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Objective: To assess 'time in range' as a novel measure of treatment response in diabetic macular oedema (DMO)., Methods: This post hoc analysis of the Protocol T randomised clinical trial included 660 individuals with centre-involved DMO and best-corrected visual acuity (BCVA) letter score ≤78-≥24 (approximate Snellen equivalent 20/32-20/320). Study participants received intravitreal aflibercept 2.0 mg, repackaged (compounded) bevacizumab 1.25 mg, or ranibizumab 0.3 mg given up to every 4 weeks using defined retreatment criteria. Mean time in range was calculated using a BCVA letter score threshold of ≥69 (20/40 or better; minimum driving requirement in many regions), with sensitivity analyses using BCVA thresholds from 100 to 0 (20/10 to 20/800) in 1-letter increments., Results: Time in range was defined as either the absolute or relative duration above a predefined BCVA threshold, measured in weeks or as a percentage of time, respectively. Using a BCVA letter score threshold of ≥69 (20/40 or better), the least squares mean time in range (adjusted for baseline BCVA) in Year 1 was 41.2 weeks with intravitreal aflibercept, 4.0 weeks longer (95% CI: 1.7, 6.3; p = 0.002) than bevacizumab and 3.6 weeks longer (1.3, 5.9; p = 0.004) than ranibizumab. Overall, mean time in range was numerically longer for intravitreal aflibercept for all BCVA letter score thresholds between 92 and 30 (20/20 to 20/250). In the Day 365-728 analysis, time in range was 3.9 (1.3, 6.5) and 2.4 (0.0, 4.9) weeks longer with intravitreal aflibercept vs bevacizumab and vs ranibizumab (p = 0.011 and 0.106), respectively., Conclusion: BCVA time in range may represent another way to describe visual outcomes and potential impact on vision-related functions over time for patients with DMO and provide a better understanding, for physicians and patients, of the consistency of treatment efficacy., (© 2023. The Author(s).)

Purpose: To use optical coherence tomography angiography (OCTA) parameters from both the retinal and choroidal microvasculature to detect the presence and severity of diabetic retinopathy (DR)., Method: This is a cross-sectional case-control study. OCTA parameters from retinal vasculature, fovea avascular zone (FAZ) and choriocapillaris were evaluated from 3×3 mm 2 fovea-centred scans. Areas under the receiver operating characteristic (ROC) curve were used to compare the discriminative power on the presence of diabetes mellitus (DM), the presence of DR and need for referral: group 1 (no DM vs DM no DR), group 2 (no DR vs any DR) and group 3 (non-proliferative DR (NPDR) vs proliferative DR (PDR))., Results: 35 eyes from 27 participants with no DM and 132 eyes from 75 with DM were included. DR severity was classified into three groups: no DR group (62 eyes), NPDR (51 eyes), PDR (19 eyes). All retinal vascular parameters, FAZ parameters and choriocapillaris parameters were strongly altered with DR stages (p<0.01), except for the deep plexus FAZ area (p=0.619). Choriocapillaris parameters allowed to better discriminate between no DM versus DM no DR group compared with retinal parameters (areas under the ROC curve=0.954 vs 0.821, p=0.006). A classification model including retinal and choroidal microvasculature significantly improved the discrimination between DR and no DR compared with each parameter separately (p=0.029)., Conclusions: Evaluating OCTA parameters from both the retinal and choroidal microvasculature in 3×3 mm scans improves the discrimination of DM and early DR., Competing Interests: Competing interests: GT reported receiving travel support from Carl Zeiss Pte Ltd; receiving personal fees and consultancy fees from Novartis; receiving grants from Bayer AG and Santen Pharmaceutical Company, Ltd; and receiving travel support from Alcon outside the submitted work., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

