We previously reported that it was beneficial to apply binomial pointwise linear regression (PLR) to detect 24-2 glaucomatous visual field (VF) progression, compared to mean deviation (MD) trend ...analysis and permutation analysis of PLR (PoPLR). The purpose of the current study was to validate the usefulness of the binomial PLR method to detect VF progression in the central 10 degrees in glaucoma patients.
Reliability assessment.
A series of 15 VFs (Humphrey Field Analyzer 10-2 SITA-standard) from 97 eyes in 69 primary open-angle glaucoma patients, obtained over 8.5 ± 1.3 years (mean ± SD), were investigated. PLR was performed by regressing the total deviation of all test points on the series of 15 VFs. VF progression was determined from the analyses of VF test points using the binomial test (1-sided, P < .025). The time needed to detect VF progression was also investigated. The results were compared with PoPLR and MD trend analyses.
The binomial PLR was comparable to PoPLR and MD trend analyses in the positive predictive value (0.19 to 0.80), the negative predictive value (0.86 to 1.0), and the false positive rate (0.0 to 0.13) to evaluate glaucomatous VF progression. The time needed to detect VF progression (4.2 ± 1.8 years) was significantly shorter with the binomial PLR method compared with PoPLR and MD trend analysis (P = .04, P = .012, respectively).
The binomial PLR method detected glaucomatous VF progression in the central 10 degrees significantly earlier than PoPLR and MD trend analyses.
To investigate retinal vessel shift (RVS) and its association with axial length (AL) elongation in junior high school students.
Total 161 eyes of 161 healthy junior high school students were ...prospectively studied. Optical AL and anterior chamber depth (ACD) measurements, and fundus photography were performed in the first and third grades. Eyes of subjects in the first and third grade that had perfect matching among all the retinal vessels were allocated to the RVS(-) group, otherwise allocated to the RVS(+) group. In the RVS(+) group, the peripapillary retinal arteries angle (PRAA) was measured for quantitative analysis of RVS; the angle between the major retinal arteries. The variables related to PRAA were identified using model selection with the corrected Akaike information criterion.
Forty-two eyes (26.1%) were allocated to the RVS(+) group. There were seven patterns in the RVS of those in the RVS(+) group, including clockwise shift in the supra temporal area (5 eyes), infra temporal area (7 eyes), and nasal area (9 eyes); anticlockwise shift in the supra temporal area (7 eyes), infra temporal area (5 eyes), and nasal area (2 eyes); and distal shift in the temporal area (7 eyes). The optimal model for the PRAA narrowing included larger AL and body weight in the first grade, and greater AL elongation.
Various (seven) RVS patterns were observed in about 25% of the junior high school students within two years. RVS was associated with AL elongation, and useful to reveal the mechanism of myopic retinal stretch.
The aim of the study was to investigate the usefulness of processing visual field (VF) using a variational autoencoder (VAE). The training data consisted of 82,433 VFs from 16,836 eyes. Testing ...dataset 1 consisted of test-retest VFs from 104 eyes with open angle glaucoma. Testing dataset 2 was series of 10 VFs from 638 eyes with open angle glaucoma. A VAE model to reconstruct VF was developed using the training dataset. VFs in the testing dataset 1 were then reconstructed using the trained VAE and the mean total deviation (mTD) was calculated (mTD
). In testing dataset 2, the mTD value of the tenth VF was predicted using shorter series of VFs. A similar calculation was carried out using a weighted linear regression where the weights were equal to the absolute difference between mTD and mTD
. In testing dataset 1, there was a significant relationship between the difference between mTD and mTD
from the first VF and the difference between mTD in the first and second VFs. In testing dataset 2, mean squared prediction errors with the weighted mTD trend analysis were significantly smaller than those form the unweighted mTD trend analysis.
