Comprehensive stratum corneum ceramide profiling reveals reduced acylceramides in ichthyosis patient with CERS3 mutations

The stratum corneum (SC) of the epidermis acts as a skin permeability barrier, and abnormalities in SC formation lead to several skin disorders. Lipids, especially the epidermis-specific ceramide classes omega-O-acylceramides (acylceramides) and protein-bound ceramides, are essential for skin barrier formation. Ceramide synthase 3 (CERS3) is involved in the synthesis of acylceramides and protein-bound ceramides, and CERS3 mutations cause autosomal recessive congenital ichthyosis. In the present study, we measured ceramide synthase activity and performed comprehensive SC ceramide profiling in an ichthyosis patient with compound heterozygous CERS3 mutations: nonsense mutation p.Arg75* and missense mutation p.Arg229His. The activity of p.Arg75* and p.Arg229His mutant CERS3 proteins was reduced to 4% and 56%, respectively, of the wild-type protein. In the patient's SC, acylceramide levels were greatly reduced, but the levels of protein-bound ceramides remained almost unchanged. Non-acylated ceramide levels were also affected in the patient; in particular, the levels of ceramides composed of sphingosine and non-hydroxy or alpha-hydroxy fatty acid were substantially higher than in healthy controls. These results suggest that a reduction in acylceramide levels alone leads to ichthyosis. Although protein-bound ceramides are synthesized from acylceramides, levels of acylceramides and protein-bound ceramides are not necessarily correlated

Association of early bedtime at 3 years of age with higher academic performance and better non-cognitive skills in elementary school

Abstract This study investigated the relationship between sleep habits in early childhood and academic performance and non-cognitive skills in the first grade. We retrospectively analyzed a longitudinal population-based cohort from birth through early childhood, up to elementary school, in Amagasaki City, Japan. The primary outcome was academic performance in the first grade. Other outcomes were self-reported non-cognitive skills. Overall, 4395 children were enrolled. Mean national language scores for children with bedtimes at 18:00–20:00, 21:00, 22:00, and ≥ 23:00 were 71.2 ± 19.7, 69.3 ± 19.4, 68.3 ± 20.1, and 62.5 ± 21.3, respectively. Multiple regression analysis identified bedtime at 3 years as a significant factor associated with academic performance. However, sleep duration was not significantly associated with academic performance. Bedtime at 3 years also affected non-cognitive skills in the first grade. Diligence decreased with a later bedtime (21:00 vs. 18:00–20:00; odds ratio [OR]: 1.98, 95% confidence interval [CI] 1.27–3.09; 22:00 vs. 18:00–20:00; OR: 2.15, 95% CI 1.37–3.38; ≥ 23:00 vs. 18:00–20:00; OR: 2.33, 95% CI 1.29–4.20). Thus, early bedtime at 3 years may be associated with a higher academic performance and better non-cognitive skills in the first grade. Optimum early-childhood sleep habits may positively impact academic future

Change in Viral Load during Antiviral Therapy Is Not Useful for the Prediction of Hearing Dysfunction in Symptomatic Congenital Cytomegalovirus Infection

For symptomatic congenital cytomegalovirus infections (CCMVI), the usefulness of changes in viral load during valganciclovir (VGCV) treatment for the prediction of hearing dysfunction (HD) is unclear. To determine the utility of viral load change in the whole blood or urine for the prediction of HD, we performed a retrospective study to compare viral load changes during VGCV treatment between CCMVI infants with (n = 12) or without (n = 8) HD at six months of corrected age, whose blood and urine viral loads were measured continuously for eight weeks from April 2009 to December 2019. There was no significant difference in the changes in both the blood and urine viral loads after the initiation of VGCV treatment between CCMVI infants between the groups. Moreover, this negative result was maintained in the analysis for each six weeks or six months treatment period. In conclusion, the change in viral load during antiviral therapy is not useful for the prediction of HD at six months of corrected age in symptomatic CCMVI

Association of perinatal factors with neurodevelopmental referrals in a population-based cohort study in Japan