Frequent antivascular endothelial growth factor injections in neovascular age-related macular degeneration (nAMD) often lead to poor compliance and suboptimal outcomes. A longer-acting agent has been a pressing unmet need until recently. Brolucizumab, an antivascular endothelial growth factor agent, is a single-chain antibody fragment approved by the US Food and Drug Administration (FDA) on October 8, 2019, for treating nAMD. It delivers more molecules at equivalent volumes of aflibercept, thus achieving a longer-lasting effect. We reviewed literature published in English between January 2016 and October 2022 from MEDLINE, PubMed, Cochrane database, Embase, and Google scholar using the keywords: "Brolucizumab, real-world data, intraocular inflammation (IOI), safety, and efficacy". Brolucizumab showed reduced injection frequency, better anatomic outcomes, and noninferior vision gains compared with aflibercept in HAWK and HARRIER studies. However, post hoc studies on brolucizumab revealed a higher-than-expected incidence of IOI, leading to the early termination of 3 studies: MERLIN, RAPTOR, and RAVEN for nAMD, branch retinal vein occlusion, and central retinal vein occlusion, respectively. Contrastingly real-world data showed encouraging outcomes in terms of fewer IOI cases. The subsequent amendment of the treatment protocol resulted in reduced IOI. Thereafter US FDA approved its use in diabetic macular edema on June 1, 2022. Based on major studies and real-world data, this review shows that brolucizumab is effective for treating naive and refractory nAMD. The risk of IOI is acceptable and manageable, but proper preinjection screening and high-vigilance care of IOI are needed. More studies are warranted to evaluate further the incidence, best prevention, and treatment measures for IOI., Competing Interests: J.C.: Consultant/speaker—Salutaris, Erasca, Novartis, Allergan, AcuViz, Ocular Therapeutics, OD-OS. S.M.H.: Consultant/speaker—EyePoint Pharmaceuticals, Allergan, Alimera Sciences, Novartis, Biogen, Bausch & Lomb and Regeneron. C.M.G.C.: speaker/consultant for and grants from—Bayer, Novartis, Roche, Allergan, Topcon, Zeiss, Boehringer Ingelheim; supported by the National Medical Research Council Singapore Open Fund Large Collaborative Grant (NMRC/LCG/004/2018). The remaining authors have no funding or conflicts of interest to declare., (Copyright © 2023 Asia-Pacific Academy of Ophthalmology. Published by Wolters Kluwer Health, Inc. on behalf of the Asia-Pacific Academy of Ophthalmology.)

Retinal microperimetry (MP) is a procedure that assesses the retinal sensitivity while the fundus is directly observed, and an eye tracker system is active to compensate for involuntary eye movements during testing. With this system, the sensitivity of a small locus can be accurately determined, and it has become an established ophthalmic test for retinal specialists. Macular diseases are characterized by chorioretinal changes; therefore, the condition of the retina and choroid requires careful and detailed evaluations to perform effective therapy. Age-related macular degeneration is a representative retinal disease in which the macular function has been evaluated by the visual acuity throughout the course of the disease process. However, the visual acuity represents the physiological function of only the central fovea, and the function of the surrounding macular area has not been sufficiently evaluated throughout the different stages of the macula disease process. The new technique of MP can compensate for such limitations by being able to test the same sites of the macular area repeatedly. This is especially useful in the recent management of age-related macular degeneration or diabetic macular edema during anti-vascular endothelial growth factor treatments because MP can assess the effectiveness of the treatment. MP examinations are also valuable in diagnosing Stargardt disease as they can detect visual impairments before any abnormalities are found in the retinal images. The visual function needs to be carefully assessed along with morphologic observations by optical coherence tomography. In addition, the assessment of retinal sensitivity is useful in the presurgical or postsurgical evaluations., Competing Interests: SH belongs to Department of Advanced Ophthalmic Imaging at Tokyo Medical and Dental University, which is funded by NIDEK co. There are no other conflict of interest regarding this review article., (Copyright © 2023 Asia-Pacific Academy of Ophthalmology. Published by Wolters Kluwer Health, Inc. on behalf of the Asia-Pacific Academy of Ophthalmology.)

