Receptor activity-modifying proteins of adrenomedullin (RAMP2/3): Roles in the pathogenesis of ARDS.

Acute respiratory distress syndrome (ARDS) is a life-threatening lung condition characterized by widespread inflammation and pulmonary edema. Adrenomedullin (AM), a bioactive peptide with various functions, is expected to be applied in treating ARDS. Its functions are regulated primarily by two receptor activity-modifying proteins, RAMP2 and RAMP3, which bind to the AM receptor calcitonin receptor-like receptor (CLR). However, the roles of RAMP2 and RAMP3 in ARDS remain unclear. We generated a mouse model of ARDS via intratracheal administration of lipopolysaccharide (LPS), and analyzed the pathophysiological significance of RAMP2 and RAMP3. RAMP2 expression declined with LPS administration, whereas RAMP3 expression increased at low doses and decreased at high doses of LPS. After LPS administration, drug-inducible vascular endothelial cell-specific RAMP2 knockout mice (DI-E-RAMP2-/-) showed reduced survival, increased lung weight, and had more apoptotic cells in the lungs. DI-E-RAMP2-/- mice exhibited reduced expression of Epac1 (which regulates vascular endothelial cell barrier function), while RAMP3 was upregulated in compensation. In contrast, after LPS administration, RAMP3-/- mice showed no significant changes in survival, lung weight, or lung pathology, although they exhibited significant downregulation of iNOS, TNF-α, and NLRP3 during the later stages of inflammation. Based on transcriptomic analysis, RAMP2 contributed more to the circulation-regulating effects of AM, whereas RAMP3 contributed more to its inflammation-regulating effects. These findings indicate that, while both RAMP2 and RAMP3 participate in ARDS pathogenesis, their functions differ distinctly. Further elucidation of the pathophysiological significance and functional differences between RAMP2 and RAMP3 is critical for the future therapeutic application of AM in ARDS.

Evaluating initial responses to brolucizumab in patients undergoing conventional anti-VEGF therapy for diabetic macular edema: a retrospective, single-center, observational study.

Our retrospective, single-center, observational study aimed to evaluate the initial responses to intravitreal injection of brolucizumab (IVBr) in patients undergoing anti-vascular endothelial growth factor (VEGF) therapy for diabetic macular edema (DME). In total, 23 eyes of 20 patients with DME treated with at least one intravitreal injection of ranibizumab or aflibercept within one year and then switched to IVBr were included. Best corrected visual acuity (BCVA), central macular thickness (CMT), and macular volume (MV) on optical coherence tomography images were evaluated just before the most recent conventional anti-VEGF (ranibizumab/aflibercept) injection therapy (V1), one month after the most recent traditional anti-VEGF therapy (V2), just before the first IVBr (V3), and one month after the first IVBr (V4). BCVA, CMT, MV, and presence of intraocular inflammation (IOI) were evaluated at each visit. Anterior chamber flare values were also examined at V3 and V4. BCVA showed significant improvement at V2 (0.30 ± 0.23) than V1 (0.39 ± 0.29) and at V4 (0.34 ± 0.26) than V3 (0.48 ± 0.34) (P = 0.002, P < 0.001). However, no significant difference was observed between V2 and V4 (P = 0.257). CMT was significantly thinner at V2 (346.8 ± 90.2 µm) than V1 (495.5 ± 123.8 µm), and at V4 (322.2 ± 95.7 µm) than V3 (536.5 ± 166.0 µm) (P < 0.001, P < 0.001), but no significant difference was observed between V2 and V4 (P = 0.140). MV was significantly smaller at V2 (11.6 ± 2.0 mm3) than V1 (12.6 ± 1.9 mm3) and at V4 (11.2 ± 2.0 mm3) than V3 (12.6 ± 2.0 mm3) (P < 0.001, P < 0.001), and even significantly smaller at V4 than V2 (P = 0.009). No patient had IOI. No significant changes were observed in anterior chamber flare values between V3 and V4 (25.6 ± 14.6 vs. 24.0 ± 11.5 photon count/ms; P = 0.543). Both CMT and MV significantly reduced without any adverse events one month after switching from conventional anti-VEGF to IVBr therapy for DME, including IOI. MV was significantly lower for IVBr than anti-VEGF therapy after one month of treatment. Therefore, brolucizumab may be a viable treatment option for DME patients considering switching from conventional anti-VEGF agents for various reasons, such as poor response or inability to extend dosing intervals.