The aim of the current study is to identify possible new Ocular Response Analyzer (ORA) waveform parameters related to changes of retinal structure/deformation, as measured by the peripapillary ...retinal arteries angle (PRAA), using a generative deep learning method of variational autoencoder (VAE). Fifty-four eyes of 52 subjects were enrolled. The PRAA was calculated from fundus photographs and was used to train a VAE model. By analyzing the ORA waveform reconstructed (noise filtered) using VAE, a novel ORA waveform parameter (Monot1-2), was introduced, representing the change in monotonicity between the first and second applanation peak of the waveform. The variables mostly related to the PRAA were identified from a set of 41 variables including age, axial length (AL), keratometry, ORA corneal hysteresis, ORA corneal resistant factor, 35 well established ORA waveform parameters, and Monot1-2, using a model selection method based on the second-order bias-corrected Akaike information criterion. The optimal model for PRAA was the AL and six ORA waveform parameters, including Monot1-2. This optimal model was significantly better than the model without Monot1-2 (p = 0.0031, ANOVA). The current study suggested the value of a generative deep learning approach in discovering new useful parameters that may have clinical relevance.
This study aimed to compare blue-on-yellow (B/Y) perimetry with white-on-white (W/W) perimetry in eyes with branch retinal vein occlusion (BRVO). The following measurements were performed in 29 eyes ...of 29 patients with resolved BRVO: W/W and B/Y perimetries using 10-2 test grid, retinal volume (RV) using optical coherence tomography (OCT), and vessel densities (VD) of the superficial capillary layer (VDs) and deep capillary layer (VDd) using OCT angiography (OCTA). First, the difference in the retinal sensitivity (RS) between BRVO-affected and unaffected areas was compared between RS_B/Y and RS_W/W in the parafoveal and extrafoveal areas. Moreover, the structure-function relationship between vessel density and RS was compared between B/Y and W/W perimetries (RS_B/Y and RS_W/W, respectively). The difference in RS between BRVO-affected and unaffected areas was significantly larger with RS_B/Y than with RS_W/W in both the parafoveal and extrafoveal areas. In the parafoveal area, VDs, VDd, and RV were significantly correlated with both RS_W/W and RS_B/Y. In contrast, in the extrafoveal area, only VDd was included in the optimal models. Our findings suggest that RS_B/Y more strongly reflects the anatomical structure and BRVO-affected area.
Cynomolgus monkeys are widely used in preclinical studies during drug development because of their evolutionary closeness to humans, including their cytochrome P450s (P450s). Most cynomolgus monkey ...P450s are almost identical (≥90%) to human P450s; however, CYP2C76 has low sequence identity (approximately 80%) to any human CYP2Cs. Although CYP2C76 has no ortholog in humans and is partly responsible for species differences in drug metabolism between cynomolgus monkeys and humans, a broad evaluation of potential substrates for CYP2C76 has not yet been conducted. In this study, a screening of 89 marketed compounds, including human CYP2C and non-CYP2C substrates or inhibitors, was conducted to find potential CYP2C76 substrates. Among the compounds screened, 19 chemicals were identified as substrates for CYP2C76, including substrates for human CYP1A2 (7-ethoxyresorufin), CYP2B6 (bupropion), CYP2D6 (dextromethorphan), and CYP3A4/5 (dextromethorphan and nifedipine), and inhibitors for CYP2B6 (sertraline, clopidogrel, and ticlopidine), CYP2C8 (quercetin), CYP2C19 (ticlopidine and nootkatone), and CYP3A4/5 (troleandomycin). CYP2C76 metabolized a wide variety of the compounds with diverse structures. Among them, bupropion and nifedipine showed high selectivity to CYP2C76. As for nifedipine, CYP2C76 formed methylhydroxylated nifedipine, which was not produced by monkey CYP2C9, CYP2C19, or CYP3A4, as identified by mass spectrometry and estimated by a molecular docking simulation. This unique oxidative metabolite formation of nifedipine could be one of the selective marker reactions of CYP2C76 among the major CYP2Cs and CYP3As tested. These results suggest that monkey CYP2C76 contributes to bupropion hydroxylation and formation of different nifedipine oxidative metabolites as a result of its relatively large substrate cavity.
The effectiveness of currently approved drugs for amyotrophic lateral sclerosis (ALS) is restricted; there is a need to develop further treatments. Initial studies have shown ultrahigh-dose ...methylcobalamin to be a promising agent.
To validate the efficacy and safety of ultrahigh-dose methylcobalamin for patients with ALS enrolled within 1 year of onset.