Rationale: Diabetic retinopathy (DR) is a major complication of diabetes mellitus causing significant vision loss. DR is a multifactorial disease involving changes in retinal microvasculature and neuronal layers, and aberrations in vascular endothelial growth factors (VEGF) and inflammatory pathways. Despite the success of anti-VEGF therapy, many DR patients do not respond well to the treatment, emphasizing the involvement of other molecular players in neuronal and vascular aberrations in DR. Methods: We employed advanced mass spectrometry-based proteome profiling to obtain a global snapshot of altered protein abundances in vitreous humor from patients with proliferative DR (PDR) in comparison to individuals with epiretinal membrane without active DR or other retinal vascular complications. Global proteome correlation map and protein-protein interaction networks were used to probe into the functional inclination of proteins and aberrated molecular networks in PDR vitreous. In addition, peptide-centric analysis of the proteome data was carried out to identify proteolytic processing, primarily ectodomain shedding events in PDR vitreous. Functional validation experiments were performed using preclinical models of ocular angiogenesis. Results: The vitreous proteome landscape revealed distinct dysregulations in several metabolic, signaling, and immune networks in PDR. Systematic analysis of altered proteins uncovered specific impairment in ectodomain shedding of several transmembrane proteins playing critical roles in neurodegeneration and angiogenesis, pointing to defects in their regulating sheddases, particularly ADAM10, which emerged as the predominant sheddase. We confirmed that ADAM10 protease activity was reduced in animal models of ocular angiogenesis and established that activation of ADAM10 can suppress endothelial cell activation and angiogenesis. Furthermore, we identified the impaired ADAM10-AXL axis as a driver of retinal angiogenesis. Conclusion: We demonstrate restoration of aberrant ectodomain shedding as an effective strategy for treating PDR and propose ADAM10 as an attractive therapeutic target. In all, our study uncovered impaired ectodomain shedding as a prominent feature of PDR, opening new possibilities for advancement in the DR therapeutic space., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Background: To evaluate the ability of handheld chromatic pupillometry to reveal and localise retinal neural dysfunction in diabetic patients with and without diabetic retinopathy (DR)., Methods: This cross-sectional study included 82 diabetics (DM) and 93 controls (60.4 ± 8.4 years, 44.1% males). DM patients included those without (n = 25, 64.7 ± 6.3 years, 44.0% males) and with DR (n = 57, 60.3 ± 8.5 years, 64.9% males). Changes in horizontal pupil radius in response to blue (469 nm) and red (640 nm) light stimuli were assessed monocularly, in clinics, using a custom-built handheld pupillometer. Pupillometric parameters (phasic constriction amplitudes [predominantly from the outer retina], maximal constriction amplitudes [from the inner and outer retina] and post-illumination pupillary responses [PIPRs; predominantly from the inner retina]) were extracted from baseline-adjusted pupillary light response traces and compared between controls, DM without DR, and DR. Net PIPR was defined as the difference between blue and red PIPRs., Results: Phasic constriction amplitudes to blue and red lights were decreased in DR compared to controls (p < 0.001; p < 0.001). Maximal constriction amplitudes to blue and red lights were decreased in DR compared to DM without DR (p < 0.001; p = 0.02), and in DM without DR compared to controls (p < 0.001; p = 0.005). Net PIPR was decreased in both DR and DM without DR compared to controls (p = 0.02; p = 0.03), suggesting a wavelength-dependent (and hence retinal) pupillometric dysfunction in diabetic patients with or without DR., Conclusions: Handheld chromatic pupillometry can reveal retinal neural dysfunction in diabetes, even without DR. Patients with DM but no DR displayed primarily inner retinal dysfunction, while patients with DR showed both inner and outer retinal dysfunction., (© 2022 The Authors. Clinical & Experimental Ophthalmology published by John Wiley & Sons Australia, Ltd on behalf of Royal Australian and New Zealand College of Ophthalmologists.)

