PURPOSE Although several agents targeting epidermal growth factor receptor ( EGFR) exon 20 insertions (ex20ins) have recently been approved by the US Food and Drug Administration, toxicities related to the inhibition of wild-type (WT) EGFR are common with these agents and affect overall tolerability. Zipalertinib (CLN-081, TAS6417) is an oral EGFR tyrosine kinase inhibitor (TKI) with a novel pyrrolopyrimidine scaffold leading to enhanced selectivity for EGFR ex20ins-mutant versus WT EGFR with potent inhibition of cell growth in EGFR ex20ins-positive cell lines. METHODS This phase 1/2a study of zipalertinib enrolled patients with recurrent or metastatic EGFR ex20ins-mutant non–small-cell lung cancer (NSCLC) previously treated with platinum-based chemotherapy. RESULTS Seventy-three patients were treated with zipalertinib at dose levels including 30, 45, 65, 100, and 150 mg orally twice a day. Patients were predominantly female (56%), had a median age of 64 years, and were heavily pretreated (median previous systemic therapies 2, range 1-9). Thirty six percent of patients had received previous non-ex20ins EGFR TKIs and 3/73 (4.1%) patients received previous EGFR ex20ins TKIs. The most frequently reported treatment-related adverse events of any grade included rash (80%), paronychia (32%), diarrhea (30%), and fatigue (21%). No cases of grade 3 or higher drug-related rash or diarrhea were observed at 100 mg twice a day or below. Objective responses occurred across all zipalertinib dose levels tested, with confirmed partial response (PR) observed in 28/73 (38.4%) response-evaluable patients. Confirmed PRs were seen in 16/39 (41%) response-evaluable patients at the dose of 100 mg twice a day. CONCLUSION Zipalertinib has encouraging preliminary antitumor activity in heavily pretreated patients with EGFR ex20ins-mutant NSCLC, with an acceptable safety profile, including low frequency of high-grade diarrhea and rash.
AIM:To evaluate the effectiveness of atropine 0.01% in young premyopic and low-myopic children. METHODS:Children (5-9 years old) with premyopia (spherical equivalent refraction, SER+1.00 to -0.49D, n 156) or low myopia (SER -0.50 to -1.50D, n 52), with at least 1 parent with myopia <-3.00D, were randomised to receive placebo or atropine 0.01% eye-drops in a 1:1 ratio. Cycloplegic autorefraction and axial length were measured every 6 months over 2 years. RESULTS:Mean baseline SER was +0.5+/-0.04D in premyopia and -1.00±0.06D in the low-myopia eyes. Progression over 2 years in premyopic eyes was -0.96±0.10D vs -0.82±0.10D (p=0.328), or 0.72±0.03 mm vs 0.63±0.04 mm (p=0.161) in the placebo and atropine groups, respectively. Progression in eyes remaining emmetropic was -0.43±0.37D vs -0.29±0.37D (p=0.007) or 0.49±0.22 mm vs 0.41±0.38 mm (p=0.209) in the placebo versus atropine-treated eyes, respectively; while eyes which became myopic progressed by -1.78±0.82D vs -1.63±0.82D (p=0.121) or 1.08±0.34 mm vs 0.96±0.14 mm (p=0.010). Incident myopia at 2 years was 42.6% in placebo and 44.8% in atropine 0.01% treated eyes (p=0.896). In the low-myopia group, placebo versus atropine treated eyes progressed by -1.65±0.15D vs -1.23±0.15D (p=0.066) or 0.86±0.07 mm vs 0.68±0.05 mm (p=0.062) at 2 years. There was no difference in near acuity, glare (2.7%) or allergy (6.0%) between treatment groups. CONCLUSIONS:Although there were no significant differences in myopia progression between atropine and placebo treated eyes, there were trends towards less myopic shift in atropine-treated eyes in premyopic eyes which remained emmetropic and in eyes with low myopia.
