Improvement of ß-Cell Function After Switching From DPP-4 Inhibitors to Oral Semaglutide: SWITCH-SEMA2 Post Hoc Analysis.

CONTEXT: Whether continuation of dipeptidyl peptidase-4 inhibitors (DPP-4is) or switching to oral semaglutide is more beneficial for ß-cell function is unclear. OBJECTIVE: To assess the efficacy of switching from DPP-4is to oral semaglutide for ß-cell function compared with DPP-4i continuation. METHODS: Post hoc analysis of SWITCH-SEMA 2, a multicenter prospective randomized controlled trial on the switch to oral semaglutide vs DPP-4i continuation without dose adjustment for 24 weeks in subjects with type 2 diabetes treated with DPP-4is, was conducted. Changes in markers for glucose metabolism, including homeostatic model assessment (HOMA2) scores and disposition index (DI), were compared between the groups. RESULTS: A total of 146 subjects (semaglutide group, 69; DPP-4i group, 77) were analyzed. In the semaglutide group, glycemic control, liver enzyme deviations, and lipid profiles improved after 24 weeks. Regarding indices for ß-cell function, changes in HOMA2-ß as well as DI, reflecting the ability of ß-cells to compensate for insulin resistance, were significantly higher in the semaglutide group compared with the DPP-4i group (mean change, +10.4 vs +0.6 in HOMA2-ß [P = .001] and +0.09 vs 0.0 in DI [P < .001]). Improvement in DI in the semaglutide group was correlated significantly to changes in body mass index (BMI), HbA1c, and fatty liver index reflecting liver steatosis. Multiple linear regression analysis revealed that dose of semaglutide (≥ 7 mg/day), reduction in fatty liver index, and metformin nonuse were independently associated with improvement of DI. CONCLUSION: Switching to oral semaglutide ameliorated ß-cell function compared with DPP-4is, presumably via tissue-to-tissue crosstalk between liver and ß-cells.

Real-world clinical evidence of oral semaglutide on metabolic abnormalities in subjects with type 2 diabetes: a multicenter retrospective observational study (the Sapporo-Oral SEMA study).

Oral semaglutide has potent anti-hyperglycemic efficacy in phase III trials. However, the complicated dosing instructions hamper to use this drug; therefore, we evaluated the efficacy and safety of oral semaglutide in subjects with type 2 diabetes in a real-world clinical setting. In this multi-center retrospective observational study, we analyzed subjects with type 2 diabetes newly treated with an oral semaglutide for >6 months at four medical centers located in Sapporo, Japan. The changes in glycated hemoglobin, body weight, and other metabolic parameters were evaluated and any adverse event leading to semaglutide discontinuation were recorded from February 2021 to December 2022. This study was registered with the University Hospital Medical Information Network Center (UMIN000050583). Of 543 subjects who met the inclusion criteria, data for 434 subjects (age 55.5 ± 12.6 years; body mass index 29.6 ± 6.0 kg/m2) were analyzed. After a 6 months of observation period, semaglutide 3 mg, 7 mg, or 14 mg was used by 55 (12.7%), 241 (55.5%), and 138 (31.8%) of subjects, respectively. Both glycated hemoglobin and body weight significantly improved: 7.65 ± 1.11% to 6.88 ± 0.91% (p < 0.001) and 80.2 ± 19.2 kg to 77.6 ± 19.2 kg (p < 0.001), respectively. Efficacy was also confirmed in the subgroup switched from other anti-hyperglycemic agents, including dipeptidyl peptidase-4 inhibitors. In total, 154 subjects had symptomatic gastrointestinal symptoms and 39 (7.2%) were discontinued semaglutide due to the adverse events. None of the participants experienced severe hypoglycemic events. Oral semaglutide in subjects with type 2 diabetes improved glycemic control and body weight in a real-world clinical setting.

Glycaemic control efficacy of switching from dipeptidyl peptidase-4 inhibitors to oral semaglutide in subjects with type 2 diabetes: A multicentre, prospective, randomized, open-label, parallel-group comparison study (SWITCH-SEMA 2 study).

