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Abstract Background Repeated inhalation of granulocyte-macrophage colony-stimulating factor (GM-CSF) was recently approved in Japan as a treatment for autoimmune pulmonary alveolar proteinosis. However, the detailed physiological and pathological effects of repeated inhalation in the long term, especially at increasing doses, remain unclear. Methods In this chronic safety study, we administered 24 cynomolgus monkeys (Macaca fascicularis) aged 2–3 years with aerosolized sargramostim (a yeast-derived recombinant human GM-CSF [rhGM-CSF]) biweekly for 26 weeks across four dosing groups (0, 5, 100, and 500 µg/kg/day). We measured the serum GM-CSF antibody (GM-Ab) concentration by an ELISA and assessed the neutralizing capacity of GM-Ab using the GM-CSF-dependent cell line TF-1. We subjected lung tissue samples taken from all monkeys at 27 weeks to histopathological assessment using a sargramostim-specific monoclonal antibody to detect localization of residual sargramostim. Results All the animals maintained good body condition and showed steady weight gain throughout the study. The pathological analyses of the lung revealed the formation of induced bronchus-associated lymphoid tissue (iBALT) in the lower respiratory tract, even at the clinical dose of 5 µg/kg/day. There was a relationship between the number or size of BALT and sargramostim dose or the serum GM-Ab levels. Immunohistochemical analyses revealed GM-Ab–producing cells in the follicular region of iBALT, with residual sargramostim in the follicles. Leucocyte counts were inversely correlated with GM-Ab levels in the high-dose groups. Additionally, serum GM-Ab from the treated animals significantly suppressed the alveolar macrophage proliferation activity of both Cynomolgus recombinant and rhGM-CSF in vitro. Conclusion Long-term repeated inhalation of sargramostim led to iBALT formation in the lower respiratory tract, even at the clinical dose of 5 µg/kg/day, with the extent of iBALT formation increasing in a dose-dependent manner. Inhaled sargramostim was localized to the follicular region of iBALT nodules, which may induce the production of GM-Ab.

Abstract Background Immune checkpoint inhibitors have recently become the standard of care in the first‐line treatment of extensive‐stage small cell lung cancer. Although immune‐related adverse events have been reported to influence prognosis in non‐small cell lung cancer patients, few studies have investigated the prognostic value of immune‐related adverse events in small cell lung cancer patients. In this study, we evaluated the prognosis of patients who developed immune‐related adverse events after first‐line treatment with immune checkpoint inhibitor‐based chemotherapy for extensive‐stage small cell lung cancer. Methods We enrolled 90 patients with extensive‐stage small cell lung cancer who received immune checkpoint inhibitor‐based chemotherapy as first‐line treatment from September 2019 to December 2022 in six hospitals in Japan. The patients were categorized into groups with and without immune‐related adverse events. Results There were 23 patients with and 67 without immune‐related adverse events. Seventeen patients had grade 1–2 immune‐related adverse events, and nine (including overlapping cases) had grade ≥3. The most frequent immune‐related adverse event was a skin rash. The median survival time was 22 months in patients with immune‐related adverse events and 9.3 months in patients without immune‐related adverse events. The hazard ratio was 0.40 (95% confidence interval: 0.19–0.83, p = 0.013). Conclusions The results of this study show that immune‐related adverse events are associated with improved survival outcomes in patients with extensive‐stage small cell lung cancer.

Abstract This retrospective study was performed to classify diabetic macular edema (DME) based on the localization and area of the fluid and to investigate the relationship of the classification with visual acuity (VA). The fluid was visualized using en face optical coherence tomography (OCT) images constructed using swept-source OCT. A total of 128 eyes with DME were included. The retina was segmented into: Segment 1, mainly comprising the inner nuclear layer and outer plexiform layer, including Henle’s fiber layer; and Segment 2, mainly comprising the outer nuclear layer. DME was classified as: foveal cystoid space at Segment 1 and no fluid at Segment 2 (n = 24), parafoveal cystoid space at Segment 1 and no fluid at Segment 2 (n = 25), parafoveal cystoid space at Segment 1 and diffuse fluid at Segment 2 (n = 16), diffuse fluid at both segments (n = 37), and diffuse fluid at both segments with subretinal fluid (n = 26). Eyes with diffuse fluid at Segment 2 showed significantly poorer VA, higher ellipsoid zone disruption rates, and greater central subfield thickness than did those without fluid at Segment 2 (P