Rod photoreceptors are essential for vision under dim light conditions and are highly vulnerable in retinal degenerative diseases. Here, we demonstrate that both human and rodent rods undergo a minute and rapid contraction of their outer segments upon photoisomerization, the first step of phototransduction. The contraction is explained as an electromechanical manifestation of the rod early receptor potential generated in the disk membranes, which is challenging to access in electrophysiology. The in vivo optical imaging of light-evoked electrical activity in rodent rods was facilitated by an ultrahigh-resolution point-scan optical coherence tomography (OCT) system, combined with an unsupervised learning approach to separate the light-evoked response of the rod outer segment tips from the retinal pigment epithelium-Bruch's membrane complex. In humans, an adaptive optics line-scan OCT facilitated high-speed recordings in rods. The non-invasive in vivo optical imaging of rhodopsin activation extends the diagnostic capability of optoretinography, and may facilitate personalized, objective assessment of rod dysfunction and visual cycle impairment in inherited and age-related macular degeneration.
PURPOSE:To investigate regional differences in the epidemiology and treatment of retinopathy of prematurity (ROP) from 2016 to 2023. STUDY DESIGN:Retrospective multicenter cohort study METHODS: Premature infants screened for ROP at a single tertiary referral center in each of five countries/regions (Taiwan, Hong Kong, Singapore, India, and Portugal) during the study period. Demographic characteristics, incidences of ROP and type 1 ROP, and treatment modalities were analyzed. Screening criteria followed local protocols. Logistic regression was used to assess trends, and intergroup comparisons were performed using Kruskal-Wallis and chi-square tests. RESULTS:A total of 15,031 premature infants were enrolled. Demographics varied significantly (p <0.001); India had the highest gestational age and birth weight, and the lowest proportion of very low birth weight and extremely low birth weight infants with type 1 ROP (p <0.001). Hong Kong had the lowest ROP incidence, while Singapore showed a significant increase over time (p = 0.003). Type 1 ROP rates were higher in Taiwan and India than in Hong Kong and Singapore, with a significant decline observed only in Taiwan (p = 0.005). Anti-Vascular Endothelial Growth Factor (Anti-VEGF) injections were increasingly preferred as initial treatment, with bevacizumab being the most frequently used (87.3%). CONCLUSION:From 2016 to 2023, ROP incidence and treatment showed significant regional differences. ROP increased in Singapore, while type 1 ROP decreased significantly in Taiwan. Although anti-VEGF therapy has become more common, laser treatment remains dominant in Hong Kong.
Healthier lifestyles are consistently associated with better healthy ageing, yet whether these benefits are comparable across countries and to what extent they depend on broader social and environmental contexts remains poorly understood. We harmonised data from six representative ageing cohorts spanning 32 countries. Cross-sectional analyses included 155,644 adults aged ≥50 years, and longitudinal analyses were conducted in 76,366 participants from five cohorts. A Healthy Lifestyle Score was constructed based on smoking status, alcohol consumption, physical activity and body mass index (BMI), and its association with the ATHLOS Healthy Ageing Index was examined. Using survey-weighted, within-country models, we estimated standardised predictive margins across lifestyle levels and quantified cross-national heterogeneity. Effect modification by country-level social determinants of health (SDOH) was assessed using random-effects meta-analysis and meta-regression. Across nearly all countries, healthier lifestyles were associated with higher health-ageing scores. However, the magnitude of these associations varied markedly. The difference in the Healthy Ageing Index between the healthiest and least healthy lifestyle levels ranged from 1.80 (95% CI: 1.40–2.19) in India to 8.12 (95% CI: 5.84–10.41) in Austria. Greater economic development, higher healthcare access and quality, stronger climate-adaptation capacity and broader urban infrastructure coverage were associated with larger lifestyle-related gains in healthy ageing. In contrast, income inequality, greater exposure to extreme climate events and a higher reliance on out-of-pocket health expenditure were linked to attenuated gains. Longitudinal joint modelling yielded consistent cumulative patterns over time. Together, these findings indicate that the health benefits of healthy lifestyles are not universally transferable and depend critically on social and environmental contexts, underscoring the need to integrate individual-level lifestyle interventions with structural policies to promote equitable healthy ageing.
