Genome Analysis in Sick Neonates and Infants: High-yield Phenotypes and Contribution of Small Copy Number Variations.

OBJECTIVE: To delineate the diagnostic efficacy of medical exome, whole exome, and whole genome sequencing according to primary symptoms, the contribution of small copy number variations, and the impact of molecular diagnosis on clinical management. STUDY DESIGN: This was a prospective study of 17 tertiary care centers in Japan, conducted between April 2019 and March 2021. Critically ill neonates and infants less than 6 months of age were recruited in neonatal intensive care units and in outpatient clinics. The patients underwent medical exome, whole exome, or whole genome sequencing as the first tier of testing. Patients with negative results after medical exome or whole exome sequencing subsequently underwent whole genome sequencing. The impact of molecular diagnosis on clinical management was evaluated through contacting primary care physicians. RESULTS: Of the 85 patients, 41 (48%) had positive results. Based on the primary symptoms, patients with metabolic phenotypes had the highest diagnostic yield (67%, 4/6 patients), followed by renal (60%, 3/5 patients), and neurologic phenotypes (58%, 14/24 patients). Among them, 4 patients had pathogenic small copy number variations identified using whole genome sequencing. In the 41 patients with a molecular diagnosis, 20 (49%) had changes in clinical management. CONCLUSIONS: Genome analysis for critically ill neonates and infants had a high diagnostic yield for metabolic, renal, and neurologic phenotypes. Small copy number variations detected using whole genome sequencing contributed to the overall molecular diagnosis in 5% of all the patients. The resulting molecular diagnoses had a significant impact on clinical management.

The 24-hour intraocular pressure control by tafluprost/timolol fixed combination after switching from the concomitant use of tafluprost and timolol gel-forming solution, in patients with primary open-angle glaucoma.

OBJECTIVE: The aim of this study was to evaluate the 24-hour intraocular pressure (IOP)-control effect of the tafluprost/timolol fixed combination (TAF/TIM-FC) in patients with primary open-angle glaucoma after they switched from the concomitant use of tafluprost and timolol gel-forming solution. PATIENTS AND METHODS: Twenty patients with primary open-angle glaucoma (12 male and 8 female; mean ± SD age, 57.0±7.1 years) were included in this study. The patients were treated for 8 weeks with the concomitant administration of tafluprost and timolol gel-forming solution (evening dosing). At the end of this period, the patients underwent 24-hour IOP monitoring (measured at 21:00, 01:00, 05:00, 09:00, 13:00 and 17:00). IOP was measured with Goldmann applanation tonometer (GAT) and Icare PRO at sitting position at all timepoints and additionally, at supine position with Icare PRO tonometer at 01:00 and 05:00. The patients were then all switched to TAF/TIM-FC treatment (evening dosing). After 8 weeks, the 24-hour IOP monitoring was repeated. RESULTS: Nineteen patients completed the study. The mean 24-hour IOPs in the concomitant and TAF/TIM-FC phases were 13.8±2.7 vs 13.3±2.8 mmHg (P=0.0033) with the GAT in the sitting position and 13.96±2.56 vs 13.48±2.56 mmHg (P=0.0120) with the Icare PRO in habitual positions. In comparison with the concomitant phase, significantly lower IOP was observed for the TAF/TIM-FC phase at 21:00 and 01:00 with the GAT and at 01:00 with the Icare PRO. In addition, the maximum IOP and fluctuations in IOP in habitual positions were lower for the TAF/TIM-FC phase than for the concomitant phase. CONCLUSION: TAF/TIM-FC showed a stable 24-hour IOP-lowering effect and was equally or more effective than the concomitant use of tafluprost and timolol gel, both when sitting and when in habitual positions.