AIM: To assess whether oral semaglutide provides better glycaemic control, compared with dipeptidyl peptidase-4 inhibitor (DPP-4i) continuation, in people with type 2 diabetes. MATERIALS AND METHODS: In this multicentre, open-label, prospective, randomized, parallel-group comparison study, participants receiving DPP-4is were either switched to oral semaglutide (3-14 mg/day) or continued on DPP-4is. The primary endpoint was the change in glycated haemoglobin (HbA1c) over 24 weeks. Secondary endpoints included changes in metabolic parameters and biomarkers, along with the occurrence of adverse events. Factors associated with HbA1c improvement were also explored. RESULTS: In total, 174 eligible participants were enrolled; 17 dropped out of the study. Consequently, 82 participants in the DPP-4i group and 75 participants in the semaglutide group completed the study and were included in the analysis. Improvement in HbA1c at week 24 was significantly greater when switching to semaglutide compared with DPP-4i continuation [-0.65 (95% confidence interval: -0.79, -0.51) vs. +0.05 (95% confidence interval: -0.07, 0.16) (p < .001)]. Body weight, lipid profiles and liver enzymes were significantly improved in the semaglutide group than in the DPP-4i continuation group. Multiple linear regression analysis revealed that baseline HbA1c and homeostasis model assessment 2-R were independently associated with HbA1c improvement after switching to semaglutide. Seven participants in the semaglutide group discontinued medication because of gastrointestinal symptoms. CONCLUSIONS: Although the potential for gastrointestinal symptoms should be carefully considered, switching from DPP-4is to oral semaglutide may be beneficial for glycaemic control and metabolic abnormalities in people with higher HbA1c and insulin resistance.

Prospective analysis of patient-reported outcomes and physician-reported outcomes with gynecologic cancer chemotherapy.

OBJECTIVE: Gynecologic cancer chemotherapy impacts the quality of life (QOL) of patients, with lasting adverse events that may require treatment adjustments or discontinuation. Consequently, real-time symptom monitoring before outpatient visits has resulted in improved QOL for patients and extended survival times. This study investigated whether there are differences between electronic patient-reported outcomes (e-PRO-CTCAE) and physician-assessed outcomes (NCI-CTCAE) evaluated in an outpatient setting in gynecologic cancer chemotherapy. METHODS: The study was conducted on 50 patients who received their first chemotherapy treatment at St. Marianna University Hospital Obstetrics and Gynecology from July 1, 2021 to December 31, 2022. PRO-CTCAE and NCI-CTCAE were evaluated at each instance of chemotherapy and 2 weeks after. The PRO-CTCAE was additionally collected weekly using e-PRO. RESULTS: The values for "Joint Pain," "Nausea," "Taste Disturbance," "Constipation," "Insomnia," "Fatigue," "Limb Edema," and "Concentration Impairment" were consistently higher in PRO-CTCAE than in NCI-CTCAE, indicating that physicians underestimated the severity of adverse events. In contrast, there was no significant difference in "Peripheral Neuropathy," demonstrating that physicians had a good understanding of this condition in patients. The weekly responses obtained from e-PRO revealed that symptom exacerbations peaked outside of clinic visits. CONCLUSIONS: This study demonstrated physicians tend to underestimate most adverse events. Moreover, the responses using e-PRO revealed peak symptom deterioration occurred outside of outpatient visits. This suggested that e-PRO and actions taken in response to them can improve patients' QOL.

INCIDENCE AND RISK FACTORS OF INTRAOCULAR INFLAMMATION AFTER BROLUCIZUMAB TREATMENT IN JAPAN: A Multicenter Age-Related Macular Degeneration Study.