Abstract Although the causes of neurodevelopmental disorders remain unknown, several environmental risk factors have attracted considerable attention. We conducted a retrospective, longitudinal, population-based cohort study using data from infant health examinations of children born to mothers with pregnancies between April 1, 2014 and March 31, 2016 in Kobe City to identify the perinatal factors associated with neurodevelopmental referrals in 3-year-old children. There were 15,223 and 1283 children in the normal and referral groups, respectively. Neurodevelopmental referrals at the health checkup for 3-year-old children were significantly associated with the lack of social support during pregnancy (adjusted odds ratio [aOR] 1.99, 99% CI 1.14–3.45, p = 0.001), history of psychiatric consultation (aOR 1.56, 99% CI 1.10–2.22, p = 0.001), no social assistance post-delivery (aOR 1.49, 99% CI 1.03–2.16, p = 0.006), Edinburgh Post-natal Depression Scale (EPDS) score ≥ 9 (aOR 1.36, 99% CI 1.01–1.84, p = 0.008), infant gender (male) (aOR 2.51, 99% CI 2.05–3.06, p < 0.001), and cesarean delivery (aOR 1.39, 99% CI 1.11–1.75, p < 0.001). In conclusion, this exploratory study in the general Japanese population identified six perinatal factors associated with neurodevelopmental referrals in 3-year-old children: infant gender (male), cesarean section, maternal history of psychiatric consultation, EPDS score ≥ 9, lack of social support during pregnancy, and no social assistance post-delivery

Neurodevelopmental Outcomes at 18 Months of Corrected Age for Late Preterm Infants Born at 34 and 35 Gestational Weeks

To date, the difference in neurodevelopmental outcomes between late preterm infants (LPI) born at 34 and 35 gestational weeks (LPI-34 and LPI-35, respectively) has not been elucidated. This retrospective study aimed to evaluate neurodevelopmental outcomes at 18 months of corrected age for LPI-34 and LPI-35, and to elucidate factors predicting neurodevelopmental impairment (NDI). Records of all LPI-34 (n = 93) and LPI-35 (n = 121) admitted to our facility from 2013 to 2017 were reviewed. Patients with congenital or chromosomal anomalies, severe neonatal asphyxia, and without developmental quotient (DQ) data were excluded. Psychomotor development was assessed as a DQ using the Kyoto Scale of Psychological Development at 18 months of corrected age. NDI was defined as DQ &lt; 80 or when severe neurodevelopmental problems made neurodevelopmental assessment impossible. We compared the clinical characteristics and DQ values between LPI-34 (n = 62) and LPI-35 (n = 73). To elucidate the factors predicting NDI at 18 months of corrected age, we compared clinical factors between the NDI (n = 17) and non-NDI (n = 118) groups. No significant difference was observed in DQ values at 18 months of corrected age between the groups in each area and overall. Among clinical factors, male sex, intraventricular hemorrhage (IVH), hyperbilirubinemia, and severe hyperbilirubinemia had a higher prevalence in the NDI group than in the non-NDI group, and IVH and/or severe hyperbilirubinemia showed the highest Youden Index values for predicting NDI. Based on the results of this study, we can conclude that no significant difference in neurodevelopmental outcomes at 18 months of corrected age was observed between LPI-34 and LPI-35. Patients with severe hyperbilirubinemia and/or IVH should be considered to be at high risk for developing NDI

Online three-dimensional OFDI-guided versus angiographyguided PCI in bifurcation lesions: Design and rationale of the randomised OPTIMUM trial

Aims: The feasibility of offline optical coherence tomography (OCT) guidance in bifurcation (with either two-dimensional or three-dimensional images) and its potential benefits have been demonstrated in retrospective studies; however, these have not yet been investigated prospectively. The aim of this trial is to determine the superiority of online three-dimensional optical frequency domain imaging (3D-OFDI)- guided stenting to angiography-guided percutaneous coronary intervention (PCI) in terms of incomplete stent apposition (ISA) at the bifurcation segment. Methods and results: The OPTIMUM trial is a randomised, superiority, multicentre clinical trial. The primary endpoint of this trial is the post-procedural percentage of malapposed struts assessed by OFDI in the main branch bifurcation region after final kissing balloon dilatation (FKBD). A total of 106 patients will be randomly allocated to either 3D-OFDI guidance or angiography guidance PCI. Bifurcation lesions will be treated with a provisional single-stent strategy using the Ultimaster sirolimus-eluting stent. Patients randomised to the 3D-OFDI guidance arm will undergo OFDI assessment in the main branch (MV) after rewiring into the jailed side branch following stent implantation, while in the angiography guidance arm re-crossing of a wire into the side branch will be performed using conventional fluoroscopic/angiographic guidance. In patients in the 3D-OFDI guidance arm, if the position of the wire is not located in the optimal cell, further attempts to redirect the wire to the optimal cell will be performed, with subsequent OFDI acquisitions to confirm the re-crossing position. The proximal optimisation technique and FKBD are mandatory in this trial. The study will provide a 90% power to show superiority of 3D-OFDI guidance PCI compared with angiography-guided PCI. Conclusions: The OPTIMUM trial will be the first prospective, randomised trial to evaluate the efficacy and safety of online 3D-OFDI-guided PCI in bifurcation lesions. ClinicalTrials.gov Identifier: NCT02972489

