Search

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and vaccination elicit both T cell and B cell immune responses in immunocompetent individuals. However, the mechanisms underlying the antiviral effects mediated by CD4 + T cells are not fully understood. In this study, we analyzed the culture supernatant (SN) from polyclonally stimulated human CD4 + T cells as a model for soluble mediators derived from SARS-CoV-2-stimulated CD4 + T cells. Interestingly, this SN inhibited SARS-CoV-2 propagation in a viral strain- and host cell type-dependent manner. The original wild-type showed the highest susceptibility, whereas the Delta variant exhibited resistance in the human monocyte cell line. In addition, antibody-dependent enhancement (ADE) of infection with the original strain was also abolished in the presence of the SN. The findings showed that the inhibitory effect on viral propagation by the SN was mostly attributed to interferon-γ (IFN-γ) that was present in the SN. These results highlight the potential role of IFN-γ as an anti-SARS-CoV-2 mediator derived from CD4 + T cells, and suggest that we need to understand the SARS-CoV-2 strain-dependent sensitivity to IFN-γ in controlling clinical outcomes. In addition, characterization of new SARS-CoV-2 variants in terms of IFN-γ-sensitivity will have important implications for selecting therapeutic strategies., (© 2024. The Author(s).)

During the COVID-19 pandemic, widespread school closures were implemented globally based on the assumption that transmission among children in the school environment is common. However, evidence regarding secondary infection rates by school type and level of contact is lacking. Our study estimated the frequency of SARS-CoV-2 infection in school settings by examining the positivity rate according to school type and level of contact by using data from a large-scale school-based PCR project conducted in Okinawa, Japan, during 2021-2022. Our results indicate that, despite detection of numerous positive cases, the average number of secondary infections remained relatively low at ≈0.5 cases across all types of schools. Considering the profound effects of prolonged closures on educational access, balancing public health benefits against potential long-term effects on children is crucial.

We estimated the seroprevalence of anti-SARS-COV-2 IgG in different island groups in Okinawa. A cross-sectional sero-survey was repeated in three periods between July 2020 and February 2021. A total of 2683 serum samples were collected from six referral medical centers, each covering a separate region in Okinawa. In the main island, the seroprevalence was 0.0% (0/392, 95% CI: 0.0-0.9), 0.6% (8/1448, 0.2-1.1), and 1.4% (8/582, 0.6-2.7) at the 1 st , 2 nd , and 3 rd sero-survey, respectively. In the remote islands, the seroprevalence was 0.0% (0/144, 95% CI: 0.0-2.5) and 1.6% (2/123, 0.2-5.8) at the 2 nd and 3 rd survey, respectively. The case detection ratio was 2.7 (95% CI: 1.3-5.3) in the main island and 2.8 (0.7-11.1) in the remote islands during the 3 rd survey. The case detection ratio was the highest in people aged 20-29 years (8.3, 95% CI: 3.3-21.4) in the main island and in those aged 50-59 years (14.1, 2.1-92.7) in the remote islands, suggesting under-reporting of clinical cases by the surveillance system in these subgroups. A sero-survey during an emerging infectious disease epidemic can be useful for validating the reliability of the surveillance system by providing the case detection ratio.

In middle to late 2023, a sublineage of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron XBB, EG.5.1 (a progeny of XBB.1.9.2), is spreading rapidly around the world. We performed multiscale investigations, including phylogenetic analysis, epidemic dynamics modeling, infection experiments using pseudoviruses, clinical isolates, and recombinant viruses in cell cultures and experimental animals, and the use of human sera and antiviral compounds, to reveal the virological features of the newly emerging EG.5.1 variant. Our phylogenetic analysis and epidemic dynamics modeling suggested that two hallmark substitutions of EG.5.1, S:F456L and ORF9b:I5T are critical to its increased viral fitness. Experimental investigations on the growth kinetics, sensitivity to clinically available antivirals, fusogenicity, and pathogenicity of EG.5.1 suggested that the virological features of EG.5.1 are comparable to those of XBB.1.5. However, cryo-electron microscopy revealed structural differences between the spike proteins of EG.5.1 and XBB.1.5. We further assessed the impact of ORF9b:I5T on viral features, but it was almost negligible in our experimental setup. Our multiscale investigations provide knowledge for understanding the evolutionary traits of newly emerging pathogenic viruses, including EG.5.1, in the human population., (© 2024 The Author(s). Microbiology and Immunology published by The Societies and John Wiley & Sons Australia, Ltd.)