Diabetic macular ischaemia (DMI) is traditionally defined and graded based on the angiographic evidence of an enlarged and irregular foveal avascular zone. However, these anatomical changes are not surrogate markers for visual impairment. We postulate that there are vascular phenotypes of DMI based on the relative perfusion deficits of various retinal capillary plexuses and choriocapillaris. This review highlights several mechanistic pathways, including the role of hypoxia and the complex relation between neurons, glia, and microvasculature. The current animal models are reviewed, with shortcomings noted. Therefore, utilising the advancing technology of optical coherence tomography angiography (OCTA) to identify the reversible DMI phenotypes may be the key to successful therapeutic interventions for DMI. However, there is a need to standardise the nomenclature of OCTA perfusion status. Visual acuity is not an ideal endpoint for DMI clinical trials. New trial endpoints that represent disease progression need to be developed before irreversible vision loss in patients with DMI. Natural history studies are required to determine the course of each vascular and neuronal parameter to define the DMI phenotypes. These DMI phenotypes may also partly explain the development and recurrence of diabetic macular oedema. It is also currently unclear where and how DMI fits into the diabetic retinopathy severity scales, further highlighting the need to better define the progression of diabetic retinopathy and DMI based on both multimodal imaging and visual function. Finally, we discuss a complete set of proposed therapeutic pathways for DMI, including cell-based therapies that may provide restorative potential., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

To determine the differential impact of the irreversible eye diseases on vision-related quality of life (VRQoL) in a multi-ethnic Asian population. 2652 participants from the Singapore Epidemiology of Eye Disease Study, with any of the following early and late-stage eye conditions including age-related macular degeneration (AMD, n = 158), diabetic retinopathy (DR, n = 105; non vision threatening [non-VTDR]; VTDR), glaucoma (n = 57) and myopic macular degeneration (MMD, n = 106), or none of the above (controls, 2226 [83.9%]) were included. Rasch-scaled scores of the Emotional well-being Mobility and Reading subscales of the Impact of Vision Impairment (IVI) questionnaire, collectively referred to as "VRQoL" were assessed. Multivariable linear regression analyses and pairwise comparisons adjusting for age, gender, ethnicity, socio-economic status, BMI, smoking, alcohol use, presence of systemic diseases and presenting VI were performed to assess and compare the impact of the presence and severity of each eye condition on the three IVI domains. Multivariable adjusted pairwise comparisons of VRQoL between early stages of the four eye diseases showed no significant differences (all P > 0.05). For late stage diseases, individuals with VTDR had significantly larger decrements in Emotional well-being compared to glaucoma (β - 0.81; 95% CI - 1.47 to - 0.16) and MMD (β - 1.17; 95% CI - 2.16 to - 0.18); and Reading decrements compared to glaucoma (β - 0.66; 95% CI - 1.22 to - 0.11). When compared to late glaucoma, individuals with late AMD (β - 0.76; 95% CI - 1.50 to - 0.01) had significantly larger IVI Mobility subscale decrements. VTDR and late AMD, appear to have the greatest impact on VRQoL, compared to late glaucoma and MMD, suggesting a differential impact of late-stage eye disease categorization on VRQoL., (© 2022. The Author(s).)

Purpose: To prospectively evaluate whether diabetic macular ischemia detected with coherence tomography angiography (OCTA) is associated with change in functional outcomes over a period of one year., Methods: This is a one-year prospective, observational study that included 56 eyes with varying levels of diabetic retinopathy. All participants underwent best corrected visual acuity evaluation, swept-source OCTA and microperimetry at baseline and repeated at one year. Parafoveal vessel densities (VD) and foveal avascular zone (FAZ) areas were generated from OCTA in the superficial and deep vascular plexuses. The influence of baseline and change in OCTA parameters on change in visual acuity and retinal sensitivity over one year was evaluated., Results: Over the one-year follow-up period, 16% (9) of eyes had at least one line worsening in BCVA and 7% (4) of eyes had at least 5% decrease in retinal sensitivity compared to baseline. Diabetic retinopathy progressed in 12.5%. Mean superficial vascular plexus (SVP) FAZ area increased (0.32 ± 0.15 to 0.39 ± 0.18 mm2, P = 0.003) and parafoveal VD in deep vascular plexus (DVP) decreased (49.8 ± 3.7% to 48.8 ± 2.9%, P = 0.040) at one year compared to baseline. In the multivariate regression analysis, larger baseline DVP FAZ area was associated with worsening of BCVA over one year (β = 0.16 logMAR per mm2, 95% CI 0.02 to 0.31, P = 0.032). In addition, larger decreases in SVP VD (β = -4.18 db per 10% decrease, 95% CI -6.55 to -1.80, P = 0.002) was associated with worsening of retinal sensitivity over one year., Conclusions: Progression of parafoveal microvasculature changes over one year can be detected using OCTA. Larger baseline DVP FAZ area on OCTA is predictive of worsening in visual outcomes, and larger decreases in SVP VD were associated with worsening of retinal sensitivity over a course of one year in diabetic individuals.