Impact of local COVID-19 alert levels on rhegmatogenous retinal detachment.

PURPOSE: To investigate the impact of the local alert levels regarding coronavirus disease 2019 (COVID-19) on the clinical patterns of rhegmatogenous retinal detachment (RRD) in Japan. STUDY DESIGN: Retrospective, single-center, consecutive case series. METHODS: We compared two groups of RRD patients, a COVID-19 pandemic group and a control group. Based on the local alert levels in Nagano, five periods during the COVID-19 pandemic were further analyzed: epidemic 1 (state of emergency), inter-epidemic 1, epidemic 2 (second epidemic duration), inter-epidemic 2, and epidemic 3 (third epidemic duration). Patients' characteristics, including symptoms' duration before visiting our hospital, macula status, and retinal detachment (RD) recurrence rate in each period, were compared with those in a control group. RESULTS: There were 78 patients in the pandemic group and 208 in the control group. The pandemic group had a longer duration of symptoms than the control group (12.0 ± 13.5 days vs. 8.9 ± 14.7 days, P = 0.0045). During the epidemic 1 period, patients had a higher rate of macula-off RRD (71.4% vs. 48.6%) and RD recurrence (28.6% vs. 4.8%) than the control group. This period also demonstrated the highest rates compared to all other periods in the pandemic group. CONCLUSION: During the COVID-19 pandemic, RRD patients significantly delayed visiting a surgical facility. They showed a higher rate of macula-off and recurrence compared to the control group during the state of emergency than during other periods of the COVID-19 pandemic, although the difference was not statistically significant due to the small sample size.

Retinal arterial occlusive vasculitis after multiple intravitreal brolucizumab injections for diabetic macular edema.

Purpose: To describe a case of unilateral retinal arterial occlusive vasculitis after multiple intravitreal brolucizumab (IVBr) treatments for diabetic macular edema (DME). Observations: A 68-year-old Japanese woman who had a 3-year history of insulin-dependent diabetes mellitus presented with decreased vision in the right eye (oculus dexter, OD). After two consecutive IVBr (3 mg) treatments for DME, spaced 6 weeks apart, her best corrected visual acuity improved from 20/32 to 20/28 OD, as central macular thickness (CMT) decreased from 368 µm to 253 µm on optical coherence tomography (OCT). Immediately after the 3rd IVBr, the right intraocular pressure (IOP) increased. One week later, iritis (aqueous flares: 65.0 photon count [PC]/ms) was observed, followed by localized vasculitis 2 weeks later. One month after the 3rd IVBr, extensive vasculitis and vasculitis occluding retinal arterioles were identified. Based on the history of IVBr use and clinical findings, intraocular inflammation (IOI) and subsequent retinal arterial occlusive vasculitis due to IVBr was diagnosed. Topical steroid administration (i.e., eye drops and subtenon injection) resulted in improvement of IOI after 3 months. She subsequently underwent two intravitreal aflibercept injections for DME and panretinal photocoagulation (PRP) to prevent the development of proliferative changes due to diabetic retinopathy. One year after the diagnosis of retinal arterial occlusive vasculitis, the patient had slight loss of vision (20/50) compared to baseline, due to the progression of cataracts, and OCT angiography (OCTA) showed extensive non-perfusion area on the temporal side. However, other examination findings (IOP: 16 mmHg, aqueous flares: 30.5 PC/ms, CMT: 283 µm) were stable. Conclusions and importance: Diagnosis and treatment at a relatively early stage after the onset of IOI prevented severe visual impairment in this case. Topical betamethasone eye drops reduced anterior chamber inflammation associated with IVBr; however, vascular sheathing worsened when topical drops alone was used. Occlusive retinal vasculitis, diagnosed with fluorescein angiography (FA) and OCTA, appeared to stabilize when subtenon triamcinolone injection was added to topical steroid administration. Because the central macula was not involved, severe vision loss was prevented. It is unknown if topical steroid administration would be adequate to prevent worsening of occlusive vasculitis in other cases. Although not used in this case, oral prednisone is one treatment option that may prevent severe vision loss. However, it requires monitoring of side effects, such as elevated blood glucose levels. PRP is also an option in cases where progression of proliferative changes is a concern, as was done in this case. With these considerations in mind, it is important to diagnose brolucizumab-associated IOI and subsequent retinal arterial occlusive vasculitis in DME patients early and initiate treatment to prevent severe visual impairment. Diagnosing new IOI and subsequent retinal arterial occlusive vasculitis is more difficult in DME than in neovascular age-related macular degeneration because of the inflammatory component often associated vascular occlusions. Therefore, early IOI diagnosis and follow-up using various instruments such as laser flare cell meter, wide-field color imaging, OCT/OCTA, and FA, in addition to usual comprehensive ophthalmologic examinations, is crucial.