Purpose: To investigate the long-term outcomes of congenital cataract surgery performed within the first 6 months of life., Setting: 11 ophthalmic surgical sites in Japan., Design: Retrospective chart review., Methods: Medical charts were retrospectively reviewed for 216 eyes of 121 patients. The age at surgery was 2.9 ± 1.7 months, with follow-up duration 13.0 ± 2.3 years. The cohort consisted of 83 cases with bilateral aphakia, 12 with bilateral pseudophakia, 20 with unilateral aphakia, and 6 with unilateral pseudophakia., Results: Surgical intervention within the critical period of visual system development (10 weeks for bilateral and 6 weeks for unilateral cases) led to significantly better final visual acuity than surgery conducted after this time frame. The incidence of secondary glaucoma was similar between groups while the occurrence of visual axis opacification was more frequent with earlier surgery. A forward stepwise multiple regression analysis revealed that the final visual acuity was significantly associated with laterality of cataract (better outcomes in bilateral cases), phakic status (with pseudophakia outperforming aphakia), presence of systemic and ocular comorbidities, and development of secondary glaucoma. Secondary glaucoma was significantly more prevalent in aphakic eyes than pseudophakic eyes., Conclusions: In patients with genuine congenital cataract, surgery within the critical period of visual development results in better final visual acuity, albeit with an increased risk of visual axis opacification. The use of IOL with sophisticated surgical techniques shows promise even in congenital cataract surgery., (Copyright © 2024 Published by Wolters Kluwer on behalf of ASCRS and ESCRS.)