PURPOSE: To investigate the incidence of intraocular inflammation (IOI) and its risk factors following intravitreal injections of brolucizumab for neovascular age-related macular degeneration in Japan. METHODS: A total of 1,351 Japanese consecutive patients with neovascular age-related macular degeneration who were treated with brolucizumab from May 2020 to May 2022 at 14 institutions were examined. The variables analyzed were the number of brolucizumab injections, time to onset of IOI, and risk factors. RESULTS: Intraocular inflammation developed in 152 eyes (11.3%). Retinal vasculitis and/or retinal occlusion occurred in 53 eyes (3.9%). Ninety-four patients received bilaterally, bilateral IOI occurred in five patients (5.3%). Sixteen eyes (1.2%) had irreversible visual acuity loss and nine eyes (0.67%) had visual loss of three lines or more due to retinal vasculitis and/or retinal occlusion. The cumulative IOI incidence was 4.5%, 10.3%, and 12.2% at 30, 180, and 365 days (1-year), respectively. History of IOI (including retinal vasculitis) and/or retinal occlusion (odds ratio [OR], 5.41; P = 0.0075) and female sex (OR, 1.99; P = 0.0004) were significantly associated with IOI onset. CONCLUSION: The 1-year cumulative incidence of IOI in Japanese neovascular age-related macular degeneration patients treated with brolucizumab was 12.2%. History of IOI (including retinal vasculitis) and/or retinal occlusion and female sex were significant risk factors.

Hand function and quality of life in patients with diabetes mellitus before and during the COVID-19 pandemic.

This study aimed to investigate the effects of the coronavirus disease 2019 (COVID-19) pandemic on patients with diabetes mellitus using patient-rated outcome measures focusing on hand function and quality of life, as well as patients' mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. It was a part of a longitudinal research involving patients with diabetes mellitus living in Sapporo, Japan. Among the 594 patients surveyed before the COVID-19 pandemic from March to June 2019, 417 patients who could be re-surveyed from March to June 2021 were included. We compared the patient-rated outcome measures, namely the Hand10 for hand function and EuroQol five-dimension questionnaire for assessing quality of life in the same population of patients with diabetes mellitus, before and during the COVID-19 pandemic. The results indicated no deterioration in the Hand10 (3.9 vs 3.6) and quality of life scores (0.89 vs 0.9), including mobility (1.25 vs 1.17), self-care (1.1 vs 1.08), pain/discomfort (1.43 vs 1.35), and anxiety/depression (1.21 vs 1.2), during the COVID-19 pandemic when compared with the pre-pandemic values. Usual activity values on the EuroQol five-dimension subscale significantly improved during the pandemic compared to those before the pandemic (1.21 vs 1.12, p<0.01). This study highlighted the effects of the COVID-19 pandemic on patients with diabetes mellitus by comparing patient-rated outcome measures in two different social situations. Patients with diabetes mellitus living in Sapporo, Japan maintained hand function and quality of life by continuing their usual activities during the COVID-19 pandemic.

Synthesis and biological activity of photostable and persistent abscisic acid analogs.

The plant hormone abscisic acid (ABA) plays a critical role in various environmental stress responses and has long been expected to be used in agriculture. However, the practical use of ABA has been limited, mainly because of its photoinstability and rapid biodegradation. We previously developed photostable ABA agonists, BP2A and Me 1',4'-trans-diol BP2A, in which the dienoic acid side chain of ABA was replaced with phenylacetic acid. This finding validated our structure-based approach in designing photostable agonists and provided a basis for developing a more potent or long-lasting ABA agonist. In this study, we synthesized novel BP2A analogs in which the cyclohexenone ring was modified to avoid catabolism by the ABA metabolic enzyme, ABA 8'-hydroxylase. All synthesized analogs showed higher photostability than BP2A under sunlight. In an Arabidopsis seed germination assay, (+)-compounds 5 and 6 with a tetralone ring displayed significantly stronger ABA agonist activity than (+)-BP2A. In contrast, in the in vitro phosphatase assays, both compounds showed comparable or weaker ABA receptor (PYL1) agonistic activity than (+)-BP2A, suggesting that the stronger ABA-like activity of (+)-5 and (+)-6 may arise from their metabolic stability in vivo. This study provides data relevant to designing photostable and persistent ABA agonists.

Sall1 and Sall4 cooperatively interact with Myocd and SRF to promote cardiomyocyte proliferation by regulating CDK and cyclin genes.