Abstract This retrospective study investigated foveal and perifoveal retinal sensitivities using microperimetry before and after surgery for rhegmatogenous retinal detachment (RRD). Consecutive patients with RRD who underwent vitrectomy or scleral buckling were included. Comprehensive ophthalmological examinations, including microperimetry and swept-source optical coherence tomography, were performed before and 6 months after surgery. Pre- and postoperative retinal sensitivities at the fovea and 4 perifoveal measurement points farthest from the fixation point, both vertically and horizontally (superior, inferior, nasal, and temporal) were examined. A total of 34 foveal and 136 perifoveal measurement points in 34 eyes of 34 patients were evaluated. The postoperative retinal sensitivity was significantly higher than the preoperative value at foveal and perifoveal points with (P

Abstract Background Structural changes of the choroid, such as choroidal thickening, have been indicated in amblyopic eyes with hyperopic anisometropia as compared to fellow or healthy eyes. The purpose of the present study was to investigate choroidal vascular density (CVD) in children with unilateral hyperopic amblyopia. Methods This study included 88 eyes of 44 patients with unilateral amblyopia due to hyperopic anisometropia with or without strabismus and 29 eyes of 29 age-matched normal controls. The CVD of Haller’s layer was quantified from en-face images constructed by 3-dimensional swept-source optical coherence tomography images flattened relative to Bruch’s membrane. The analysis area was a 3 × 3-mm square of macula after magnification correction. Relationships between CVD and other parameters [best-corrected visual acuity (BCVA), refractive error and subfoveal choroidal thickness (SFCT)] were investigated, and CVDs were compared between amblyopic, fellow, and normal control eyes. Results Mean CVD was 59.11 ± 0.66% in amblyopic eyes, 59.23 ± 0.81% in fellow eyes, and 59.29 ± 0.74% in normal control eyes. CVD showed a significant positive relationship with SFCT (p = 0.004), but no relationships with other parameters. No significant differences in CVD were evident among amblyopic, fellow, and normal control eyes after adjusting for SFCT (p = 0.502). Conclusions CVD was unrelated to BCVA, and CVD did not differ significantly among amblyopic, fellow and normal control eyes. These results suggest that the local CVD of Haller’s layer is unaffected in unilateral hyperopic amblyopic eyes.

Elastic layer-structured metal-organic framework (MOF)-11 {ELM-11: [Cu(BF4)2 (4,4′-bipyridine)2]}, which is a crystalline porous material, is a promising adsorbent for high-throughput and high-efficiency separation processes of CO2 because of its peculiar adsorption characteristics originating from the flexibility of the crystal framework. However, the exposure of ELM-11 to water vapor has been reported to reduce its CO2 capacity, which is problematic for processing feed gases that contain a certain concentration of water vapor. In this study, we investigated the stability of ELM-11 against water vapor exposure to reveal the mechanism of CO2 capacity reduction. Our combined measurements of adsorption isotherms and X-ray diffraction patterns indicated that the CO2 capacity reduction was caused by the partial formation of a crystalline subphase upon adsorption of water molecules and the subsequent formation of an amorphous phase to relax the crystalline grain boundaries. Because a higher supply rate of water molecules resulted in a larger amount of subphase formation, we concluded that the structural subphase was a metastable kinetically controlled structure, formed through the rate-dependent adsorption of water molecules. These results suggest that slowing the adsorption rate is an effective approach to suppress the formation of the subphase; therefore, we proposed the covering of ELM-11 surfaces with porous shells. We used ELM-12 {[Cu(CF3SO3)2 (4,4′-bipyridine)2]} as a shell material because of its robust stability against water adsorption and affinity with ELM-11. The ELM-12 shell decreased the adsorption rate of water molecules compared with that of bare ELM-11, resulting in the suppression of subphase formation and preventing CO2 capacity reduction. Although further optimization of the shell thickness and coverage is required to keep the capacity completely unchanged, controlling the adsorption rate of water molecules is successfully demonstrated to be possible with shell formation, which is key for industrial applications of ELM-11.