Background: Although several SARS-CoV-2-related coronaviruses (SC2r-CoVs) were discovered in bats and pangolins, the differences in virological characteristics between SARS-CoV-2 and SC2r-CoVs remain poorly understood. Recently, BANAL-20-236 (B236) was isolated from a rectal swab of Malayan horseshoe bat and was found to lack a furin cleavage site (FCS) in the spike (S) protein. The comparison of its virological characteristics with FCS-deleted SARS-CoV-2 (SC2ΔFCS) has not been conducted yet., Methods: We prepared human induced pluripotent stem cell (iPSC)-derived airway and lung epithelial cells and colon organoids as human organ-relevant models. B236, SARS-CoV-2, and artificially generated SC2ΔFCS were used for viral experiments. To investigate the pathogenicity of B236 in vivo, we conducted intranasal infection experiments in hamsters., Findings: In human iPSC-derived airway epithelial cells, the growth of B236 was significantly lower than that of the SC2ΔFCS. A fusion assay showed that the B236 and SC2ΔFCS S proteins were less fusogenic than the SARS-CoV-2 S protein. The infection experiment in hamsters showed that B236 was less pathogenic than SARS-CoV-2 and even SC2ΔFCS. Interestingly, in human colon organoids, the growth of B236 was significantly greater than that of SARS-CoV-2., Interpretation: Compared to SARS-CoV-2, we demonstrated that B236 exhibited a tropism toward intestinal cells rather than respiratory cells. Our results are consistent with a previous report showing that B236 is enterotropic in macaques. Altogether, our report strengthens the assumption that SC2r-CoVs in horseshoe bats replicate primarily in the intestinal tissues rather than respiratory tissues., Funding: This study was supported in part by AMED ASPIRE (JP23jf0126002, to Keita Matsuno, Kazuo Takayama, and Kei Sato); AMED SCARDA Japan Initiative for World-leading Vaccine Research and Development Centers "UTOPIA" (JP223fa627001, to Kei Sato), AMED SCARDA Program on R&D of new generation vaccine including new modality application (JP223fa727002, to Kei Sato); AMED SCARDA Hokkaido University Institute for Vaccine Research and Development (HU-IVReD) (JP223fa627005h0001, to Takasuke Fukuhara, and Keita Matsuno); AMED Research Program on Emerging and Re-emerging Infectious Diseases (JP21fk0108574, to Hesham Nasser; JP21fk0108493, to Takasuke Fukuhara; JP22fk0108617 to Takasuke Fukuhara; JP22fk0108146, to Kei Sato; JP21fk0108494 to G2P-Japan Consortium, Keita Matsuno, Shinya Tanaka, Terumasa Ikeda, Takasuke Fukuhara, and Kei Sato; JP21fk0108425, to Kazuo Takayama and Kei Sato; JP21fk0108432, to Kazuo Takayama, Takasuke Fukuhara and Kei Sato; JP22fk0108534, Terumasa Ikeda, and Kei Sato; JP22fk0108511, to Yuki Yamamoto, Terumasa Ikeda, Keita Matsuno, Shinya Tanaka, Kazuo Takayama, Takasuke Fukuhara, and Kei Sato; JP22fk0108506, to Kazuo Takayama and Kei Sato); AMED Research Program on HIV/AIDS (JP22fk0410055, to Terumasa Ikeda; and JP22fk0410039, to Kei Sato); AMED Japan Program for Infectious Diseases Research and Infrastructure (JP22wm0125008 to Keita Matsuno); AMED CREST (JP21gm1610005, to Kazuo Takayama; JP22gm1610008, to Takasuke Fukuhara; JST PRESTO (JPMJPR22R1, to Jumpei Ito); JST CREST (JPMJCR20H4, to Kei Sato); JSPS KAKENHI Fund for the Promotion of Joint International Research (International Leading Research) (JP23K20041, to G2P-Japan Consortium, Keita Matsuno, Takasuke Fukuhara and Kei Sato); JST SPRING (JPMJSP2108 to Shigeru Fujita); JSPS KAKENHI Grant-in-Aid for Scientific Research C (22K07103, to Terumasa Ikeda); JSPS KAKENHI Grant-in-Aid for Scientific Research B (21H02736, to Takasuke Fukuhara); JSPS KAKENHI Grant-in-Aid for Early-Career Scientists (22K16375, to Hesham Nasser; 20K15767, to Jumpei Ito); JSPS Core-to-Core Program (A. Advanced Research Networks) (JPJSCCA20190008, to Kei Sato); JSPS Research Fellow DC2 (22J11578, to Keiya Uriu); JSPS Research Fellow DC1 (23KJ0710, to Yusuke Kosugi); JSPS Leading Initiative for Excellent Young Researchers (LEADER) (to Terumasa Ikeda); World-leading Innovative and Smart Education (WISE) Program 1801 from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) (to Naganori Nao); Ministry of Health, Labour and Welfare (MHLW) under grant 23HA2010 (to Naganori Nao and Keita Matsuno); The Cooperative Research Program (Joint Usage/Research Center program) of Institute for Life and Medical Sciences, Kyoto University (to Kei Sato); International Joint Research Project of the Institute of Medical Science, the University of Tokyo (to Terumasa Ikeda and Takasuke Fukuhara); The Tokyo Biochemical Research Foundation (to Kei Sato); Takeda Science Foundation (to Terumasa Ikeda and Takasuke Fukuhara); Mochida Memorial Foundation for Medical and Pharmaceutical Research (to Terumasa Ikeda); The Naito Foundation (to Terumasa Ikeda); Hokuto Foundation for Bioscience (to Tomokazu Tamura); Hirose Foundation (to Tomokazu Tamura); and Mitsubishi Foundation (to Kei Sato)., Competing Interests: Declaration of interests Yuki Yamamoto and Tetsuharu Nagamoto are founders and shareholders of HiLung, Inc. Yuki Yamamoto is a co-inventor of patents (PCT/JP2016/057254; "Method for inducing differentiation of alveolar epithelial cells", PCT/JP2016/059786, "Method of producing airway epithelial cells"). Jumpei Ito has consulting fees and honoraria for lectures from Takeda Pharmaceutical Co. Ltd. Kei Sato has consulting fees from Moderna Japan Co., Ltd. and Takeda Pharmaceutical Co. Ltd. and honoraria for lectures from Gilead Sciences, Inc., Moderna Japan Co., Ltd., and Shionogi & Co., Ltd. The other authors declare that no competing interests exist., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Myeloid-derived suppressor cells (MDSCs) are heterogeneous immature myeloid cells with immunosuppressive functions. It is known that MDSCs are expanded at inflammatory sites after migrating from bone marrow (BM) or spleen (Sp). In chronic inflammatory diseases such as rheumatoid arthritis (RA), previous reports indicate that MDSCs are increased in BM and Sp, but detailed analysis of MDSCs in inflamed joints is very limited., Objective: The purpose of this study is to characterize the MDSCs in the joints of mice with autoimmune arthritis., Methods: We sorted CD11b + Gr1 + cells from joints (Jo), bone marrow (BM) and spleen (Sp) of SKG mice with zymosan (Zym)-induced arthritis and investigated differentially expressed genes (DEGs) by microarray analysis. Based on the identified DEGs, we assessed the suppressive function of CD11b + Gr1 + cells from each organ and their ability to differentiate into osteoclasts., Results: We identified MDSCs as CD11b + Gr1 + cells by flow cytometry and morphological analysis. Microarray analysis revealed that Jo-CD11b + Gr1 + cells had different characteristics compared with BM-CD11b + Gr1 + cells or Sp-CD11b + Gr1 + cells. Microarray and qPCR analysis showed that Jo-CD11b + Gr1 + cells strongly expressed immunosuppressive DEGs ( Pdl1, Arg1, Egr2 and Egr3 ). Jo-CD11b + Gr1 + cells significantly suppressed CD4 + T cell proliferation and differentiation in vitro , which confirmed Jo-CD11b + Gr1 + cells as MDSCs. Microarray analysis also revealed that Jo-MDSCs strongly expressed DEGs of the NF-κB non-canonical pathway ( Nfkb2 and Relb ), which is relevant for osteoclast differentiation. In fact, Jo-MDSCs differentiated into osteoclasts in vitro and they had bone resorptive function. In addition, intra-articular injection of Jo-MDSCs promoted bone destruction., Conclusions: Jo-MDSCs possess a potential to differentiate into osteoclasts which promote bone resorption in inflamed joints, while they are immunosuppressive in vitro ., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Fujikawa, Sendo, del Peral Fanjul, Yamada, Uto, Yamamoto, Nagamoto, Morinobu and Saegusa.)