Sall1 and Sall4 (Sall1/4), zinc-finger transcription factors, are expressed in the progenitors of the second heart field (SHF) and in cardiomyocytes during the early stages of mouse development. To understand the function of Sall1/4 in heart development, we generated heart-specific Sall1/4 functionally inhibited mice by forced expression of the truncated form of Sall4 (ΔSall4) in the heart. The ΔSall4-overexpression mice exhibited a hypoplastic right ventricle and outflow tract, both of which were derived from the SHF, and a thinner ventricular wall. We found that the numbers of proliferative SHF progenitors and cardiomyocytes were reduced in ΔSall4-overexpression mice. RNA-sequencing data showed that Sall1/4 act upstream of the cyclin-dependent kinase (CDK) and cyclin genes, and of key transcription factor genes for the development of compact cardiomyocytes, including myocardin (Myocd) and serum response factor (Srf). In addition, ChIP-sequencing and co-immunoprecipitation analyses revealed that Sall4 and Myocd form a transcriptional complex with SRF, and directly bind to the upstream regulatory regions of the CDK and cyclin genes (Cdk1 and Ccnb1). These results suggest that Sall1/4 are critical for the proliferation of cardiac cells via regulation of CDK and cyclin genes that interact with Myocd and SRF.

Narrowing Ratio of Retinal Veins at Arteriovenous Crossing in Patients With Branch Retinal Vein Occlusion Versus That in Healthy Individuals.

Purpose: This cross-sectional study aimed to clarify the differences in the retinal venous narrowing ratio (VNR) at retinal arteriovenous crossing by optical coherence tomography (OCT) among the eyes with branch retinal vein occlusion (BRVO), fellow eyes of patients with BRVO, and eyes of individuals without BRVO and to determine factors that influence the VNR. Methods: We studied 31 eyes of young participants, 54 eyes of an older control group, 56 fellow eyes of patients with BRVO, and 48 eyes with BRVO. Cross-sectional OCT images were used to determine the VNR at two arteriovenous crossings per eye. Results: Overall, 378 arteriovenous crossings were analyzed. The VNR of arterial overcrossings of fellow eyes (27.7% ± 11.1%) and BRVO eyes (27.3% ± 9.76%) were significantly higher than those in the young (16.0% ± 7.9%, all P < 0.001) and control (22.0% ± 8.81%, P < 0.001, P = 0.003, respectively) groups. The VNR of arterial overcrossings was significantly larger than that of venous overcrossings (24.0% ± 10.5% vs. 20.6% ± 13.0%, P = 0.021). A linear mixed-effects model showed that the VNR was significantly higher in arterial overcrossings, crossings with larger arterial internal diameters, smaller venous internal diameters, and participants with older age and a BRVO history. Conclusions: The VNR in arterial overcrossings was higher in BRVO eyes and even in the fellow eyes. Thus, a higher VNR in arterial overcrossings may contribute to BRVO development, and crossings with factors contributing to higher VNR might be associated with a risk of BRVO.

Preferable effects of pemafibrate on liver function and fibrosis in subjects with type 2 diabetes complicated with liver damage.

BACKGROUND: Pemafibrate has been reported to ameliorate lipid profiles and liver dysfunction. However, which patients derive benefit from the hepatoprotective effects of pemafibrate is unclear. METHODS: We conducted a sub-analysis of the PARM-T2D study where subjects with type 2 diabetes complicated by hypertriglyceridemia were prospectively treated with pemafibrate or conventional therapies for 52 weeks. From the original cohort, subjects who had metabolic-associated fatty liver disease without changing their treatment regimens for comorbidities were analyzed. Eligible subjects (n = 293) (average age 61.2 ± 11.7 years, 37.5% female) treated with pemafibrate (pemafibrate, n = 152) or controls who did not change their treatment regimens (controls, n = 141) were divided into three groups based on their alanine aminotransferase (ALT) levels: ALT ≤ upper normal limit (UNL) (pemafibrate, n = 65; controls, n = 50), UNL < ALT ≤ 2×UNL (pemafibrate, n = 58; controls, n = 54), and 2×UNL < ALT (pemafibrate, n = 29; controls, n = 27). RESULTS: Pemafibrate treatment significantly ameliorated ALT levels (from 29 to 22 U/L, p < 0.001 by Wilcoxon's signed-rank test) in the total cohort and subjects with high ALT levels (2×ULN < ALT), and improved liver fibrosis as assessed by the Fibrosis-4 index (mean change - 0.05 (95% confidence interval: -0.22 to - 0.02), p < 0.05 versus baseline by the Mann-Whitney U-test and p < 0.05 versus the ALT ≤ UNL group by the Kruskal-Wallis test followed by Dunn's post-hoc analysis). CONCLUSIONS: The hepatoprotective effects of pemafibrate were dominant in subjects with type 2 diabetes complicated with liver dysfunction. TRIAL REGISTRATION: This study was registered with the University Hospital Medical Information Network Center Clinical Trials Registry (UMIN000037385).