Wide-field swept-source OCT angiography (23 × 20 mm) for detecting retinal neovascularization in eyes with proliferative diabetic retinopathy.

PURPOSE: Xephilio OCT-S1 can capture single-acquisition 23 × 20-mm wide-field swept-source optical coherence tomography angiography (SS-OCTA) images and high-resolution images using artificial intelligence. We aimed to evaluate the ability of wide-field SS-OCTA in the detection of retinal neovascularizations (NVs) in eyes with proliferative diabetic retinopathy (PDR). METHODS: This retrospective study included 64 eyes of 36 patients (age, 57 ± 10 years; 10 female, 26 male) with PDR. All patients underwent a comprehensive ophthalmological examination, including fluorescein angiography (FA), as well as fovea- and disc-centered 23 × 20-mm OCTA imaging (A-scan/B-scan, 928/807). We compared and examined the number of NV sites identified using conventional methods (merging the findings from biomicroscopy/color fundus photography, FA) and the number of NV sites identified using vitreoretinal interface and superficial retinal slabs of wide-field SS-OCTA images, including the position of NVs (nasal upper, nasal lower, temporal upper, temporal lower, or disc). RESULTS: We identified 168 NVs (32/40/45/35/16, in the abovementioned order) using the conventional method. Fovea-centered 23 × 20-mm OCTA images revealed 162 (96%) NVs (27/39/45/35/16). This method tended to miss nasal NV. In contrast, disc-centered 23 × 20-mm OCTA images identified nearly all NVs, detecting 166 (99%) NVs (32/40/44/34/16) in total. All NVs could be visualized using two wide-field OCTA images: fovea- and disc-centered. CONCLUSION: Wide-field (23 × 20 mm) SS-OCTA-especially disc-centered-using Xephilio OCT-S1 identified nearly all NVs in eyes with PDR, with a single acquisition, thereby demonstrating its potential clinical application.

Morphological Changes in the Foveal Avascular Zone after Panretinal Photocoagulation for Diabetic Retinopathy Using OCTA: A Study Focusing on Macular Ischemia.

Background and objectives: This study aimed to analyze the morphological changes in the foveal avascular zone (FAZ) after panretinal photocoagulation (PRP) in patients with diabetic retinopathy, with a particular focus on the presence or absence of comorbid diabetic macular ischemia (DMI), using optical coherence tomography angiography (OCTA). Materials and Methods: Treatment-naïve 25 eyes of 16 patients who received PRP were examined in this retrospective case series. FAZ area, perimeter, and circularity were calculated on a 3 × 3-mm en-face OCTA image before PRP (baseline) and 1 and 3 months after PRP. The patients were divided into two groups according to coexisting DMI, and each group was statistically analyzed. Results: In patients with DMI (9 eyes), FAZ area significantly decreased from the baseline to 3 months after PRP (0.86 ± 0.56 to 0.61 ± 0.31 mm2, p = 0.018), whereas FAZ perimeter and circularity remained unchanged following treatment (p = 0.569 and 0.971, respectively). In patients without DMI (16 eyes), FAZ parameters did not show statistically significant changes across the 3-month follow-up period. Conclusion: PRP significantly reduces FAZ area in patients with DMI.

Temporal Change in Anterior Chamber Depth after Combined Vitrectomy and Cataract Surgery Using Different Sizes of Intraocular Lens.