We assessed the 10-year postoperative outcomes of pediatric cataract patients who underwent surgery at the age of 6 years or younger. A retrospective review of medical charts was conducted for 457 eyes of 277 patients, with the age at surgery averaging 1.3 ± 1.5 years (mean ± SD) and the follow-up duration averaging 12.8 ± 2.4 years (ranging from 10 to 17 years). The cohort included 250 eyes of 125 cases with bilateral aphakia (age at surgery 0.5 ± 0.8 years), 110 eyes of 55 cases with bilateral pseudophakia (1.9 ± 1.6 years), 42 cases with unilateral aphakia (1.1 ± 1.3 years), and 55 cases with unilateral pseudophakia (2.6 ± 1.7). A forward stepwise multiple regression analysis revealed that the best-corrected visual acuity at the final visit was significantly associated with laterality of cataract (with bilateral cases showing better results compared to unilateral cases), presence of systemic comorbidities, presence of ocular comorbidities, development of glaucoma, and phakic status (with better results in the pseudophakia group than the aphakia group). The age at surgery did not significantly affect visual acuity outcomes. A multiple logistic regression analysis demonstrated that the incidence of secondary glaucoma was significantly linked to younger age at surgery, phakic status (higher in aphakic than pseudophakic eyes), and presence of systemic comorbidities. In conclusion, after pediatric cataract surgery, final visual acuity was better in patients with bilateral cataracts, those treated with an intraocular lens, and cases without systemic or ocular comorbidities and secondary glaucoma. The development of secondary glaucoma was linked to younger age at surgery, aphakic status, and presence of systemic comorbidities., (© 2023. The Author(s).)