Coronary artery established through amniote evolution.

Coronary arteries are a critical part of the vascular system and provide nourishment to the heart. In humans, even minor defects in coronary arteries can be lethal, emphasizing their importance for survival. However, some teleosts survive without coronary arteries, suggesting that there may have been some evolutionary changes in the morphology and function of coronary arteries in the tetrapod lineage. Here, we propose that the true ventricular coronary arteries were newly established during amniote evolution through remodeling of the ancestral coronary vasculature. In mouse (Mus musculus) and Japanese quail (Coturnix japonica) embryos, the coronary arteries unique to amniotes are established by the reconstitution of transient vascular plexuses: aortic subepicardial vessels (ASVs) in the outflow tract and the primitive coronary plexus on the ventricle. In contrast, amphibians (Hyla japonica, Lithobates catesbeianus, Xenopus laevis, and Cynops pyrrhogaster) retain the ASV-like vasculature as truncal coronary arteries throughout their lives and have no primitive coronary plexus. The anatomy and development of zebrafish (Danio rerio) and chondrichthyans suggest that their hypobranchial arteries are ASV-like structures serving as the root of the coronary vasculature throughout their lives. Thus, the ventricular coronary artery of adult amniotes is a novel structure that has acquired a new remodeling process, while the ASVs, which occur transiently during embryonic development, are remnants of the ancestral coronary vessels. This evolutionary change may be related to the modification of branchial arteries, indicating considerable morphological changes underlying the physiological transition during amniote evolution.

Coronary arteries are tasked with supplying the heart with oxygenated blood and nutrients. Any blockage or developmental problem in these blood vessels can have severe and sometimes lethal consequences. Due to their importance for health, researchers have extensively studied how coronary arteries form in humans and mice; a more limited range of studies have also looked at their equivalent in zebrafish. However, little is known about these structures develop in animals such as birds, amphibians, or other groups of fish. This makes it difficult to retrace the evolutionary processes that have given rise to the coronary arteries we are familiar with in mammals. To address this knowledge gap, Mizukami et al. set out to compare blood vessel development around the heart of mammals, birds, amphibians, and fish. To do this, they performed detailed anatomical studies of blood vessel structure at different stages of development in mice as well as quail, frogs and newts, zebrafish and sharks. In both mice and quail, small arterial subepicardial vessels (or ASVs) emerged early in development around the heart; these subsequently reorganised and remodelled themselves to give rise to the 'true' coronary arteries characteristic of the mature heart. Frogs and newts also developed similar ASV-like structures; however, unlike their mammalian and bird equivalents, these vessels did not reorganise, instead being retained into adulthood. In fish, blood vessel development resembled that of amphibians, suggesting that the coronary artery-like structures seen in some fish are an 'ancestral' form of ASVs, rather than the equivalent of the mature coronary arteries in mammals and birds. This work sheds light on the evolutionary processes shaping essential structures in the heart. In the future, Mizukami et al. hope that this knowledge will help develop a greater range of experimental animal models for studying heart disease and potential treatments.

Approximate spectral decomposition of Fisher information matrix for simple ReLU networks.

We argue the Fisher information matrix (FIM) of one hidden layer networks with the ReLU activation function. For a network, let W denote the d×p weight matrix from the d-dimensional input to the hidden layer consisting of p neurons, and v the p-dimensional weight vector from the hidden layer to the scalar output. We focus on the FIM of v, which we denote as I. Under certain conditions, we characterize the first three clusters of eigenvalues and eigenvectors of the FIM. Specifically, we show that the following approximately holds. (1) Since I is non-negative owing to the ReLU, the first eigenvalue is the Perron-Frobenius eigenvalue. (2) For the cluster of the next maximum values, the eigenspace is spanned by the row vectors of W. (3) The direct sum of the eigenspace of the first eigenvalue and that of the third cluster is spanned by the set of all the vectors obtained as the Hadamard product of any pair of the row vectors of W. We confirmed by numerical calculation that the above is approximately correct when the number of hidden nodes is about 10000.

