Long-term efficacy and safety of brolucizumab in neovascular age-related macular degeneration: A multicentre retrospective real-world study.

PURPOSE: To investigate the long-term efficacy and safety of intravitreal brolucizumab (BRZ) injections in patients with typical neovascular age-related macular degeneration (typical nAMD) and polypoidal choroidal vasculopathy (PCV). METHODS: This multicentre retrospective study included 401 eyes of 398 patients with nAMD who received BRZ injection(s), with a follow-up duration of ≥12 months. Changes in best-corrected visual acuity (BCVA), retinal fluid evaluation and central subfield thickness (CST) on optical coherence tomography were assessed. The efficacy of BRZ was compared between typical nAMD and PCV groups. RESULTS: Analyses were conducted with 280 eyes of 278 patients with typical nAMD and 121 eyes of 120 patients with PCV (mean age, 71.1 ± 8.6 years). 29 eyes (7.2%) were treatment naïve. The mean follow-up period was 15.3 ± 2.8 months; the mean number of BRZ injections within 1 year was 4.5 ± 1.7. BCVA was maintained during the follow-up period, and CST significantly improved from the first injection month and was maintained for 12 months in both the typical nAMD and PCV groups. The dry macula proportion increased from 2.7% at baseline to 56.1% at 1 month and 42.9% at 12 months. Among the 18 eyes that underwent indocyanine green angiography both before and after treatment, 10 (55.6%) showed polyp regression. Overall, the incidence of intraocular inflammation (IOI), retinal vasculitis and occlusive retinal vasculitis was 9.4% (38 eyes), 1.2% (5 eyes) and 0.5% (2 eyes), respectively. IOI occurred from the first to the sixth injections, with an average IOI onset of 28.5 ± 1.4 days. All eyes achieved IOI resolution, although the two eyes with occlusive retinal vasculitis showed a severe visual decline after IOI resolution. CONCLUSION: Brolucizumab was effective in maintaining BCVA and managing fluid in eyes with nAMD for up to 1 year, exhibiting a high polyp regression rate. However, the not uncommon incidence of IOI and the severe visual decline caused by the rare occlusive retinal vasculitis following BRZ treatment underscore the importance of careful monitoring and timely management.

Nationwide incidence of congenital and infantile cataract requiring surgery in Korea.

Congenital and infantile (CI) cataract is one of the most important and preventable cause of blindness in children, but the incidence has not been studied in Korea. We collected data from the national claims database of the National Health Insurance Service of Korea from 2002 through 2019. We identified children who underwent cataract surgery within the age of 5 years, and cumulative incidence rates were calculated for each of the three age criteria. 989 patients out of 4,221,459 births underwent surgery with CI cataract during the period. The cumulative incidence rates per 10,000 births were 1.60 (0-1 years), 2.38 (0-3 years), and 2.95 (0-5 years), respectively. The incidence peaked in the 2007 birth cohort, which coincides with the start of the national screening program for infants/children. Primary intraocular lens implantation was performed in 439 patients (44%). Strabismus and glaucoma requiring surgery occurred in 291 patients (29.4%) and 32 patients (3.2%), respectively, within 8 years after cataract surgery. The incidence rates of CI cataract in Korea appear to be comparable to previous studies in other regions. The early screening program for infants may reduce delayed diagnosis and increase the proportion of patients undergoing surgery at a critical time for visual development.

Sound-to-Touch Crossmodal Pitch Matching for Short Sounds.

This article explores how to relate sound and touch in terms of their spectral characteristics based on crossmodal congruence. The context is the audio-to-tactile conversion of short sounds frequently used for user experience improvement across various applications. For each short sound, a single-frequency amplitude-modulated vibration is synthesized so that their intensive and temporal characteristics are very similar. It leaves the vibration frequency, which determines the tactile pitch, as the only variable. Each sound is paired with many vibrations of different frequencies. The congruence between sound and vibration is evaluated for 175 pairs (25 sounds × 7 vibration frequencies). This dataset is employed to estimate a functional relationship from the sound loudness spectrum of sound to the most harmonious vibration frequency. Finally, this sound-to-touch crossmodal pitch mapping function is evaluated using cross-validation. To our knowledge, this is the first attempt to find general rules for spectral matching between sound and touch.

Genotypic Profile and Clinical Characteristics of CRX-Associated Retinopathy in Koreans.