Abstract Background We recently reported that lamellar macular hole (LMH) with lamellar hole-associated epiretinal proliferation (LHEP) can be effectively treated by embedding the LHEP into the retinal cleavage to improve foveal contour and visual acuity. Here, we report a case of LMH with LHEP for which we performed embedding of the LHEP combined with internal limiting membrane (ILM) inversion. We then evaluated the effects of this surgery on macular morphology and visual functions. Case presentation A 62-year-old man presented with visual disturbance (20/29) and metamorphopsia in his right eye. B-scan optical coherence tomography (OCT) imaging revealed the presence of both partial-thickness defect of the macula with degenerative retinal cleavage and LHEP at the surface of the retina. En face OCT imaging showed the absence of retinal fold. We performed phacoemulsification with intraocular lens implantation, vitrectomy, embedding of LHEP into the retinal cleavage, and ILM inversion. Three months after the surgery, both foveal contour and visual acuity (20/20) were improved and metamorphopsia was reduced. Conclusion Embedding of the LHEP combined with ILM inversion may be an effective treatment for LMH with LHEP.

PurposeThis study aimed to evaluate the shape of the extraocular muscles (EOMs) in normal subjects using the en-face images of anterior segment optical coherence tomography (AS-OCT). The EOM insertion and the direction of the muscle fibers were investigated.Subjects and methodsA total of 97 healthy normal subjects (194 eyes) at Okayama University Hospital (age, 47.1±21.5 years; range, 8-79 years) participated in the study. A series of 256 tomographic images of the rectus EOMs were captured using the C-scan function of the AS-OCT (CASIA2, TOMEY Co., Japan), and the images were converted to en-face images in multi-TIFF format. The anterior chamber angle to EOM insertion distance (AID) and the angle of the muscle fibers from the insertion site (angle of muscles) were measured from the images. The correlations of AID and angle of muscles with age and axial length were investigated and evaluated.ResultsAID and angle of muscles were significantly correlated with age or axial length in some EOMs. The AIDs of medial rectus (MR) (P = 0.000) and superior rectus (SR) (P = 0.005) shortened with age. The AIDs of MR (P = 0.001) and inferior rectus (IR) (P = 0.035) elongated with axial length, whereas lateral rectus (LR) (P = 0.013) shortened. The angles of MR (P = 0.001) and LR (P = 0.000) were found to have a more downward direction toward the posterior in older subjects.ConclusionEn-face images can be created by AS-OCT, and the shape of the EOMs in normal subjects using these image measurements was available. With the ability to assess the EOMs, AID and angle of muscles are expected give useful information for treating and diagnosing strabismus-related diseases.

Abstract Background Coats disease is a retinal disease characterized by exudative retinal detachment due to abnormal retinal blood vessels. Coats disease is generally treated using laser photocoagulation and cryotherapy to ablate the abnormal retinal blood vessels. However, if abnormal blood vessels are present near the posterior pole of the eye and there is a severe exudative change there, it is difficult to perform these standard treatments. We describe a case of Coats disease with severe exudative retinal change and retinal vascular abnormality near the posterior pole for which we performed photodynamic therapy and successfully suppressed the disease and improved vision. Case presentation A 15-year-old Japanese boy presented to hospital with a chief complaint of decreased vision in his right eye. At the initial examination, corrected visual acuity of the right eye was 20/100. On the right fundus, exudative retinal detachment with subretinal haemorrhage was observed from the upper intermediate periphery to the posterior pole. Abnormal telangiectatic vessels and microaneurysms were found at the nasal peripheral retina. From these findings, we diagnosed the case as Coats disease. We conducted photodynamic therapy for the right eye. At 10 months after treatment, both the subretinal haemorrhage and the exudative retinal detachment had disappeared completely. Further, the retinal structure of the macula had recovered, and right vision had improved to 20/20. Conclusion Photodynamic therapy may be an effective and safe treatment for Coats disease in cases that present with abnormal retinal vessels close to the posterior pole of the eye.

