mg, or 0.002 mg. When the fellow eye required treatment, one dose higher was administered. Total dose administered at baseline was defined as the sum of doses given to each eye within 3 days of initial study-eye injection. Main Outcomes and Measures: Plasma bevacizumab concentration at 2 and 4 weeks after injection and the percentage change in plasma VEGF concentrations from pretreatment levels. Results: A total of 83 infants (mean [SD] age, 25 [2] weeks; 48 boys [58%]) were included in this study. Higher doses of bevacizumab administered at baseline were associated with higher plasma bevacizumab concentrations at 2 weeks (ρ, 0.53; 95% CI, 0.31-0.70) and 4 weeks (ρ, 0.44; 95% CI, 0.18-0.64). Plasma VEGF concentrations decreased by 50% or more from pretreatment levels in 40 of 66 infants (61%) at 2 weeks and 31 of 61 infants (51%) at 4 weeks, but no association was observed between the total dose of bevacizumab administered at baseline and percentage change in plasma VEGF concentrations 2 weeks (ρ, -0.04; 95% CI, -0.28 to 0.20) or 4 weeks (ρ, -0.17; 95% CI, -0.41 to 0.08) after injection. Conclusions and Relevance: Results of this phase 1 dose de-escalation case series study revealed that bevacizumab doses as low as 0.002 mg were associated with reduced plasma VEGF levels for most infants at 2 and 4 weeks after intravitreal administration; however, no association was observed between total bevacizumab dose administered and reductions in plasma VEGF levels from preinjection to 2 weeks or 4 weeks. Additional studies are needed to evaluate the long-term effects of low-dose bevacizumab on neurodevelopment and retinal structure.

Rasch-calibrated Intermittent Exotropia Symptom Questionnaire for Children.

SIGNIFICANCE: A rigorously designed and calibrated symptom questionnaire for childhood intermittent exotropia would be useful for clinical care and for research. PURPOSE: The aim of this study was to Rasch-calibrate and evaluate the previously developed Child Intermittent Exotropia Symptom Questionnaire using data gathered as part of a randomized clinical trial. METHODS: The questionnaire was administered to 386 children aged 3 to 10 years with intermittent exotropia who were enrolled in a randomized clinical trial comparing overminus with nonoverminus spectacles. Participants were followed at 6 and 12 months while on treatment and at 18 months off treatment. Factor analysis determined dimensionality, and Rasch analysis evaluated questionnaire performance. Logit values were converted to 0 (best) to 100 (worst). We evaluated differences in questionnaire scores between treatment groups and time points, and correlations with control scores. RESULTS: The Child Intermittent Exotropia Symptom Questionnaire was unidimensional. Rasch analysis indicated that there was no notable local dependence and no significant differential item functioning for sex or age. There was suboptimal targeting (mean logit, -1.62), and person separation was somewhat poor (0.95). There were no significant differences in the Child Intermittent Exotropia Symptom score between overminus spectacles and nonoverminus spectacles at 6, 12, and 18 months. Combining data from both treatment groups, there was significant improvement from baseline at all follow-up visits (e.g., mean change from baseline to 12 months, -6.6 points; 95% confidence interval, -8.6 to -4.6). Child Intermittent Exotropia Symptom scores were not correlated with distance or near control scores at 12 months. CONCLUSIONS: The seven-item Rasch-scored Child Intermittent Exotropia Symptom Questionnaire is limited by suboptimal performance. Future study is needed to determine whether it may be useful for clinical practice and for research.

Parent-provided photographs as an outcome measure for childhood chalazia.

PURPOSE: To determine whether smartphone photographs of children's eyelids are reliable for diagnosing the presence of chalazia. METHODS: In this prospective cross-sectional study, 60 participants, 7 months to 16.5 years of age, at four sites were enrolled; all participants had a chalazion measuring at least 2 mm on at least one eyelid based on an in-person clinical examination by a pediatric eye care professional. Smartphone photographs taken by the parent during the office visit were uploaded to the study website. A masked reader assessed each photograph for the presence or absence of chalazia; results were compared with the gold standard clinical examination results. Sensitivity and specificity for the presence of chalazion by eyelid were calculated. RESULTS: Photographs were available for 240 eyelids; 85 had at least one chalazion and 155 were without a chalazion based on clinical examination. The masked reader correctly classified 68 of 85 eyelids with at least one chalazion and 151 of 155 eyelids without chalazia for a sensitivity of 80% (95% CI, 72%-86%) and a specificity of 97% (95% CI, 94%-99%). Sensitivity improved to 89% for chalazia 5 mm or larger and 94% when superficially located within the eyelid. CONCLUSIONS: Parental smartphone photographs appear to be useful in assessing chalazia in children as an alternative to in-office follow-up examinations. These photographs may be a valuable outcome measure in future clinical trials of chalazia treatment, especially when assessing larger lesions.

Visual Acuity and Ophthalmic Outcomes 5 Years After Cataract Surgery Among Children Younger Than 13 Years.