This study aimed to investigate the clinical characteristics of Korean patients with retinal dystrophy associated with pathogenic variants of cone rod homeobox-containing gene (CRX). We retrospectively enrolled Korean patients with CRX-associated retinal dystrophy (CRX-RD) who visited two tertiary referral hospitals. Pathogenic variants were identified using targeted panel sequencing or whole-exome sequencing. We analyzed clinical features and phenotypic spectra according to genotype. Eleven patients with CRX-RD were included in this study. Six patients with cone-rod dystrophy (CORD), two with macular dystrophy (MD), two with Leber congenital amaurosis (LCA), and one with retinitis pigmentosa (RP) were included. One patient (9.1%) had autosomal recessive inheritance, and the other ten patients (90.9%) had autosomal dominant inheritance. Six patients (54.5%) were male, and the mean age of symptom onset was 27.0 ± 17.9 years. At the first presentation, the mean age was 39.4 ± 20.6 years, and best-corrected visual acuity (BCVA) (logMAR) was 0.76 ± 0.90 in the better eye. Negative electroretinography (ERG) was observed in seven (63.6%) patients. Nine pathogenic variants were identified, including two novel variants, c.101-1G>A and c.898T>C:p.(*300Glnext*118). Taken together with the variants reported in prior studies, all variants within the homeodomain are missense variants, whereas most variants downstream of the homeodomain are truncating variants (88%). The clinical features of pathogenic variants within the homeodomain are either CORD or MD with bull's eye maculopathy, whereas variants downstream of the homeodomain cause more diverse phenotypes, with CORD and MD in 36%, LCA in 40%, and RP in 24%. This is the first case series in Korea to investigate the CRX-RD genotype-phenotype correlation. Pathogenic variants downstream of the homeodomain of the CRX gene are present as RP, LCA, and CORD, whereas pathogenic variants within the homeodomain are mainly present as CORD or MD with bull's eye maculopathy. This trend was similar to previous genotype-phenotype analyses of CRX-RD. Further molecular biologic research on this correlation is required.

THREE-DIMENSIONAL HEADS-UP VITRECTOMY VERSUS CONVENTIONAL MICROSCOPIC VITRECTOMY FOR PATIENTS WITH EPIRETINAL MEMBRANE.

PURPOSE: To investigate the efficacy and safety of 3D heads-up display (3D-HUD) vitrectomy compared with conventional microscopy (CM) vitrectomy in epiretinal membrane (ERM) surgery. METHODS: Epiretinal membrane removal with or without internal limiting membrane (ILM) peeling was performed using a 3D-HUD or CM system. The mean changes in best-corrected visual acuity (BCVA) and in central macular thickness (CMT) and postoperative complications were assessed. RESULTS: Baseline demographics were comparable except for the follow-up period. Both BCVA and CMT improved at the final visit (all P < 0.05). The ERM recurrence and dissociated optic nerve fiber layer (DONFL) rates were lower in the 3D group (both P < 0.05). conventional microscopic vitrectomy (odds ratio [OR] = 12.86, P = 0.02) and absence of ILM peeling (OR = 45.25, P < 0.05) were associated with ERM recurrence. In the DONFL, CM vitrectomy (OR = 1.98, <0.05) and combined phacovitrectomy (OR = 2.33, P = 0.03) were analyzed as risk factors for DONFL. CONCLUSION: The improvement in BCVA and CMT in ERM surgery using a 3D-HUD is comparable with that of CM vitrectomy, with a significantly low rate of ERM recurrence and DONFL occurrence. Therefore, 3D vitrectomy might have an advantage for ERM surgery.

Dietary supplementation with Pediococcus pentosaceus enhances the innate immune response in and promotes growth of Litopenaeus vannamei shrimp.