Predictive factors for outcomes of half-dose photodynamic therapy combined with aflibercept for pachychoroid neovasculopathy.

PURPOSE: To assess the effects of half-dose photodynamic therapy (PDT) combined with an intravitreous aflibercept (IVA) injection for pachychoroid neovasculopathy (PNV) and its predictive factors. METHODS: Clinical information of 43 patients (43 eyes) with PNV obtained before and 6 months after treatment with half-dose PDT combined with IVA was retrospectively analyzed. Patients were categorized into the sufficient (25 eyes, 58.1%) or insufficient (18 eyes, 41.9%) group based on resolution or persistence/recurrence of subretinal fluid (SRF), respectively, and clinical data were compared. Macular neovascularization (MNV) change was studied in 30 cases with available pre- and post-treatment optical coherence tomography angiography images. RESULTS: The sufficient group included younger patients with better baseline best-corrected visual acuity (BCVA), more treatment-naïve eyes, and smaller MNV lesions at baseline than the insufficient group (all, P < 0.047). Complete SRF resolution was 81.8% in treatment-naïve eyes and only 33.3% in previously treated eyes. MNV expanded after half-dose PDT was combined with IVA regardless of the treatment outcome (P = 0.003). CONCLUSION: Half-dose PDT combined with IVA was effective for PNV treatment, especially for younger patients with good baseline BCVA, treatment-naïve eyes, and small MNV sizes at baseline. MNV expanded after treatment regardless of the treatment outcomes.

Comparison of the Relationship between Visual Acuity and Motor Function in Non-Elderly and Elderly Adults.

This study aimed to clarify the relationship between visual acuity and motor function in younger and elderly participants and to compare differences between non-elderly and elderly participants. In total, 295 participants who underwent visual and motor functional examinations were included; participants with visual acuity ≥0.7 were assigned to the normal group (N group) and those with visual acuity ≤0.7 were assigned to the low-visual-acuity group (L group). Motor function was compared between the N and L groups; the analysis was performed by grouping participants into those aged >65 years (elderly) and those aged <65 years (non-elderly). The non-elderly group (average age, 55.6 ± 6.7 years) had 105 and 35 participants in the N and L groups, respectively. Back muscle strength was significantly lower in the L group than in the N group. The elderly group (average age, 71.1 ± 5.1 years) had 102 and 53 participants in the N and L groups, respectively. Gait speed was significantly lower in the L group than in the N group. These results reveal differences in the relationship between vision and motor function in non-elderly and elderly adults and indicate that poor vision is associated with lower back-muscle strength and walking speed in younger and elderly participants, respectively.

Improvement of glycaemic control and treatment satisfaction by switching from liraglutide or dulaglutide to subcutaneous semaglutide in patients with type 2 diabetes: A multicentre, prospective, randomized, open-label, parallel-group comparison study (SWITCH-SEMA 1 study).

AIM: To investigate the effects of switching from liraglutide or dulaglutide to once-weekly semaglutide on glycaemic control and treatment satisfaction in patients with type 2 diabetes. MATERIALS AND METHODS: In this multicentre, open-labelled, prospective, randomized, parallel-group comparison study, patients treated with liraglutide 0.9-1.8 mg/day (plan A) or dulaglutide 0.75 mg/week (plan B) were either switched to semaglutide or continued current therapy. The primary endpoint was the mean change in glycated haemoglobin over 24 weeks. The secondary endpoints included the changes of Diabetes Treatment Satisfaction Questionnaire scores, body weight and metabolic indices. RESULTS: In total, 110 patients were enrolled, and 10 were excluded; therefore, 37 patients in plan A and 63 patients in plan B completed the study. Glycated haemoglobin levels were significantly reduced in the semaglutide group in both plans [plan A, 7.8% ± 1.0% to 7.8% ± 0.7% (liraglutide) vs. 7.9% ± 0.7% to 7.3% ± 0.7% (semaglutide), p < .01; plan B, 7.8% ± 1.0% to 7.9% ± 1.2% (dulaglutide) vs. 7.8% ± 0.8% to 7.1% ± 0.6% (semaglutide), p < .01]. Semaglutide also improved Diabetes Treatment Satisfaction Questionnaire scores in both groups (plan A, +0.1 vs. +8.3, p < .01; plan B, -1.2 vs. +3.5, p < .01). Switching from dulaglutide yielded greater reductions in body weight and improved metabolic parameters. CONCLUSIONS: Once-weekly semaglutide administration improved glycaemic control and treatment satisfaction after switching from liraglutide or dulaglutide. These results highlighted a useful treatment option for patients with metabolic abnormalities despite glucagon-like receptor-1 receptor agonist treatment.