Objectives: Stroke patients frequently exhibit loss of independence of urination, and their lower urinary tract symptoms change with the phase of stroke. However, it is unclear whether switching prescribed drugs for lower urinary tract symptoms during hospitalization from acute care wards to convalescence rehabilitation wards affects patients' independence of urination at discharge. It is also unclear whether the impact of switching varies by stroke type. This retrospective cohort study aimed to examine these issues., Materials and Methods: We analyzed 990 patients registered in the Kaga Regional Cooperation Clinical Pathway for Stroke database during 2015-2019. Prescriptions for lower urinary tract symptoms from pre-onset to convalescence rehabilitation were surveyed. Logistic regression analysis was performed to examine the association between switching drugs and independence of urination based on bladder management and voiding location at discharge. Stroke types were also examined in subgroup analyses., Results: About 21 % of patients had their lower urinary tract symptoms prescriptions switched during hospitalization. Switching was positively associated with independence of bladder management (odds ratio 1.65, 95 % confidence interval 1.07 to 2.49) and voiding location (odds ratio 2.72, 95 % confidence interval 1.72 to 4.37). Similar associations were observed in different stroke types., Conclusions: Approximately 20 % of patients had their lower urinary tract symptoms medications switched upon transfer from acute to convalescence rehabilitation wards. Switching was significantly associated with improved urinary independence at discharge. Consistent results were observed across different stroke types, suggesting that switching medications contributes to urinary independence after stroke, regardless of the etiology or severity of stroke., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The unremitting emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants necessitates ongoing control measures. Given its rapid spread, the new Omicron subvariant BA.5 requires urgent characterization. Here, we comprehensively analyzed BA.5 with the other Omicron variants BA.1, BA.2, and ancestral B.1.1. Although in vitro growth kinetics of BA.5 was comparable among the Omicron subvariants, BA.5 was much more fusogenic than BA.1 and BA.2. Airway-on-a-chip analysis showed that, among Omicron subvariants, BA.5 had enhanced ability to disrupt the respiratory epithelial and endothelial barriers. Furthermore, in our hamster model, in vivo pathogenicity of BA.5 was slightly higher than that of the other Omicron variants and less than that of ancestral B.1.1. Notably, BA.5 gains efficient virus spread compared with BA.1 and BA.2, leading to prompt immune responses. Our findings suggest that BA.5 has low pathogenicity compared with the ancestral strain but enhanced virus spread /inflammation compared with earlier Omicron subvariants., (© 2023. The Author(s).)

Purpose: We constructed a custom-made vitreoretinal surgical simulator using a silicone mold and described its practicality., Methods: We obtained spherical silicone molds, mannequins, and spray material from an internet-based vendor and combined them with expired surgical instruments to complete the simulator. Vitreoretinal experts confirmed the practicality of the simulator after simulated vitrectomy, and the results of the questionnaires were confirmed by nonvitreoretinal experts., Results: Vitreoretinal experts observed that the simulated eyeball and the actual eyeball were similar in size and rigidity and that the intraocular practice swing seemed to be useful for the prevention of complications. The semitransparency and open-sky structure of the silicone material ensured visibility. The simulated membrane, which was spray glue, provided an excellent peeling sensation. In the results of the nonvitreoretinal experts' questionnaires, the average scores of all items were generally high, which supported the claims of the simulator's usefulness., Conclusion: This report describes the simplicity and cost-effectiveness of our custom-made simulator and its contribution in creating an ideal training environment that does not necessitate travel to special facilities that offer a large number of pig eyes and vitreous surgical machines. The simple shape seems to allow many possibilities, and further verification at multiple facilities is necessary., (© 2023. The Author(s).)

In late 2022, SARS-CoV-2 Omicron subvariants have become highly diversified, and XBB is spreading rapidly around the world. Our phylogenetic analyses suggested that XBB emerged through the recombination of two cocirculating BA.2 lineages, BJ.1 and BM.1.1.1 (a progeny of BA.2.75), during the summer of 2022. XBB.1 is the variant most profoundly resistant to BA.2/5 breakthrough infection sera to date and is more fusogenic than BA.2.75. The recombination breakpoint is located in the receptor-binding domain of spike, and each region of the recombinant spike confers immune evasion and increases fusogenicity. We further provide the structural basis for the interaction between XBB.1 spike and human ACE2. Finally, the intrinsic pathogenicity of XBB.1 in male hamsters is comparable to or even lower than that of BA.2.75. Our multiscale investigation provides evidence suggesting that XBB is the first observed SARS-CoV-2 variant to increase its fitness through recombination rather than substitutions., (© 2023. The Author(s).)