To reach the sustainable development goals on health management in Litopenaeus vannamei shrimp culture, Pediococcus pentosaceus AB01 was supplemented in shrimp diet. In this study, the control diet and three experimental diets containing P. pentosaceus AB01 (108 , 109 , 1010 CFU/g) were separately introduced to L. vannamei for a 28 days feeding trial. After the feeding trial, percent weight gain, feeding efficiency, and feed conversion ratio (FCR) were significantly elevated in L. vannamei administered with P. pentosaceus AB01 at 109 and 1010 colony-forming unit (CFU)/g. Protease, amylase, and trypsin were found at higher levels in the probiotic-supplied groups. The feeding of shrimps with P. pentosaceus AB01 significantly increased innate immune response and levels of related biochemical parameters in the haemolymph. After the white spot syndrome virus (WSSV) challenge, supplementation of P. pentosaceus AB01 had significant positive effects (p < .05) on survival rate, compared to that of the control diet. The higher resistance of L. vannamei to WSSV might have been due to alterations in the gut microbiome composition and upregulation of the Toll-Like Receptor (TLR) signalling pathway. Hence, P. pentosaceus AB01 may be a promising alternative feed to promote growth rate, modulate microbiota composition, and enhance immunity in L. vannamei shrimp.

Absolute Quantification of N-Glycosylation of Alpha-Fetoprotein Using Parallel Reaction Monitoring with Stable Isotope-Labeled N-Glycopeptide as an Internal Standard.

Alpha-fetoprotein (AFP) is a well-established serum biomarker for hepatocellular carcinoma (HCC) in clinical laboratories. However, AFP levels can often be high in benign liver diseases such as liver cirrhosis. For this reason, specifically, the level of the aberrant N-glycosylation of AFP has been proposed as a HCC biomarker to improve diagnostic performance using targeted mass spectrometry (MS). In this study, we developed an endoglycosidase-assisted absolute quantification (AQUA) method by which to measure N-glycosylated AFP levels in serum using liquid chromatography-parallel reaction monitoring with immunoprecipitation. Especially, an isotopically labeled synthetic N-glycopeptide with N-acetylhexosamine (HexNAc) attached to asparagine (N) was used as an internal standard. The efficacy of this method was demonstrated by quantifying the N-glycosylation of AFP in human serum. As a result, we showed that the lower limit of the quantification of a stable isotope-labeled N-glycopeptide reached an attomolar level. Our method also had a linear dynamic range from 2 to 6000 ng/mL for N-glycosylated AFP levels. Finally, the N-glycosylation levels of AFP were measured in HCC patients and in healthy donors with the coefficient of variation in both cases (<10% CV). To the best of our knowledge, this is the first report of the AQUA of N-glycosylated AFP in human sera using a stable isotope-labeled glycopeptide as an internal standard. The results demonstrate that our method can facilitate the discovery and verification of aberrant glycoprotein biomarkers in human serum and plasma through sensitive and precise quantification.

Computational classification of core and outer fucosylation of N-glycoproteins in human plasma using collision-induced dissociation in mass spectrometry.

RATIONALE: Glycoprotein fucosylation, one of the major posttranslational modifications, is known to be highly involved in proteins related to various cancers. Fucosylation occurs in the core and/or outer sites of N-glycopeptides. Elucidation of the fucosylation type of N-glycoproteins is therefore important. However, it has remained a challenge to classify the fucosylation types of N-glycopeptides using collision-induced dissociation (CID) tandem mass (MS/MS) spectra. METHODS: The relative intensities of the Y1 F, Y2 F, Y3 F, and Y4 F product ions in the CID-MS/MS spectra of the IgG N-glycopeptides were measured for core fucosylation. The Core Fucose Index (CFI) was then calculated by multiplication of the relative intensities with a weight factor from logistic regression to differentiate between the core and none fucosylation. From the relative intensities of the B2 F and B3 SF ions of the MS/MS spectra of the AGP N-glycopeptides for outer fucosylation, the Outer Fucose Index (OFI) was calculated to differentiate between the outer and none fucosylation. RESULTS: In order to classify core and/or outer fucosylation of N-glycoproteins, we defined the fucosylation score (F-score) by a sigmoidal equation using a combination of the CFI and the OFI. For application, we classified the fucosylation types of N-glycoproteins in human plasma with 99.7% accuracy from the F-score. Human plasma samples showed 54.4%, 33.3%, 10.3%, and 1.6% for none, core, outer, and dual fucosylated N-glycopeptides, respectively. Core fucosylation was abundant at mono- and bi-antennary N-glycopeptides. Outer fucosylation was abundant at tri- and tetra-antennary N-glycopeptides. In total, 113 N-glycopeptides of 29 glycoproteins from 3365 glycopeptide spectral matches (GPSMs) were classified for different types of fucosylation. CONCLUSIONS: We established an F-score to classify three different fucosylation types: core, outer, and dual types of N-glycopeptides. The fucosylation types of 20 new N-glycopeptides from 11 glycoproteins in human plasma were classified using the F-score. Therefore, the F-score can be useful for the automatic classification of different types of fucosylation in N-glycoproteins of biological fluids including plasma, serum, and urine.