IMPORTANCE: Cataract is an important cause of visual impairment in children. Data from a large pediatric cataract surgery registry can provide real-world estimates of visual outcomes and the 5-year cumulative incidence of adverse events. OBJECTIVE: To assess visual acuity (VA), incidence of complications and additional eye operations, and refractive error outcomes 5 years after pediatric lensectomy among children younger than 13 years. DESIGN, SETTING, AND PARTICIPANTS: This prospective cohort study used data from the Pediatric Eye Disease Investigator Group clinical research registry. From June 2012 to July 2015, 61 eye care practices in the US, Canada, and the UK enrolled children from birth to less than 13 years of age who had undergone lensectomy for any reason during the preceding 45 days. Data were collected from medical record reviews annually thereafter for 5 years until September 28, 2020. EXPOSURES: Lensectomy with or without implantation of an intraocular lens (IOL). MAIN OUTCOMES AND MEASURES: Best-corrected VA and refractive error were measured from 4 to 6 years after the initial lensectomy. Cox proportional hazards regression was used to assess the 5-year incidence of glaucoma or glaucoma suspect and additional eye operations. Factors were evaluated separately for unilateral and bilateral aphakia and pseudophakia. RESULTS: A total of 994 children (1268 eyes) undergoing bilateral or unilateral lensectomy were included (504 [51%] male; median age, 3.6 years; range, 2 weeks to 12.9 years). Five years after the initial lensectomy, the median VA among 701 eyes with available VA data (55%) was 20/63 (range, 20/40 to 20/100) in 182 of 316 bilateral aphakic eyes (58%), 20/32 (range, 20/25 to 20/50) in 209 of 386 bilateral pseudophakic eyes (54%), 20/200 (range, 20/50 to 20/618) in 124 of 202 unilateral aphakic eyes (61%), and 20/65 (range, 20/32 to 20/230) in 186 of 364 unilateral pseudophakic eyes (51%). The 5-year cumulative incidence of glaucoma or glaucoma suspect was 46% (95% CI, 28%-59%) in participants with bilateral aphakia, 7% (95% CI, 1%-12%) in those with bilateral pseudophakia, 25% (95% CI, 15%-34%) in those with unilateral aphakia, and 17% (95% CI, 5%-28%) in those with unilateral pseudophakia. The most common additional eye surgery was clearing the visual axis, with a 5-year cumulative incidence of 13% (95% CI, 8%-17%) in participants with bilateral aphakia, 33% (95% CI, 26%-39%) in those with bilateral pseudophakia, 11% (95% CI, 6%-15%) in those with unilateral aphakia, and 34% (95% CI, 28%-39%) in those with unilateral pseudophakia. The median 5-year change in spherical equivalent refractive error was -8.38 D (IQR, -11.38 D to -2.75 D) among 89 bilateral aphakic eyes, -1.63 D (IQR, -3.13 D to -0.25 D) among 130 bilateral pseudophakic eyes, -10.75 D (IQR, -20.50 D to -4.50 D) among 43 unilateral aphakic eyes, and -1.94 D (IQR, -3.25 D to -0.69 D) among 112 unilateral pseudophakic eyes. CONCLUSIONS AND RELEVANCE: In this cohort study, development of glaucoma or glaucoma suspect was common in children 5 years after lensectomy. Myopic shift was modest during the 5 years after placement of an intraocular lens, which should be factored into implant power selection. These results support frequent monitoring after pediatric cataract surgery to detect glaucoma, visual axis obscuration causing reduced vision, and refractive error.

Effects of urolithin A on osteoclast differentiation induced by receptor activator of nuclear factor-κB ligand via bone morphogenic protein 2.

Urolithin A (UA) is an intestinal microbial metabolite derived from ellagitannins and a promising agent for treating osteoarthritis. However, its effects on osteoporosis are unclear. This study explored the effects of urolithin A (UA) on receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclasts and its underlying molecular mechanisms. RANKL treatment significantly increased tartrate-resistant acid phosphatase (TRACP) or osteoclast marker levels (P < 0.05), while adding UA decreased the RANKL-induced levels (P < 0.05) in RAW264.7 cells. Total RNA isolated from RANKL- or RANKL + UA-treated cells was sequenced, and the obtained transcriptome dataset revealed 2,399 differentially expressed genes. They were enriched in multiple pathways involved in rheumatoid arthritis, ERK1 and ERK2 cascade, regulation of inflammatory response, ECM-receptor interactions, and TNF signaling. Scanning electron microscopy showed that RANKL promoted bone resorption pits in bone biopsy specimens, whereas UA inhibited their formation. When bone morphogenic protein 2 (BMP2) was shRNA-silenced, the bone resorption pits were restored. Moreover, while RANKL significantly enhanced the levels of p-ERK2/ERK2, p-p38/p38, p-Akt1/Akt1, p-ERK1/ERK1, and osteoclast-related proteins (P < 0.05), UA reduced them. BMP2 silencing also reversed the UA inhibitory effect. Thus, UA represses the RANKL-induced osteoclast differentiation of RAW264.7 cells by regulating Akt1, p38, and ERK1/2 signaling, and BMP2 likely reverses the UA inhibitory effect via these pathways. We propose BMP2 as a potential drug target for treating bone metabolic diseases, such as osteoporosis.