Diabetic macular ischemia (DMI) is a common complication of diabetic retinopathy that can lead to progressive and irreversible visual loss. Despite substantial clinical burden, there are no treatments for DMI, no validated clinical trial endpoints, and few clinical trials focusing on DMI. Therefore, generating consensus on validated endpoints that can be used in DMI for the development of effective interventions is vital. In this review, we discuss potential endpoints appropriate for use in clinical trials of DMI, and consider the data required to establish acceptable and meaningful endpoints. A combination of anatomical, functional, and patient-reported outcome measures will provide the most complete picture of changes that occur during the progression of DMI. Potential endpoint measures include change in size of the foveal avascular zone measured by optical coherence tomography angiography and change over time in best-corrected visual acuity. However, these endpoints must be supported by further research. We also recommend studies to investigate the natural history and progression of DMI. In addition to improving understanding of how patient demographics and comorbidities such as diabetic macular edema affect clinical trial endpoints, these studies would help to build the consensus definition of DMI that is currently missing from clinical practice and research., (The Author(s). Published by S. Karger AG, Basel.)

Purpose: The aim of this consensus article was to provide comprehensive recommendations in the management of diabetic macular edema (DME) by reviewing recent clinical evidence., Design: A questionnaire containing 47 questions was developed which encompassed clinical scenarios such as treatment response to anti-vascular endothelial growth factor and steroid, treatment side effects, as well as cost and compliance/reimbursement in the management of DME using a Dephi questionnaire as guide., Methods: An expert panel of 12 retinal specialists from Singapore, Malaysia, Philippines, India and Vietnam responded to this questionnaire on two separate occasions. The first round responses were compiled, analyzed and discussed in a round table discussion where a consensus was sought through voting. Consensus was considered achieved, when 9 of the 12 panellists (75%) agreed on a recommendation., Results: The DME patients were initially profiled based on their response to treatment, and the terms target response, adequate response, nonresponse, and inadequate response were defined. The panellists arrived at a consensus on various aspects of DME treatment such as need for classification of patients before treatment, first-line treatment options, appropriate time to switch between treatment modalities, and steroid-related side effects based on which recommendations were derived, and a treatment algorithm was developed., Conclusions: This consensus article provides comprehensive, evidence-based treatment guidelines in the management of DME in Asian population. In addition, it also provides recommendations on other aspects of DME management such as steroid treatment for stable glaucoma patients, management of intraocular pressure rise, and recommendations for cataract development.

Diabetic retinopathy is a leading cause of vision impairment and blindness. We systematically reviewed studies published from Jan 1, 1980, to Jan 7, 2018, assessed the methodological quality, and described variations in incidence of diabetic retinopathy by region with a focus on population-based studies that were conducted after 2000 (n=8, including two unpublished studies). Of these eight studies, five were from Asia, and one each from the North America, Caribbean, and sub-Saharan Africa. The annual incidence of diabetic retinopathy ranged from 2·2% to 12·7% and progression from 3·4% to 12·3%. Progression to proliferative diabetic retinopathy was higher in individuals with mild disease compared with those with no disease at baseline. Our Review suggests that more high-quality population-based studies capturing data on the incidence and progression of diabetic retinopathy with stratification by age and sex are needed to consolidate the evidence base. Our data is useful for conceptualisation and development of major public health strategies such as screening programmes for diabetic retinopathy., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Aim: We aimed to characterise specific morphological and vascular features of the choroid in Indian adults with diabetes and diabetic retinopathy (DR)., Methods: Consecutive participants from the Singapore Indian Eye Study's 6-year follow-up examination underwent choroidal imaging using spectral domain optical coherence tomography (OCT) with enhanced depth imaging. Raw OCT images were loaded on a