In late 2022, various Omicron subvariants emerged and cocirculated worldwide. These variants convergently acquired amino acid substitutions at critical residues in the spike protein, including residues R346, K444, L452, N460, and F486. Here, we characterize the convergent evolution of Omicron subvariants and the properties of one recent lineage of concern, BQ.1.1. Our phylogenetic analysis suggests that these five substitutions are recurrently acquired, particularly in younger Omicron lineages. Epidemic dynamics modelling suggests that the five substitutions increase viral fitness, and a large proportion of the fitness variation within Omicron lineages can be explained by these substitutions. Compared to BA.5, BQ.1.1 evades breakthrough BA.2 and BA.5 infection sera more efficiently, as demonstrated by neutralization assays. The pathogenicity of BQ.1.1 in hamsters is lower than that of BA.5. Our multiscale investigations illuminate the evolutionary rules governing the convergent evolution for known Omicron lineages as of 2022., (© 2023. The Author(s).)

An organoid is a three-dimensional (3D) in vitro cell culture emulating human organs. We applied 3D dynamic optical coherence tomography (DOCT) to visualize the intratissue and intracellular activities of human induced pluripotent stem cells (hiPSCs)-derived alveolar organoids in normal and fibrosis models. 3D DOCT data were acquired with an 840-nm spectral domain optical coherence tomography with axial and lateral resolutions of 3.8 µm (in tissue) and 4.9 µm, respectively. The DOCT images were obtained by the logarithmic-intensity-variance (LIV) algorithm, which is sensitive to the signal fluctuation magnitude. The LIV images revealed cystic structures surrounded by high-LIV borders and mesh-like structures with low LIV. The former may be alveoli with a highly dynamics epithelium, while the latter may be fibroblasts. The LIV images also demonstrated the abnormal repair of the alveolar epithelium., Competing Interests: Morishita, Mukherjee, Abd El-Sadek, Lim, Makita, Tomita, Yasuno: Yokogawa Electric Corp. (F), Sky Technology (F), Nikon (F), Kao Corp. (F), Topcon (F), Tomey Corp (F). Suzuki: Chugai Pharmaceutical Co, Ltd (R), Nippon Boehringer Ingelheim (R), Sysmex Corporation (R). Lichtenegger: None. Yamamoto: HiLung Inc. (I, P). Nagamoto: HiLung Inc. (I)., (Published by Optica Publishing Group under the terms of the Creative Commons Attribution 4.0 License. Further distribution of this work must maintain attribution to the author(s) and the published article’s title, journal citation, and DOI.)

Background: To present a novel case that developed annular choroidal detachment after intravitreal anti-vascular endothelial growth factor antibody injection in a patient after immune checkpoint inhibitor treatment., Case Presentation: A 58-year-old Japanese man presented visual impairment in the right eye. Ophthalmological examination revealed macular edema in the right eye, which suggested the possibility of age-related macular degeneration. Following the intravitreal aflibercept injection, the annular choroidal detachment was observed in the injected eye. As hypotony or thick sclera was not observed, choroidal detachment seemed to have appeared due to enhanced inflammation by intravitreal injection. The patient had a history of stage IV paranasal cavity cancer and was treated with nivolumab, an immune checkpoint inhibitor. The immune response might have been enhanced due to the use of nivolumab so that intravitreal injection triggered inflammation. Three weeks after sub-tenon injection of triamcinolone acetonide, macular edema and choroidal detachment improved., Conclusions: Intravitreal aflibercept injection caused annular choroidal detachment in our patient, presumably because the immune system was activated after nivolumab treatment. To the best of our knowledge, this is the first case report of annular choroidal detachment that developed after intravitreal injection in a patient with a history of nivolumab therapy. With the increasing use of immune checkpoint inhibitors in patients with various cancers, clinicians should be aware of these potentially associated immune-related adverse events., (© 2022. The Author(s).)

The SARS-CoV-2 Omicron BA.2.75 variant emerged in May 2022. BA.2.75 is a BA.2 descendant but is phylogenetically distinct from BA.5, the currently predominant BA.2 descendant. Here, we show that BA.2.75 has a greater effective reproduction number and different immunogenicity profile than BA.5. We determined the sensitivity of BA.2.75 to vaccinee and convalescent sera as well as a panel of clinically available antiviral drugs and antibodies. Antiviral drugs largely retained potency, but antibody sensitivity varied depending on several key BA.2.75-specific substitutions. The BA.2.75 spike exhibited a profoundly higher affinity for its human receptor, ACE2. Additionally, the fusogenicity, growth efficiency in human alveolar epithelial cells, and intrinsic pathogenicity in hamsters of BA.2.75 were greater than those of BA.2. Our multilevel investigations suggest that BA.2.75 acquired virological properties independent of BA.5, and the potential risk of BA.2.75 to global health is greater than that of BA.5., Competing Interests: Declaration of interests Y.Y. and T.N. are founders and shareholders of HiLung, Inc. Y.Y. is a co-inventor of patents (PCT/JP2016/057254; “method for inducing differentiation of alveolar epithelial cells,” PCT/JP2016/059786, “method of producing airway epithelial cells”)., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

