Trastuzumab deruxtecan (T‐DXd: DS‐8201a) is an anti‐human epidermal growth factor receptor 2 (HER2) Ab–drug conjugated with deruxtecan (DXd), a derivative of exatecan. The objective of this study was ...to characterize T‐DXd‐induced lung toxicity in cynomolgus monkeys. Trastuzumab deruxtecan was injected i.v. into monkeys once every 3 weeks for 6 weeks (10, 30, and 78.8 mg/kg) or for 3 months (3, 10, and 30 mg/kg). To evaluate the involvement of DXd alone in T‐DXd‐induced toxicity, DXd monohydrate was given i.v. to monkeys once a week for 4 weeks (1, 3, and 12 mg/kg). Interstitial pneumonitis was observed in monkeys given T‐DXd at 30 mg/kg or more. The histopathological features of diffuse lymphocytic infiltrates and slight fibrosis were similar to interstitial lung diseases (ILD)/pneumonitis related to anticancer drugs in patients, with an incidence that was dose‐dependent and dose‐frequency‐dependent. Monkeys receiving DXd monohydrate did not suffer lung toxicity, although the DXd exposure level was higher than that of DXd in the monkeys given T‐DXd. The HER2 expression in monkey lungs was limited to the bronchial level, although the lesions were found at the alveolar level. Immunohistochemical analysis confirmed that T‐DXd localization was mainly in alveolar macrophages, but not pulmonary epithelial cells. These findings indicate that monkeys are an appropriate model for investigating T‐DXd‐related ILD/pneumonitis. The results are also valuable for hypothesis generation regarding the possible mechanism of T‐DXd‐induced ILD/pneumonitis in which target‐independent uptake of T‐DXd into alveolar macrophages could be involved. Further evaluation is necessary to clarify the mechanism of ILD/pneumonitis in patients with T‐DXd therapy.
Trastuzumab deruxtecan (T‐DXd; DS‐8201a), an anti‐human epidermal growth factor receptor 2 Ab–drug conjugate with a derivative of exatecan (DXd), has been associated with interstitial lung diseases (ILD)/pneumonitis in clinical trials. This work indicates that the histopathological features of T‐DXd‐induced lung toxicity in monkeys are similar to ILD/pneumonitis associated with anticancer drugs in patients.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
We sought to construct and evaluate a deep learning (DL) model to diagnose early glaucoma from spectral-domain optical coherence tomography (OCT) images.
Artificial intelligence diagnostic tool ...development, evaluation, and comparison.
This multi-institution study included pretraining data of 4316 OCT images (RS3000) from 1371 eyes with open angle glaucoma (OAG) regardless of the stage of glaucoma and 193 normal eyes. Training data included OCT-1000/2000 images from 94 eyes of 94 patients with early OAG (mean deviation > −5.0 dB) and 84 eyes of 84 normal subjects. Testing data included OCT-1000/2000 from 114 eyes of 114 patients with early OAG (mean deviation > −5.0 dB) and 82 eyes of 82 normal subjects. A DL (convolutional neural network) classifier was trained using a pretraining dataset, followed by a second round of training using an independent training dataset. The DL model input features were the 8 × 8 grid macular retinal nerve fiber layer thickness and ganglion cell complex layer thickness from spectral-domain OCT. Diagnostic accuracy was investigated in the testing dataset. For comparison, diagnostic accuracy was also evaluated using the random forests and support vector machine models. The primary outcome measure was the area under the receiver operating characteristic curve (AROC).
The AROC with the DL model was 93.7%. The AROC significantly decreased to between 76.6% and 78.8% without the pretraining process. Significantly smaller AROCs were obtained with random forests and support vector machine models (82.0% and 67.4%, respectively).