This study aimed to investigate the temporal changes in the anterior chamber depth (ACD) and refractive prediction error (RPE) of 6 and 7 mm diameter intraocular lenses (IOLs) after cataract surgery or phacovitrectomy with or without sulfur hexafluoride (SF6) gas. We reviewed 120 eyes (120 patients) and divided them into six groups: three groups of cataract surgery alone and phacovitrectomy (with or without SF6), which were further divided according to IOL diameter (6 and 7 mm) used. We examined the ACD and IOL position using a swept-source anterior segment optical coherence tomograph at 1 day, 1 week, and 1 month postoperatively; and the RPE at 1 month postoperatively. The ACD and IOL position at postoperative day 1 in the SF6 injection groups were significantly smaller than those in the other groups (p < 0.01). At 1 week, the ACD and IOL position of the 6 mm IOL SF6 injection group was smaller than those in the other groups (p < 0.01); thus, complications such as synechia or pupillary capture should be considered in the early postopera-tive period of phacovitrectomy with SF6, especially in the 6 mm IOL. The ACD, IOL position, and RPE at 1 month did not significantly differ among the groups, regardless of the IOL diameter or SF6. In the SF6 injection groups, the ACD and IOL position gradually deepened with less gas.

Optical coherence tomography angiography findings before and after onset of foveal retinal neovascularization in diabetic retinopathy.

PURPOSE: To report a rare case of foveal retinal neovascularization (RNV) in a patient with diabetic retinopathy in whom the retinal microcirculation structure before and after the onset of the disease was evaluated using optical coherence tomography angiography (OCTA). OBSERVATIONS: A 54-year-old woman with diabetes mellitus was referred to our department for fundus evaluation, and was diagnosed with cataract and severe non-proliferative diabetic retinopathy in the left eye. Two years after we performed cataract surgery and pan-retinal photocoagulation in the left eye, OCTA detected a previously unidentified foveal RNV arising from the perifoveal capillary network. The vitreous retinal interface slab of OCTA and cross-sectional OCT images confirmed that this foveal RNV was an aberrant vessel invading the vitreous cavity. CONCLUSIONS AND IMPORTANCE: The findings in this case indicate that foveal RNV in diabetic retinopathy is derived from vessels outside the foveal avascular zone (FAZ), and OCTA is a useful examination for the diagnostic investigation of foveal RNV.

Vitreoretinal Interface Slab in OCT Angiography for Detecting Diabetic Retinal Neovascularization.

PURPOSE: To compare neovascularization identified in proliferative diabetic retinopathy (PDR) eyes by widefield swept-source (SS) OCT angiography (OCTA) using vitreoretinal interface (VRI) slab images, composed by automated and manual segmentation, with that identified by fluorescein angiography (FA). DESIGN: Retrospective study. PARTICIPANTS: Forty-two eyes of 30 treatment-naïve PDR patients who visited the outpatient clinic of the Department of Ophthalmology, Shinshu University, from June 2018 through October 2019. METHODS: All patients underwent comprehensive ophthalmologic examinations, including SS-OCTA and FA. MAIN OUTCOME MEASURES: Neovascularization detected by en face SS-OCTA 15 × 15-mm VRI slab images and by FA in the same 15 × 15-mm areas were compared in terms of number and structure. RESULTS: Among 100 neovascularizations detected by FA, 73 also were visualized as neovascularization in SS-OCTA VRI slab images using automated segmentation. The sensitivity of VRI slab images for detecting neovascularization was 73%. Among the remaining 27 neovascularizations detected only by FA, but not by VRI slab, 15 were intraretinal microvascular abnormalities with fluorescence leakage, 1 was a diabetic papillopathy, and 11 were flat neovascularizations on the internal limiting membrane surface that were missed because of segmentation error. Conversely, among the 98 neovascularizations detected on VRI slab images, 25 were not detected as neovascularizations by FA. They included 9 small neovascularizations that exhibited too little leakage on FA and 16 false-positive results that were the result of segmentation errors. After reconstruction of SS-OCTA VRI slab images by means of manual segmentation, the sensitivity of VRI slab images for detecting neovascularizations increased to 84%. CONCLUSIONS: The efficacy of SS-OCTA VRI slab images for detecting neovascularizations in PDR was comparable with that of FA. Swept-source OCTA VRI slab images may be better than FA for identifying intraretinal microvascular abnormalities and diabetic papillopathy from neovascularizations. Notably, however, FA and SS-OCTA VRI slab images demonstrated differences in identification efficacy in cases of small and flat neovascularizations. Further exploration of SS-OCTA technology is warranted to address this issue.