SAAVpedia: Identification, Functional Annotation, and Retrieval of Single Amino Acid Variants for Proteogenomic Interpretation.

Next-generation genome sequencing has enabled the discovery of numerous disease- or drug-response-associated nonsynonymous single nucleotide variants (nsSNVs) that alter the amino acid sequences of a protein. Although several studies have attempted to characterize pathogenic nsSNVs, few have been confirmed as single amino acid variants (SAAVs) at the protein level. Here we developed the SAAVpedia platform to identify, annotate, and retrieve pathogenic SAAV candidates from proteomic and genomic data. The platform consists of four modules: SAAVidentifier, SAAVannotator, SNV/SAAVretriever, and SAAVvisualizer. The SAAVidentifier provides a reference database containing 18 206 090 SAAVs and performs the identification and quality assessment of SAAVs. The SAAVannotator provides functional annotation with biological, clinical, and pharmacological information for the interpretation of condition-specific SAAVs. The SNV/SAAVretriever module enables bidirectional navigation between relevant SAAVs and nsSNVs with diverse genomic and proteomic data. SAAVvisualizer provides various statistical plots based on functional annotations of detected SAAVs. To demonstrate the utility of SAAVpedia, the proteogenomic pipeline with protein-protein interaction network analysis was applied to proteomic data from breast cancer and glioblastoma patients. We identified 1326 and 12 breast-cancer- and glioblastoma-related genes that contained one or more SAAVs, including BRCA2 and FAM49B, respectively. SAAVpedia is a suitable platform for confirming whether a genomic variant is maintained in an amino acid sequence. Furthermore, as a result of the SAAV discovery of these positive controls, the SAAVpedia could play a key role in the protein functional study for the Human Proteome Project (HPP).

Effects of strain rate on room- and cryogenic-temperature compressive properties in metastable V10Cr10Fe45Co35 high-entropy alloy.

Quasi-static and dynamic compressive properties of an FCC-based metastable HEA (composition; V10Cr10Fe45Co35 (at.%)) showing both Transformation Induced Plasticity (TRIP) and TWinning Induced Plasticity (TWIP) were investigated at room and cryogenic temperatures. During the quasi-static and dynamic compression at room temperature, the FCC to BCC TRIP occurred inside FCC grains, and resulted in very high strain-hardening rate and consequently maximum compressive strength over 1.6 GPa. The dynamic compressive strength was higher by 240 MPa than the quasi-static strength because of strain-rate-hardening effect, and kept increasing with a high strain-hardening rate as the twinning became activated. The cryogenic-temperature strength was higher than the room-temperature strength as the FCC to BCC TRIP amount increased by the decrease in stability of FCC phase with decreasing temperature. Under dynamic loading at cryogenic temperature, twins were not formed because the increase in SFE due to adiabatic heating might not be enough to reach the TWIP regime. However, the dynamically compressed specimen showed the higher strength than the quasi-statically compressed specimen as the strain-rate-hardening effect was added with the TRIP.

Mixed Infection with Plasmodium falciparum and Plasmodium ovale in a Returned Traveller: the First Case in Korea.

Mixed-species malaria infections are often unrecognized or underestimated. We hereby report the first described case of mixed infection with Plasmodium falciparum and Plasmodium ovale malaria in a returned traveller in Korea. In August 2016, a 25-year-old returned traveller from Cameroon and Democratic Republic of Congo presented with fever. He was diagnosed as P. falciparum malaria and successfully treated with artesunate. And 5 weeks after the completion of treatment, he presented with fever and diagnosed as P. ovale infection. P. ovale infection is a rare cause of malaria and often shows delayed presentation due to its dormant liver stage as hypnozoites. At re-presentation, the immunochromatographic test and microscopic examinations of our patient did not reveal P. ovale, which was only detected via polymerase chain reaction (PCR) assay. This case highlights the importance of considering malaria infection even in persons who have previously received malaria treatment. It also shows the usefulness of PCR testing for diagnosing P. ovale infections, which often present with a low level of parasitaemia.

A Proteotranscriptomic-Based Computational Drug-Repositioning Method for Alzheimer's Disease.