LONG-TERM MORPHOLOGIC CHANGES IN MACULAR NEOVASCULARIZATION UNDER AFLIBERCEPT TREATMENT WITH A TREAT-AND-EXTEND REGIMEN.

PURPOSE: To examine the morphologic changes in macular neovascularization (MNV) secondary to age-related macular degeneration after 2 years of aflibercept treatment under a treat-and-extend (T&E) regimen. METHODS: This retrospective study analyzed the medical records for 26 eyes of 25 patients diagnosed with treatment-naive neovascular age-related macular degeneration and treated with aflibercept under a treat-and-extend regimen for 2 years. The areas of the MNV and vascular structures were assessed using swept-source optical coherence tomography angiography at baseline and after 2 years of treatment. RESULTS: The mean MNV area increased significantly from 0.65 ± 0.42 mm 2 at baseline to 0.78 ± 0.45 mm 2 at 2 years. At 2 years, the mean change in the MNV area from baseline was 22% (interquartile range: 4%-60%). The baseline MNV area was negatively correlated with the change ratio of the MNV areas at 2 years and baseline ( R = -0.68, P < 0.001). Nine of the 26 eyes (34.6%) showed newly formed mature vessels, and 7 eyes (26.9%) showed prominently developing preexisting mature vessels. CONCLUSION: Macular neovascularization expanded and showed vascular maturation under aflibercept treatment with a treat-and-extend regimen. The smaller the MNV at baseline, the greater is its expansion in 2 years.

Displacement of the retina and changes in the foveal avascular zone area after internal limiting membrane peeling for epiretinal membrane.

PURPOSE: We investigated the differences in displacement of the outer and inner macular retina toward the optic disc after vitrectomy with internal limiting membrane (ILM) peeling for epiretinal membrane (ERM). Foveal avascular zone (FAZ) area changes were also investigated. STUDY DESIGN: Retrospective observational study METHODS: This retrospective observational case series included 45 eyes of 43 patients that underwent vitrectomy with ERM and ILM peeling for ERM and 38 normal eyes. The locations of the centroid of the FAZ (C-FAZ, center of the foveal inner retina) and foveal bulge (center of the foveal outer retina) were determined using 3×3mm superficial optical coherence tomography angiography. C-FAZ and foveal bulge displacements, and the pre- and postoperative FAZ areas and their associated factors, were investigated. RESULTS: Postoperative C-FAZ dislocated significantly more toward the optic disc than in pre-operative or normal eyes (P<0.001). C-FAZ and foveal bulge displaced toward the optic disc after surgery; C-FAZ showed significantly greater displacement than foveal bulge (P<0.001). The pre- and postoperative FAZ areas were correlated (P=0.01). Preoperative FAZ areas ≧0.10mm2 were reduced after surgery, and FAZ areas < 0.10mm2 were increased, independent of foveal displacement. CONCLUSION: ILM peeling during vitrectomy for ERM caused larger displacement of the inner and smaller displacement of the outer retinas, towards the optic disc. Postoperative changes in the FAZ area were dependent on the baseline FAZ area, but not on the foveal displacement. ILM may physiologically exert centrifugal tractional forces on the fovea.

SPONTANEOUS CLOSURE OF MACULAR HOLE AFTER VITRECTOMY FOR MYOPIC RETINOSCHISIS WITH FOVEAL DETACHMENT.