A Randomized Trial Evaluating Online 3-Dimensional Optical Frequency Domain Imaging-Guided Percutaneous Coronary Intervention in Bifurcation Lesions

Background: Clinical implications of online 3-dimensional optical frequency domain imaging (3D-OFDI)-guided stenting for bifurcation lesions have not been investigated in the randomized controlled trials. The purpose of this study was to determine whether online 3D-OFDI-guided stenting is superior to angiography-guided percutaneous coronary intervention (PCI) in terms of incomplete stent apposition at the bifurcation segment. Methods: The OPTIMUM trial (Online 3-Dimensional Optical Frequency Domain Imaging to Optimize Bifurcation Stenting Using UltiMaster Stent) was a randomized, multicenter clinical trial. Eligible patients had an angiographically significant stenosis in the bifurcation lesion treated with a provisional single stent strategy using the Ultimaster sirolimus eluting stent. Patients were randomly allocated to either online 3D-OFDI-guided or angiography-guided PCI. Patients randomized to 3D-OFDI guidance underwent online 3D-OFDI assessment after rewiring into the jailed side branch after stenting and proximal optimization technique, while in the angiography guidance arm, rewiring was performed using conventional fluoroscopic/angiographic guidance. The primary end point of this trial was the postprocedural average percentage of malapposed struts per lesion assessed by OFDI in the confluence zone of the main and side branches. Results: Between June 8, 2017 and September 26, 2018, 110 patients with 111 bifurcation lesions were randomized at 4 Japanese centers. Of these, 56 patients with 57 lesions were treated with 3D-OFDI-guided PCI, whereas 54 patients with 54 lesions were treated with angiography-guided PCI. In the 3D-OFDI guidance arm, the feasibility of online 3D-OFDI was 98.2%. The average percentage of incomplete stent apposition per lesion at bifurcation was lower in the 3D-OFDI guidance arm than that in the angiography guidance arm (19.5±15.8% versus 27.5±14.2%, P=0.008). The superiority of the 3D-OFDI guidance arm was also confirmed in the strut level analysis (odds ratio: 0.54 [95% CI, 0.36-0.81]; P=0.003). Conclusions: Online 3D-OFDI-guided bifurcation PCI was superior to angiography-guided bifurcation PCI in terms of acute incomplete stent apposition at bifurcation. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02972489

Online three-dimensional OFDI-guided versus angiography-guided PCI in bifurcation lesions: design and rationale of the randomised OPTIMUM trial

AIMS: The feasibility of offline optical coherence tomography (OCT) guidance in bifurcation (with either two-dimensional or three-dimensional images) and its potential benefits have been demonstrated in retrospective studies; however, these have not yet been investigated prospectively. The aim of this trial is to determine the superiority of online three-dimensional optical frequency domain imaging (3D-OFDI)-guided stenting to angiography-guided percutaneous coronary intervention (PCI) in terms of incomplete stent apposition (ISA) at the bifurcation segment. METHODS AND RESULTS: The OPTIMUM trial is a randomised, superiority, multicentre clinical trial. The primary endpoint of this trial is the post-procedural percentage of malapposed struts assessed by OFDI in the main branch bifurcation region after final kissing balloon dilatation (FKBD). A total of 106 patients will be randomly allocated to either 3D-OFDI guidance or angiography guidance PCI. Bifurcation lesions will be treated with a provisional single-stent strategy using the Ultimaster sirolimus-eluting stent. Patients randomised to the 3D-OFDI guidance arm will undergo OFDI assessment in the main branch (MV) after rewiring into the jailed side branch following stent implantation, while in the angiography guidance arm re-crossing of a wire into the side branch will be performed using conventional fluoroscopic/angiographic guidance. In patients in the 3D-OFDI guidance arm, if the position of the wire is not located in the optimal cell, further attempts to redirect the wire to the optimal cell will be performed, with subsequent OFDI acquisitions to confirm the re-crossing position. The proximal optimisation technique and FKBD are mandatory in this trial. The study will provide a 90% power to show superiority of 3D-OFDI guidance PCI compared with angiography-guided PCI. CONCLUSIONS: The OPTIMUM trial will be the first prospective, randomised trial to evaluate the efficacy and safety of online 3D-OFDI-guided PCI in bifurcation lesions. ClinicalTrials.gov Identifier: NCT02972489