A DL model for glaucoma using spectral-domain OCT offers a substantive increase in diagnostic performance.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
We aimed to develop a model to predict visual field (VF) in the central 10 degrees in patients with glaucoma, by training a convolutional neural network (CNN) with optical coherence tomography (OCT) ...images and adjusting the values with Humphrey Field Analyzer (HFA) 24-2 test. The training dataset included 558 eyes from 312 glaucoma patients and 90 eyes from 46 normal subjects. The testing dataset included 105 eyes from 72 glaucoma patients. All eyes were analyzed by the HFA 10-2 test and OCT; eyes in the testing dataset were additionally analyzed by the HFA 24-2 test. During CNN model training, the total deviation (TD) values of the HFA 10-2 test point were predicted from the combined OCT-measured macular retinal layers' thicknesses. Then, the predicted TD values were corrected using the TD values of the innermost four points from the HFA 24-2 test. Mean absolute error derived from the CNN models ranged between 9.4 and 9.5 B. These values reduced to 5.5 dB on average, when the data were corrected using the HFA 24-2 test. In conclusion, HFA 10-2 test results can be predicted with a OCT images using a trained CNN model with adjustment using HFA 24-2 test.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
MAS-related G protein coupled receptor-X2 (MRGPRX2), expressed in human mast cells, is associated with drug-induced pseudo-allergic reactions. Dogs are highly susceptible to drug-induced ...anaphylactoid reactions caused by various drugs; however, the distribution and physiological function of canine MRGPR family genes, including MRGPRX2, remain largely unknown. In the present study, we clarified the distribution of dog MRGPR family genes by real-time quantitative PCR and in situ hybridisation. We also investigated the stimulatory effects of various histamine-releasing agents, including fluoroquinolones, on HEK293 cells transiently transfected with dog MRGPR family genes to identify their physiological function. Dog MRGPRX2 and MRGPRG were distributed in a limited number of tissues, including the skin (from the eyelid, abdomen, and cheek), whereas MRGPRD and MRGPRF were extensively expressed in almost all tissues examined. Histochemical and in situ hybridisation analyses revealed that MRGPRX2 was expressed in dog connective tissue-type mast cells in the skin. Intracellular Ca
mobilisation assay revealed that HEK293 cells, expressing dog MRGPRX2 or human MRGPRX2, but not dog MRGPRD, MRGPRF, and MRGPRG, responded to histamine-releasing agents. Our results suggest that dog MRGPRX2 is the functional orthologue of human MRGPRX2 and plays an essential role in drug-induced anaphylactoid reactions in dogs.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Background
The good short-term and oncological outcomes of robot-assisted radical esophagectomy have been demonstrated, although its impact on long-term health-related quality of life (HRQoL) remains ...to be investigated. This study aimed to assess long-term HRQoL in patients after robot-assisted radical transmediastinal esophagectomy (TME), which is characterized as non-transthoracic esophagectomy comprising a robotic transhiatal approach and a video-assisted cervical approach, and transthoracic esophagectomy (TTE).
Methods
The European Organization for Research and Treatment of Cancer generic and disease-specific modules (QLQ-C30 and QLQ-OES18), nutritional status and body composition data were prospectively collected in patients undergoing TME or TTE before and at 3, 6, 12, 18, and 24 months after surgery. The results of long-term (≥ 2 years) survivors without recurrence were compared between the two groups.
Results
A total of 37 patients (TME;
n
= 18, TTE;
n
= 19) were included for analysis. Longitudinal survey of function scales revealed scores of physical, role, social, and emotional function to be significantly better in the TME group than in the TTE group at many points postoperatively. Markedly, the symptoms of general pain, esophageal pain, and dry mouth greatly worsened after surgery in the TTE group, but did not deteriorate in the TME group. In contrast, symptoms relating to eating difficulties, body composition data, and nutritional status did not differ between the groups over time. At 24 months after surgery, TME provided significantly higher scores of global QOL (
P
= 0.01) and emotional function (
P
= 0.01) and also resulted in significantly fewer problems of fatigue (
P
= 0.04), general pain (
P
= 0.04), insomnia (
P
= 0.02), and dry mouth (
P
= 0.03), as compared to TTE.
Conclusion
This study indicates that TME can provide better long-term HRQoL outcomes than TTE.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Abstract
Background and Objectives
Neighborhood places that facilitate older residents to meet and interact (third places) receive an increasing research interest as studies have consistently shown ...the benefits of social engagement for older adults’ health. This scoping review synthesized the findings of studies examining the role of third places in older adults’ social engagement.
Research Design and Methods
Searching 5 databases (CINAHL, Medline, PsycInfo, Scopus, and Web of Science) in October 2021, this study identified quantitative and qualitative studies that examined the relationships between third places and social engagement (interaction and network) among older adults.
Results
A total of 32 studies (12 quantitative and 20 qualitative studies) met the eligibility criteria. These studies examined 4 types of third place, namely, community facilities, local businesses, open/green spaces, and transition spaces. More than two thirds of the studies reviewed found that access to community facilities, local businesses, and open/green spaces were related to older adults’ social interaction. For the relationships between third places and social networks, the importance of accessible local businesses and the quality of open/green spaces was supported by fewer studies.
Discussion and Implications
The findings of quantitative and qualitative studies suggest that local places that are convenient to visit and comfortable to stay in for older adults are likely to enhance their social interaction and network. However, more specific evidence is needed to inform the planning and design of third places. The review discusses future research topics that address the gaps identified in the current literature.
MAS-related G protein-coupled receptor X2 (MRGPRX2), expressed in human mast cells, is associated with drug-induced pseudo-allergic reactions. Dogs are highly sensitive to the anaphylactoid reactions ...induced by certain drugs including fluoroquinolones. Recently, dog MRGPRX2 was identified as a functional ortholog of human MRGPRX2, with dog MRGPRX2 being particularly sensitive to fluoroquinolones. The aim of this study was to determine key residues responsible for the enhanced activity of fluoroquinolone-induced histamine release associated with MRGPRX2. Firstly, a structure model of human and dog MRGPRX2 was built by homology modeling, and docking simulations with fluoroquinolones were conducted. This model indicated that E164 and D184, conserved between human and dog, are essential for the binding to fluoroquinolones. In contrast, F78 (dog: Y) and M109 (dog: W) are unconserved residues, to which the species difference in fluoroquinolone sensitivity is attributable. Intracellular calcium mobilisation assay with human MRGPRX2 mutants, in which residues at positions 78 and 109 were substituted to those of dog MRGPRX2, revealed that M109 and F78 of human MRGPRX2 are crucial residues for enhancing the fluoroquinolone-induced histamine release. In conclusion, these key residues have important clinical implications for revealing the mechanisms and predicting the risks of fluoroquinolone-mediated pseudo-allergic reactions in humans.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Purpose
To assess the risk factors for intraocular pressure (IOP) elevation during the early period post cataract surgery.