Background: Vision plays a key role in some behavior tests for rats. Okayama University-type retinal prosthesis (OUReP) is a photoelectric dye-coupled polyethylene film which generates electric potential in response to light and stimulates nearby neurons. This study aims to assess vision in retinal dystrophic (RCS) rats, in comparison with normal rats, by selected behavior tests. We also examined whether the tests could detect vision changes in RCS rats with dye-coupled film implantation. Methods: Data sets were 5 normal rats, 4 untreated RCS rats, 7 RCS rats with dye-coupled films implanted at the age of 7 weeks after excluding unsuccessful implantation at autopsy. Behavior tests chosen were landing foot splay and visual forelimb-placing response in the menu of functional observational battery, operant-conditioning lever-press response and light/dark box test. Results: Normal visual placing response was significantly less frequent in untreated RCS rats at the age of 9 and 11 weeks, compared with normal rats (P = 0.0027, chi-square test) while normal response was significantly more frequent at the age of 9 weeks in RCS rats with dye-coupled film implantation, compared with untreated RCS rats (P = 0.0221). In operant-conditioning lever-press test, the correct response rate was significantly lower in untreated RCS rats than in normal rats at the age of 9 weeks (P < 0.05, Tukey-Kramer test) while the rate was not significantly different between normal rats and RCS rats with dye-coupled film implantation. In light/dark box test, the time to enter dark box was significantly shorter in normal rats, compared with untreated RCS rats or RCS rats with dye-coupled film implantation (P < 0.05, Tukey-Kramer test). Conclusions: Behavior tests of functional observational battery, operant-conditioning lever-press response and light/dark box test discriminated vision between normal rats and RCS rats. The visual placing response and operant-conditioning lever-press test might have sensitivity to detect vision recovery in RCS rats with OUReP implantation.

For primary open angle glaucoma (POAG), laser treatment or surgery is used when the target intraocular pressure (IOP) cannot be achieved by pharmacological agents, such as prostaglandin (PG) analogs; these drugs also have varied effects. We retrospectively reviewed the medical records of 74 POAG patients (74 eyes) whose IOP was inadequately controlled by PG analogs (bimatoprost [13 eyes], latanoprost [34 eyes], tafluprost [11 eyes], and travoprost [16 eyes]) and underwent primary trabeculectomy. The proportion of patients with no recurrent IOP elevation within 24 months post-trabeculectomy was significantly (P < 0.001) lower in the bimatoprost group (31.3%) than in the latanoprost (83.2%), tafluprost (45.5%), or travoprost groups (65.6%). Deepening of the upper eyelid sulcus (DUES) was observed before trabeculectomy in 18 of 74 eyes (24.3%) treated with bimatoprost (9 eyes; 50.0%), latanoprost (3 eyes; 16.7%), tafluprost (1 eye; 5.5%) and travoprost (5 eyes; 27.8%). The proportion of patients with no recurrent IOP elevation up to 24 months post-trabeculectomy was significantly (P < 0.0001) lower in the DUES(+) group (34.7%) than in the DUES(-) group (74.3%). Multivariate stepwise logistic regression analysis, with no recurrent IOP elevation used as dependent variable, and bimatoprost, latanoprost, travoprost, tafluprost, β-blocker, carbonic anhydrase inhibitor, brimonidine, gender, age, preoperative IOP, mean deviation, duration of PG analog use before surgery, and the number of ophthalmic solutions used as independent variables, identified only bimatoprost as a significant independent factor (P = 0.0368). Thus, the outcome of trabeculectomy varied depending on the PG analog used preoperatively, and bimatoprost use was associated with a high risk of recurrent IOP elevation up to 2 years post-trabeculectomy. This may indicate that the incidence of DUES differed with the PG analog used. Patients with glaucoma who are treated with bimatoprost should be monitored for DUES, and when these patients undergo trabeculectomy, the postoperative course of IOP should be followed carefully.

To examine factors affecting foveal avascular zone (FAZ) area in healthy eyes using swept-source optical coherence tomography angiography (OCTA).This prospective, cross-sectional study included 144 eyes of 144 individuals (77 women, 67 men) with a best corrected visual acuity of at least 20/20 and no history of ocular disorders. The area of the superficial FAZ was assessed using OCTA. Age, gender, central retinal thickness (CRT), retinal vascular density, refractive error, and axial length were examined to determine associations with FAZ area.The mean age of the subjects was 42.1 ± 20.2 years (range: 10-79 years). The mean FAZ area was 0.32 ± 0.11 mm2, while the mean retinal vascular density was 35.53 ± 0.92%. Multivariate regression analysis was performed using FAZ area as the dependent variable and age, gender, CRT, retinal vascular density, refractive error, and axial length as independent variables. The results of this analysis demonstrate that CRT and retinal vascular density were significantly associated with FAZ area in our sample (P < 0.001, R2 = 0.425). Age, gender, refractive error, and axial length were not significantly correlated with FAZ area, while CRT and retinal vascular density were negatively correlated with FAZ area (CRT: P < 0.001, R2 = 0.356; retinal vascular density: P < 0.001, R2 = 0.189).OCTA results suggest that CRT and retinal vascular density negatively affect FAZ area in healthy eyes.