After the global spread of the SARS-CoV-2 Omicron BA.2, some BA.2 subvariants, including BA.2.9.1, BA.2.11, BA.2.12.1, BA.4, and BA.5, emerged in multiple countries. Our statistical analysis showed that the effective reproduction numbers of these BA.2 subvariants are greater than that of the original BA.2. Neutralization experiments revealed that the immunity induced by BA.1/2 infections is less effective against BA.4/5. Cell culture experiments showed that BA.2.12.1 and BA.4/5 replicate more efficiently in human alveolar epithelial cells than BA.2, and particularly, BA.4/5 is more fusogenic than BA.2. We further provided the structure of the BA.4/5 spike receptor-binding domain that binds to human ACE2 and considered how the substitutions in the BA.4/5 spike play roles in ACE2 binding and immune evasion. Moreover, experiments using hamsters suggested that BA.4/5 is more pathogenic than BA.2. Our multiscale investigations suggest that the risk of BA.2 subvariants, particularly BA.4/5, to global health is greater than that of original BA.2., Competing Interests: Declaration of interests Y.Y. and T.N. are founders and shareholders of HiLung, Inc. J.K. is an employee of HiLung, Inc. Y.Y. is a co-inventor of patents (PCT/JP2016/057254; “Method for inducing differentiation of alveolar epithelial cells,” PCT/JP2016/059786, “Method of producing airway epithelial cells”)., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: Easily detecting patients with undiagnosed sleep apnea syndrome (SAS) requires a home-use SAS screening system. In this study, we validate a previously developed SAS screening methodology using a large clinical polysomnography (PSG) dataset (N = 938)., Methods: We combined R-R interval (RRI) and long short-term memory (LSTM), a type of recurrent neural networks, and created a model to discriminate respiratory conditions using the training dataset (N = 468). Its performance was validated using the validation dataset (N = 470)., Results: Our method screened patients with severe SAS (apnea hypopnea index; AHI ≥ 30) with an area under the curve (AUC) of 0.92, a sensitivity of 0.80, and a specificity of 0.84. In addition, the model screened patients with moderate/severe SAS (AHI ≥ 15) with an AUC of 0.89, a sensitivity of 0.75, and a specificity of 0.87., Conclusions: Our method achieved high screening performance when applied to a large clinical dataset., Significance: Our method can help realize an easy-to-use SAS screening system because RRI data can be easily measured with a wearable heart rate sensor. It has been validated on a large dataset including subjects with various backgrounds and is expected to perform well in real-world clinical practice., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper: [Koichi Fujiwara is with Quadlytics Inc as well as Nagoya University and Manabu Kano also is with Quadlytics Inc as well as Kyoto University. Other authors declare that the research was conducted in the absence of any commercial or financial relationship that could be construed as a potential conflict of interest.], (Copyright © 2022 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Background: A case of Epstein-Barr viral (EBV) corneal stromal keratitis during rheumatoid arthritis (RA) treatment is presented., Case Presentation: A 74-year-old female undergoing RA treatment was previously treated for bacterial corneal ulcer and herpetic keratitis and healed with antibiotic eye drops and topical anti-herpes ointment. At the first visit to our hospital, she presented with findings of monocular posterior interstitial keratitis with neovascularization mostly located in the inferior cornea with a corneal epithelial defect. The right eye showed no thinning of the corneal periphery and anterior uveitis. Her RA had subsided with oral steroid treatment, and infectious mononucleosis (IM) had not developed. EBV DNA could be detected in her corneal sample. After an extended but ineffective period to antibiotic treatment the corneal infiltrate responded rapidly to topical corticosteroids., Conclusion: EBV can cause stromal keratitis without IM during treatment for RA., (© 2022. The Author(s).)