custom-written application on MATLAB that enabled delineation for detailed morphological and vascular analyses. Multiple linear regression analyses were performed to assess differences in choroidal characteristics by diabetes DR., Results: Of the 462 recruited participants, 273 had no diabetes (mean age was 60.1±6.8 years), 100 had diabetes but no DR (61.8±7.4 years) and 89 had DR (62.4±6.0 years). In multiple regression analysis, after accounting for relevant confounders, compared with those without diabetes, participants with diabetes had significantly thinner mean choroidal thickness (CT; mean difference (MD)=-25.19 µm, p=0.001), smaller choroidal volume (MD=-0.23 mm 3 , p=0.003), more inflection points (MD=1.78, p<0.001) and lesser choroidal vascular area within the foveal (MD=-0.024 mm 2 , p=0.001) and macular (MD=-0.095 mm 2 , p<0.001) regions. Among the diabetic group, subjects with DR had significantly thicker mean CT (MD=25.91 µm, p=0.001), greater choroidal volume (MD=0.24 mm 3 , p=0.009), lesser inflection points (MD=-0.478, p=0.045) and greater choroidal vascular area at foveal (MD=0.016 mm 2 , p=0.019) and macular (MD=0.057 mm 2 , p=0.016) regions, compared with those without DR., Conclusions: Choroidal morphology and vasculature were altered in Indian adults with diabetes and DR. These findings may provide insights into choroidal changes in diabetes and DR., Competing Interests: Competing interests: CMGC: independent consultant for Bayer and Novartis; T-YW: received grant support from National Medical Research Council (NMRC) and Biomedical Research Council, Singapore directed to Singapore Eye Research Institute, Advisory Board member for Abbot, Novartis, Pfizer, Allergan, and Bayer, independent consultant for Abbot, Novartis, Pfizer, Allergan and Bayer; C-YC: received grant support from NMRC and Biomedical Research Council, Singapore directed to Singapore Eye Research Institute., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Importance: Optical coherence tomographic angiography (OCT-A) is able to visualize retinal microvasculature without the need for injection of fluorescein contrast dye. Nevertheless, it is only able to capture a limited view of macula and does not show leakage., Objectives: To evaluate the retinal microvasculature using OCT-A in patients with type 2 diabetes as well as the association of OCT-A characteristics with diabetic retinopathy (DR) and systemic risk factors., Design, Setting, and Participants: A prospective, observational study was conducted from January 1 to June 30, 2016, at medical retina clinics at the Singapore National Eye Center among 50 patients with type 2 diabetes with and without DR (n = 100 eyes). We examined the retinal microvasculature with swept-source OCT-A and a semiautomated software to measure the capillary density index (CDI) and fractal dimension (FD) at the superficial vascular plexus (SVP) and deep retinal vascular plexus (DVP). We collected data on histories of patients' glycated hemoglobin A1c, hypertension, hyperlipidemia, smoking, and renal impairment., Main Outcomes and Measures: The CDI and FD at the SVP and DVP for each severity level of DR and the association of systemic risk factors vs the CDI and FD., Results: The mean (SD) glycated hemoglobin A1c of the 50 patients (26 men and 24 women; 35 Chinese; mean [SD] age, 59.5 [8.9] years) was 7.9% (1.7%). The mean (SD) CDI at the SVP decreased from 0.358 (0.017) in patients with no DR to 0.338 (0.012) in patients with proliferative DR (P < .001) and at the DVP decreased in patients with no DR from 0.361 (0.019) to 0.345 (0.020) in patients with proliferative DR (P = .04). The mean (SD) FD at the SVP increased from 1.53 (0.05) in patients with no DR to 1.60 (0.05) in patients with proliferative DR (P < .01) and at the DVP increased from 1.55 (0.06) in patients with no DR to 1.61 (0.05) in patients with proliferative DR (P = .02). For systemic risk factors, hyperlipidemia (odds ratio [OR], 9.82; 95% CI, 6.92-11.23; P < .001), smoking (OR, 10.90; 95% CI, 8.23-12.34; P < .001), and renal impairment (OR, 3.72; 95% CI, 1.80-4.81; P = .05) were associated with reduced CDI, while increased glycated hemoglobin A1c (≥8%) (OR, 8.77; 95% CI, 5.23-10.81; P < .01) and renal impairment (OR, 10.30; 95% CI, 8.21-11.91; P < .001) were associated with increased FD., Conclusions and Relevance: Optical coherence tomographic angiography is a novel imaging modality to quantify the retinal capillary microvasculature in patients with diabetes. It can be potentially used in interventional trials to study the effect of systemic risk factors on the microvasculature that was previously not accessible in a noninvasive manner. The relevance of these findings relative to visual acuity, however, remains largely unknown at this time.