Study design
Retrospective study.
Methods
This study involved 1587 eyes that ...underwent cataract surgery at the Baptist Eye Institute, Kyoto, Japan between April 2020 and May 2021. In all subjects, risk factors for early postoperative IOP elevation (i.e., an increase of IOP of 10 mmHg or more at 1-day postoperative compared with that at baseline, or a postoperative IOP of 28 mmHg or more) were analyzed by multivariate logistic regression analysis.
Results
Of the 1587 treated eyes in this study, 100 (6.3%) experienced early-postoperative IOP elevation. Of those 100 eyes, 78.0% were men, 27.0% had an axial length (AL) of ≥ 26.5 mm, 23.0% had a history of glaucoma treatment, 11.0% had poor mydriasis and 10.0% had intraoperative floppy iris syndrome (IFIS). Multivariate analysis findings revealed that male odds ratio (OR) 4.36; 95% confidence interval (CI) 2.63–7.23; P < 0.001, AL of ≥ 26.5 mm (3.11; 1.83–5.30; P < 0.001), a history of glaucoma treatment (2.83; 1.63–4.91; P < 0.001), poorly mydriasis (2.63; 1.16–6.01; P = 0.02), IFIS (4.37; 1.78–10.74; P = 0.001) and baseline high IOP (1.09; 1.01–1.18; P = 0.03) were associated with increased IOP during the early period post cataract surgery.
Conclusions
The findings in this study reveal that male sex, high myopia, a history of glaucoma treatment, poor mydriasis, IFIS and baseline high IOP are risk factors for IOP elevation during the early period post cataract surgery.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
To develop a large-scale real clinical database of glaucoma (Japanese Archive of Multicentral Databases in Glaucoma: JAMDIG) and to investigate the effect of treatment.
The study included a total of ...1348 eyes of 805 primary open-angle glaucoma patients with 10 visual fields (VFs) measured with 24-2 or 30-2 Humphrey Field Analyzer (HFA) and intraocular pressure (IOP) records in 10 institutes in Japan. Those with 10 reliable VFs were further identified (638 eyes of 417 patients). Mean total deviation (mTD) of the 52 test points in the 24-2 HFA VF was calculated, and the relationship between mTD progression rate and seven variables (age, mTD of baseline VF, average IOP, standard deviation (SD) of IOP, previous argon/selective laser trabeculoplasties (ALT/SLT), previous trabeculectomy, and previous trabeculotomy) was analyzed.
The mTD in the initial VF was -6.9 ± 6.2 dB and the mTD progression rate was -0.26 ± 0.46 dB/year. Mean IOP during the follow-up period was 13.5 ± 2.2 mm Hg. Age and SD of IOP were related to mTD progression rate. However, in eyes with average IOP below 15 and also 13 mm Hg, only age and baseline VF mTD were related to mTD progression rate.
Age and the degree of VF damage were related to future progression. Average IOP was not related to the progression rate; however, fluctuation of IOP was associated with faster progression, although this was not the case when average IOP was below 15 mm Hg.
Drug-induced interstitial lung disease (DILD) occurs when drug exposure causes inflammation of the lung interstitium. DILD can be caused by different types of drugs, and some DILD patterns results in ...a high mortality rate; hence, DILD poses a serious problem in clinical practice as well as drug development, and strategies to diagnose and distinguish DILD from other lung diseases are necessary. We aimed to identify novel biomarkers for DILD by performing lipidomics analysis on plasma samples from patients with acute and recovery phase DILD. Having identified lysophosphatidylcholines (LPCs) as candidate biomarkers for DILD, we determined their concentrations using validated liquid chromatography/mass spectrometry biomarker assays. In addition, we evaluated the ability of LPCs to discriminate patients with acute phase DILD from those with recovery phase DILD, DILD-tolerant, or other lung diseases, and characterized their association with clinical characteristics. Lipidomics analysis revealed a clear decrease in LPC concentrations in the plasma of patients with acute phase DILD. In particular, LPC(14:0) had the highest discriminative index against recovery phase and DILD-tolerant patients. LPC(14:0) displayed no clear association with causal drugs, or subjects' backgrounds, but was associated with disease severity. Furthermore, LPC(14:0) was able to discriminate between patients with DILD and other lung diseases, including idiopathic interstitial pneumonia and lung disease associated with connective tissue disease. LPC(14:0) is a promising biomarker for DILD that could improve the diagnosis of DILD and help to differentiate DILD from other lung diseases, such as idiopathic interstitial pneumonia and connective tissue disease.
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