This was a multicenter, placebo-controlled, double-blind, randomized phase 3 clinical trial with a 12-week observation and 16-week randomized period, conducted from October 17, 2017, to September 30, 2019. Patients were recruited from 25 neurology centers in Japan; those with ALS diagnosed within 1 year of onset by the updated Awaji criteria were initially enrolled. Of those, patients fulfilling the following criteria after 12-week observation were eligible for randomization: 1- or 2-point decrease in the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) total score, a percent forced vital capacity greater than 60%, no history of noninvasive respiratory support and tracheostomy, and being ambulatory. The target participant number was 64 in both the methylcobalamin and placebo groups. Patients were randomly assigned through an electronic web-response system to methylcobalamin or placebo.
Intramuscular injection of methylcobalamin (50-mg dose) or placebo twice weekly for 16 weeks.
The primary end point was change in ALSFRS-R total score from baseline to week 16 in the full analysis set.
A total of 130 patients (mean SD age, 61.0 11.7 years; 74 men 56.9%) were randomly assigned to methylcobalamin or placebo (65 each). A total of 129 patients were eligible for the full analysis set, and 126 completed the double-blind stage. Of these, 124 patients proceeded to the open-label extended period. The least square means difference in ALSFRS-R total score at week 16 of the randomized period was 1.97 points greater with methylcobalamin than placebo (-2.66 vs -4.63; 95% CI, 0.44-3.50; P = .01). The incidence of adverse events was similar between the 2 groups.
Results of this randomized clinical trial showed that ultrahigh-dose methylcobalamin was efficacious in slowing functional decline in patients with early-stage ALS and with moderate progression rate and was safe to use during the 16-week treatment period.
ClinicalTrials.gov Identifier: NCT03548311.
The use of chimeric antigen receptor T-cell (CAR-T) therapy for hematologic malignancies is rapidly increasing, and appropriately managing adverse events (AEs) is crucial. Cytokine release syndrome ...(CRS) is a common AE of CAR-T therapy, characterized by systemic symptoms such as fever and respire-circulatory failure. We present two cases with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) accompanied by a rare complication of cervical local CRS as an acute inflammatory reaction at a specific site after CAR-T infusion. Case 1: A 60-year-old gentleman with diffuse large B cell lymphoma (DLBCL) developed grade 1 CRS on day one that required three doses of tocilizumab. Then he developed remarkable cervical edema as local CRS on day five. His local CRS spontaneously improved from day seven without additional therapy. Case 2: A 70-year-old gentleman with DLBCL developed grade 1 CRS on day two that required three doses of tocilizumab. Then he developed remarkable cervical edema and muffled voice as local CRS on day three. He received dexamethasone because of concerns about airway obstruction, and his local CRS improved immediately after dexamethasone administration. Before Tisa-Cel infusion, neither patients had a lymphoma lesion in their necks. To summarize, local CRS may occur at the site without lymphoma involvement after CAR-T therapy. An appropriate diagnosis and careful observation are required to determine the need for additional treatment.
A method of evaluating central visual field (VF) progression in eyes with retinitis pigmentosa (RP) has still to be established. We previously reported the potential merit of applying a binomial test ...to pointwise linear regression (binomial PLR) in glaucoma progression. In the current study, we investigated the usefulness of binomial PLR in eyes with RP.
A series of 10 VFs (VF 1-10, Humphrey field analyzer, 10-2 test) from 196 eyes of 103 patients with RP were collected retrospectively. The PLR was performed by regressing the total deviation of all test points with the complete series of 10 VFs. The accuracy (positive predictive value, negative predictive value, and false-positive rate) and the time required to detect VF progression with shorter VF series (from VF 1-5 to VF 1-9) were compared across the binomial PLR, a permutation analysis of PLR (PoPLR), and a mean deviation (MD) trend analysis.
In evaluating VF progression, the binomial PLR was comparable with the PoPLR and MD trend analyses in its positive predictive value (0.55 to 0.95), negative predictive value (0.67 to 0.92), and false-positive rate (0.01 to 0.05). The binomial PLR required significantly less time to detect VF progression (5.0 ± 2.0 years) than the PoPLR and MD trend analyses (P < 0.01, P < 0.001, respectively).
The application of a binomial PLR achieved reliable and earlier detection of central VF progression in eyes with RP.
A binomial PLR was useful in assessing VF progression in RP.
PDF