PURPOSE: To discuss a case of a macular hole formation after vitrectomy for myopic retinoschisis with foveal detachment and spontaneous closure, during long-term follow-up. METHODS: Case report. RESULTS: A 71-year-old man with myopic retinoschisis with foveal detachment had a vitrectomy with internal limiting membrane peeling combined with cataract surgery in the left eye. The preoperative best-corrected visual acuity was 8/20, and the axial length was 27.11 mm. A macular hole with foveal detachment was observed 1 month after surgery. However, the macular hole closed spontaneously with foveal detachment at 4 months of follow-up. Foveal detachment resolved, and the best-corrected visual acuity improved to 20/20 at nine months of follow-up. CONCLUSION: This case suggests that the macular hole formed after vitrectomy for myopic retinoschisis with foveal detachment with internal limiting membrane peeling can close spontaneously.

Add-on imeglimin versus metformin dose escalation regarding glycemic control in patients with type 2 diabetes treated with a dipeptidyl peptidase-4 inhibitor plus low-dose metformin: study protocol for a multicenter, prospective, randomized, open-label, parallel-group comparison study (MEGMI study).

INTRODUCTION: Imeglimin is a novel anti-hyperglycemic drug that improves both insulin resistance and insulin secretion. The effects of imeglimin on glycemic control were confirmed in phase III clinical trials, but little is known about its effectiveness in daily clinical practice settings, especially compared with metformin. Therefore, we aim to clarify the efficacy of imeglimin in patients with type 2 diabetes (T2D) being treated with a dipeptidyl peptidase-4 (DPP-4) inhibitor plus low-dose metformin. RESEARCH DESIGN AND METHODS: This is a multicenter, randomized, prospective, open-label, parallel-group trial. Seventy participants with T2D treated with a DPP-4 inhibitor plus metformin (500-1000 mg/day) for more than 12 weeks and a glycated hemoglobin (HbA1c) level of 52-85 mmol/mol (7.0%-9.9%) will be randomized to receive add-on imeglimin 1000 mg two times per day or metformin dose escalation for 24 weeks. Biochemical analyses and physical assessments will be performed at baseline and at the end of the study, and adverse events will be recorded. The primary endpoint is the change in HbA1c after 24 weeks. The secondary endpoints comprise the changes in blood pressure, pulse rate, body weight, abdominal circumference, and other laboratory parameters; the relationship between improvements of biological parameters including glycemic control and patient background characteristics; and side effects. RESULTS: This study will reveal new insights into the incorporation of imeglimin into the diabetes treatment strategy. CONCLUSIONS: This will be the first randomized controlled trial to compare the efficacy of adding imeglimin versus metformin dose escalation on glycemic control in patients with T2D. TRIAL REGISTRATION NUMBER: jRCT1011220005.

Analgesic effects and arthritic changes following intra-articular injection of diclofenac etalhyaluronate in a rat knee osteoarthritis model.

BACKGROUND: Diclofenac etalhyaluronate (DF-HA) is a recently developed analgesic conjugate of diclofenac and hyaluronic acid that has analgesic and anti-inflammatory effects on acute arthritis. In this study, we investigated its analgesic effect on osteoarthritis, using a rat model of monoiodoacetate (MIA). METHODS: We injected MIA into the right knees of eight 6-weeks-old male Sprague-Dawley rats. Four weeks later, rats were randomly injected with DF-HA or vehicle into the right knee. Seven weeks after the MIA injection, fluorogold (FG) and sterile saline were injected into the right knees of all the rats. We assessed hyperalgesia with weekly von Frey tests for 8 weeks after MIA administration. We took the right knee computed tomography (CT) as radiographical evaluation every 2 weeks. All rats were sacrificed 8 weeks after administration of MIA for histological evaluation of the right knee and immunohistochemical evaluation of the DRG and spinal cord. We also evaluated the number of FG-labeled calcitonin gene-related peptide (CGRP)-immunoreactive(ir) neurons in the dorsal root ganglion (DRG) and ionized calcium-binding adapter molecule 1 (Iba1)-ir microglia in the spinal cord. RESULTS: Administration of DF-HA significantly improved pain sensitivity and reduced CGRP and Iba1 expression in the DRG and spinal cord, respectively. However, computed tomography and histological evaluation of the right knee showed similar levels of joint deformity, despite DF-HA administration. CONCLUSION: DF-HA exerted analgesic effects on osteoarthritic pain, but did not affect joint deformity.