We examined the effectiveness of trabeculectomy in decreasing the slope of mean deviation (MD) in Japanese patients with progressive normal-tension glaucoma (NTG) at low intraocular pressure (IOP) levels. The charts of patients who had undergone initial trabeculectomy with adjunctive mitomycin C for progressive NTG with medically controlled IOP < 15 mmHg in 2010-2013 were retrospectively reviewed. Seventeen eyes of 13 NTG patients who had undergone at least 5 times of visual field (VF) examinations in both of preoperatively and postoperatively with postoperative follow-up of ≥ 2 years were enrolled. Preoperative and postoperative MD slopes were compared to evaluate the effectiveness of trabeculectomy in slowing progression of VF. Mean IOP (8.1 ± 2.9 mmHg) and number of IOP-lowering medications (0.8 ± 1.5) were significantly lower postoperatively than preoperatively (13.9 ± 0.9 mmHg; P < 0.001 and 3.0± 0.4; P < 0.0001). In total, 91.7% of eyes with single-digit IOP postoperatively showed improvement in MD slope, whereas only 20.0% of eyes with IOP ≥ 10 mmHg postoperatively showed the improvement. Three eyes (17.6%) showed a decrease in visual acuity (VA) of ≥ 0.1 unit; this group had a lower mean postoperative IOP (6.0 ± 1.0 vs. 8.6 ± 3.0 mmHg; P = 0.1717) and a higher mean IOP reduction rate (56.2 vs. 38.5%; P = 0.8296) than eyes with a VA decrease of < 0.1 unit or no change. Thus, in this analysis of Japanese NTG patients with medically controlled IOP < 15 mmHg, achieving an IOP < 10 mmHg with trabeculectomy was beneficial for reducing the VF progression rate in progressive NTG at low IOP levels. However, an IOP < 7 mmHg by surgery would be required careful attention to VA decline.

To investigate the tilt and decentration of the crystalline lens and the intraocular lens (IOL) relative to the corneal topographic axis using anterior segment ocular coherence tomography (AS-OCT).A sample set of 100 eyes from 49 subjects (41 eyes with crystalline lenses and 59 eyes with IOLs) were imaged using second generation AS-OCT (CASIA2, TOMEY) in June and July 2016 at Okayama University. Both mydriatic and non-mydriatic images were obtained, and the tilt and decentration of the crystalline lens and the IOL were quantified. The effects of pupil dilation on measurements were also assessed.The crystalline lens showed an average tilt of 5.15° towards the inferotemporal direction relative to the corneal topographic axis under non-mydriatic conditions and 5.25° under mydriatic conditions. Additionally, an average decentration of 0.11 mm towards the temporal direction was observed under non-mydriatic conditions and 0.08 mm under mydriatic conditions. The average tilt for the IOL was 4.31° towards the inferotemporal direction relative to the corneal topographic axis under non-mydriatic conditions and 4.65° in the same direction under mydriatic conditions. The average decentration was 0.05 mm towards the temporal direction under non-mydriatic conditions and 0.08 mm in the same direction under mydriatic conditions. A strong correlation was found between the average tilt and decentration values of the crystalline lens and the IOL under both non-mydriatic and mydriatic conditions (all Spearman correlation coefficients, r ≥ 0.800; all P < 0.001).When measured using second generation AS-OCT, both the crystalline lens and the IOL showed an average tilt of 4-6° toward the inferotemporal direction relative to the corneal topographic axis and an average decentration of less than 0.12 mm towards the temporal direction. These results were not influenced by pupil dilation and they showed good repeatability.