Numerous clinical trials of drug candidates for Alzheimer's disease (AD) have failed, and computational drug repositioning approaches using omics data have been proposed as effective alternative approaches to the discovery of drug candidates. However, little multi-omics data is available for AD, due to limited availability of brain tissues. Even if omics data exist, systematic drug repurposing study for AD has suffered from lack of big data, insufficient clinical information, and difficulty in data integration on account of sample heterogeneity derived from poor diagnosis or shortage of qualified post-mortem tissue. In this study, we developed a proteotranscriptomic-based computational drug repositioning method named Drug Repositioning Perturbation Score/Class (DRPS/C) based on inverse associations between disease- and drug-induced gene and protein perturbation patterns, incorporating pharmacogenomic knowledge. We constructed a Drug-induced Gene Perturbation Signature Database (DGPSD) comprised of 61,019 gene signatures perturbed by 1,520 drugs from the Connectivity Map (CMap) and the L1000 CMap. Drugs were classified into three DRPCs (High, Intermediate, and Low) according to DRPSs that were calculated using drug- and disease-induced gene perturbation signatures from DGPSD and The Cancer Genome Atlas (TCGA), respectively. The DRPS/C method was evaluated using the area under the ROC curve, with a prescribed drug list from TCGA as the gold standard. Glioblastoma had the highest AUC. To predict anti-AD drugs, DRPS were calculated using DGPSD and AD-induced gene/protein perturbation signatures generated from RNA-seq, microarray and proteomic datasets in the Synapse database, and the drugs were classified into DRPCs. We predicted 31 potential anti-AD drug candidates commonly belonged to high DRPCs of transcriptomic and proteomic signatures. Of these, four drugs classified into the nervous system group of Anatomical Therapeutic Chemical (ATC) system are voltage-gated sodium channel blockers (bupivacaine, topiramate) and monamine oxidase inhibitors (selegiline, iproniazid), and their mechanism of action was inferred from a potential anti-AD drug perspective. Our approach suggests a shortcut to discover new efficacy of drugs for AD.

Comparison of the analytical and clinical performances of Abbott RealTime High Risk HPV, Hybrid Capture 2, and DNA Chip assays in gynecology patients.

The detection of high-risk (HR) HPV in cervical cancer screening is important for early diagnosis of cervical cancer or pre-cancerous lesions. We evaluated the analytical and clinical performances of 3 HR HPV assays in Gynecology patients. A total of 991 specimens were included in this study: 787 specimens for use with a Hybrid Capture 2 (HC2) and 204 specimens for a HPV DNA microarray (DNA Chip). All specimens were tested using an Abbott RealTime High Risk HPV assay (Real-time HR), PGMY PCR, and sequence analysis. Clinical sensitivities for severe abnormal cytology (severe than high-grade squamous intraepithelial lesion) were 81.8% for Real-time HR, 77.3% for HC2, and 66.7% for DNA Chip, and clinical sensitivities for severe abnormal histology (cervical intraepithelial neoplasia grade 2+) were 91.7% for HC2, 87.5% for Real-time HR, and 73.3% for DNA Chip. As compared to results of the sequence analysis, HC2, Real-time HR, and DNA Chip showed concordance rates of 94.3% (115/122), 90.0% (117/130), and 61.5% (16/26), respectively. The HC2 assay and Real-time HR assay showed comparable results to each other in both clinical and analytical performances, while the DNA Chip assay showed poor clinical and analytical performances. The Real-time HR assay can be a good alternative option for HR HPV testing with advantages of allowing full automation and simultaneous genotyping of HR types 16 and 18.

A case of spine origin chondroblastoma metastasis to lung.

Chondroblastoma is a rare benign cartilaginous neoplasm that accounts for approximately 1% of all bone tumors and characteristically arises in the epiphysis of a long bone, particularly the humerus, tibia, and femur. Chondroblastoma can affect people of all ages. It is, however, most common in children and young adults between the ages of 10 and 20 years. Although most chondroblastomas are cured by limited surgical procedures, occasional lesions behave more aggressively and may even metastasis. In this case a young man with pulmonary metastatic chondroblastoma on spine is presented. Unlike previously published examples of metastatic chondroblastoma, these metastasis developed before any operative manipulation of the primary tumor. And primary tumor site was also unusual. The histologic characteristics of the primary, metastatic tumors were those of a conventional chondroblastoma.