To investigate the occurrence ratio, localization, and surgical outcomes of intraretinal cystic spaces in idiopathic epiretinal membranes (ERMs).We retrospectively reviewed the charts of 432 eyes of 398 consecutive patients with idiopathic ERM who underwent vitrectomy and ERM peeling from January 2012 to September 2015. We selected cases with intraretinal cystic space prior to surgery, detected by spectral-domain optical coherence tomography. We then evaluated the effects of ERM peeling on intraretinal cystic spaces, best corrected visual acuity, and central retinal thickness at 6 months after surgery.Twenty-four eyes (5.5%) showed intraretinal cystic spaces before surgery, present in the inner retinal layer (the inner group) in 9 eyes, in the outer retinal layer (the outer group) in 6 eyes, and in both the inner and the outer retinal layers (the combined group) in 9 eyes. Additionally, 30 eyes with ERM but without any presence of intraretinal cystic space were selected randomly and classified as the no cyst group. At 6 months after surgery, the disappearance rate of cystic spaces was significantly greater for the outer group than for the inner group (83.3% and 11.1%, respectively, P = 0.011). The mean best corrected visual acuity improved significantly after surgery in the inner group, the outer group, and the no cyst group (P < 0.05 for all three groups) but did not improve in the combined group (P = 0.58). The mean central retinal thickness decreased significantly after surgery in the inner group, the combined group, and the no cyst group (P < 0.05).Intraretinal cystic spaces were observed in 5.5% of preoperative idiopathic ERM cases. Following surgery, the cystic spaces in the outer retinal layer disappeared at higher rates than those in the inner retinal layer, suggesting that the pathophysiologies of these cystic spaces are different.

Streptococcus parauberis, which is the main causative agent of streptococcosis among olive flounder (Paralichthys olivaceus) in northeast Asia, can be distinctly divided into two groups (type I and type II) by an agglutination test. Here, the whole genome sequences of two Japanese strains (KRS-02083 and KRS-02109) were determined and compared with the previously determined genome of a Korean strain (KCTC 11537). The genomes of S. parauberis are intermediate in size and have lower GC contents than those of other streptococci. We annotated 2,236 and 2,048 genes in KRS-02083 and KRS-02109, respectively. Our results revealed that the three S. parauberis strains contain different genomic insertions and deletions. In particular, the genomes of Korean and Japanese strains encode different factors for sugar utilization; the former encodes the phosphotransferase system (PTS) for sorbose, whereas the latter encodes proteins for lactose hydrolysis, respectively. And the KRS-02109 strain, specifically, was the type II strain found to be able to resist phage infection through the clustered regularly interspaced short palindromic repeats (CRISPR)/Cas system and which might contribute valuably to serologically distribution. Thus, our genome-wide association study shows that polymorphisms can affect pathogen responses, providing insight into biological/biochemical pathways and phylogenetic diversity.

In the development of drugs that affect the central nervous system (CNS), it is important to determine whether they have dependence potential and if so, to establish an effective dose within a range that does not manifest dependency. Methods for evaluating drug dependence include selfadministration tests using experimental animals while assessment of the minimum effective dose (MED) involves gross behavioral observation. This study aims to examine the relationship between the most frequently self-administered dose (peak self-administered dose, PSAD) and the MED amongst different types of CNS depressants in order to optimize dose range selection for the evaluation of drug reinforcing effects. PSAD was investigated by intravenous self-administration in rhesus monkeys conducted as daily 2 hr-sessions under a fixed ratio 5 schedule with a 1-min time-out after each administration. MED was investigated by gross behavioral observation following cumulative dosing. For opiates, the PSAD was 0.016 mg/kg/infusion for morphine, 0.06 mg/kg/infusion for codeine, 0.25 mg/kg/infusion for butorphanol and 0.063 mg/kg/infusion for pentazocine. For anesthetics and sedatives, the PSAD was 0.5 mg/kg/infusion for pentobarbital, 0.25 mg/kg/infusion for thiopental, 0.06 mg/kg/infusion for ketamine and 0.063 mg/kg/infusion for midazolam. The PSAD/MED ratio was 1/63-1/32 for opiates and 1/8-1/2 for anesthetics and hypnosedatives. While previous research by Fujiwara et al. (2016) suggested that a dose range lower than the MED for gross behavioral effects should be used for intravenous self-administration in the evaluation of drug reinforcing effects, this study further indicates that the optimal dose range may vary depending on drug type. [ABSTRACT FROM AUTHOR]