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Purpose Determine associations between early residual fluid (ERF)-free status and improved long-term visual outcomes. Design Clinical cohort study from post hoc analysis of two phase 3 clinical trials’ data. Methods Independent of treatment allocation, patients from the multicenter, prospective, randomized, double-masked HAWK and HARRIER trials who received either brolucizumab 6 mg or aflibercept 2 mg were split into two cohorts dependent on presence or absence of ERF at week 12. Additionally, similar analyses were performed on presence or absence of early residual intraretinal fluid (IRF) and subretinal fluid (SRF) at week 12. The two groups, ERF-free (N=1051) and ERF (N=366) were compared. Changes from baseline in best-corrected visual acuity (BCVA) and central subfield thickness (CST) were determined. Results From week 12 to 96, patients who were ERF-free had greater least square (LS) mean increases from baseline for BCVA and CST compared to ERF patients. Greater LS mean differences in BCVA from week 12 to 96 were noted between ERF-free and ERF patients. A greater proportion of patients in the ERF-free cohort reported a ≥5, ≥10, or ≥15 letter improvement and a higher proportion reported BCVA ≥70 letters from baseline to week 96 compared to those with fluid. Conclusions Improvements in visual outcomes in ERF-free patients were greater than in ERF patients occurring as early as 4 weeks (week 12) following the last loading dose and continued to week 96. Therefore, ERF status may be a useful indicator of anti-vascular endothelial growth factor treatment response.

Diagnosis and management of proliferative diabetic retinopathy are reliant upon retinal imaging. A systematic literature review of non-invasive imaging to guide diagnosis and treatment of proliferative diabetic retinopathy was performed. There is a trend of moving away from invasive (e.g., fundus fluorescein angiography) to non-invasive (e.g., wide-field optical coherence tomography (OCT), OCT angiography and colour fundus photography) imaging modalities to allow for more objective assessments that can be readily repeated in a time-efficient manner without compromising patient safety. Such quantitative assessments generating large amounts of data could benefit from artificial intelligence approaches to aid clinical decision making. These non-invasive imaging modalities continue to improve both in terms of the quality of image acquisition and progress in image interpretation. It is important that newer non-invasive imaging modalities are appropriately validated in large-scale prospective observational studies or randomised clinical trials.

Visual acuity is a key outcome measure in the treatment of neovascular age-related macular degeneration (nAMD) using anti-vascular endothelial growth factor agents. Large variations in visual responses between individuals within clinical trials and real-world studies may relate to underlying differences in patient and treatment factors. Most notably, a better baseline visual acuity, younger age and smaller choroidal neovascularization lesion size have been strongly associated with achieving better visual outcomes. In addition, there is emerging evidence for other roles including genetic factors and anatomical variables such as fluid status. Apart from patient-related factors, treatments that favor a higher number of injections tend to provide better visual outcomes. Overall, the identification of predictive factors does not currently play an essential role in the clinical management of patients with nAMD. However, they have allowed for the understanding that early detection, timely management and close monitoring of the disease are required to achieve optimal visual outcomes. Further investigation into predictive factors alongside the development of novel therapeutic agents may one day provide a means to accurately predict patient outcomes. Treatment regimens that offer flexible dosing patterns such as the treat-and-extend strategy currently provide a degree of personalization during treatment.

Introduction: With neovascular age-related macular degeneration (nAMD) being a leading cause of irreversible vision loss and its implications as a major health care burden, treatment regimens that ...

Purpose To report the 10-year outcomes of eyes with neovascular age-related macular degeneration (nAMD) treated with vascular endothelial growth factor (VEGF) inhibitors. Design Ten-year, retrospective cohort study. Participants A total of 1046 patients who commenced treatment with anti-VEGF for nAMD. Methods Anti-VEGF–naive eyes diagnosed with nAMD that commenced treatment between November 2006 and December 2009 were identified. Data collected included the baseline demographics, visual acuity (VA), and number of intravitreal injections. Baseline fundus fluorescein angiograms and OCT images were graded for choroidal neovascularization type. OCT images were graded for central macular thickness (CMT) and the presence of fluid over the 10 years. Main Outcome Measures Change in vision at 10 years. Secondary outcomes included the proportion of eyes with 20/40 vision or better and 20/200 or worse, the proportion of eyes that were dry on OCT imaging, and the number of injections. Results Of 1046 eligible eyes, 10-year data were available for 293 (28%), which were included in the analyses. Eyes received 58.1 (standard deviation [SD], 33.6) injections during the 10 years. The mean CMT decreased from 355.5 μm (SD, 107.8 μm) to 264.2 (SD, 79.5) μm (P Conclusions On average, eyes with nAMD maintained starting VA when treated with VEGF inhibitors for 10 years. With ongoing regular treatment, a greater proportion of eyes achieved VA of 20/40 or better at 10 years than at presentation.

PURPOSE: To evaluate anatomical changes on ultra-wide-field fluorescein-angiography and optical coherence angiography (OCT-A) among a cohort with treatment-resistant macular edema secondary to retinal vein occlusions (RVO) switched to aflibercept. MATERIALS AND METHODS: Patients with persistent macular edema despite previous bevacizumab and/or ranibizumab were switched to aflibercept in a 48-week prospective trial. Ultra-wide-field fluorescein angiography (UWFFA) and OCT-A were performed at baseline, week-24 and week-48. The ischemic index was calculated from UWFFA and the areas of vascular perfusion. The foveal avascular zone (FAZ) were quantitatively evaluated on OCT-A. RESULTS: Eighteen patients (mean age, 70.3±8.6 years) were recruited. Mean central macular thickness (CMT) was significantly reduced at 48-weeks compared to baseline (-87.6±48.8 μm, P < 0.001 and -191.0±128.3μm, P < 0.001 among BRVO and CRVO eyes, respectively). The mean baseline ischemic index as measured on Optos wide-field angiography was 10.9%±8.3 and decreased to 5.7%±4.2 (P = 0.028), at week 48. The mean FAZ areas of the SCP and DCP reduced by -0.06 ± 0.12 mm 2 and -0.17± 0.45 mm 2 , respectively. FAZ area on OCT-A was stable in eyes with stable or improved vision but increased in size in eyes with baseline macular ischemia and those with lower gains in BCVA at week 48 (R 2 =0.719, P = 0.05 and R 2 =0.516, P = 0.01). CONCLUSION: There was a reduction in macular edema measured on OCT at 48-weeks in eyes switched to aflibercept with chronic macular edema due to retinal vein occlusion. There was also a reduction in retinal ischemia as measured using UWFFA.

Purpose To compare the incidence and progression of macular atrophy (MA) in eyes with neovascular age-related macular degeneration (nAMD) treated with anti-vascular endothelial growth factor (VEGF) agents using either a treat-and-extend (T&E) or a pro-re-nata (PRN) regimen over 4-years in a real-life setting. Design 4-year, multicenter, retrospective comparative study PARTICIPANTS: 264 patients with treatment-naive nAMD. Methods Consecutive patients with nAMD received anti-VEGF therapy according to a T&E (n=163) or PRN (n=101) regimen. Eyes were included if they had received anti-VEGF injections for a period of at least 4-years and had annual fundus autofluorescence (FAF) and optical coherence tomography (OCT) imaging using Heidelberg Spectralis. Two masked graders independently delineated areas of MA from serial FAF images using Heidelberg region finder software, and growth rates were calculated. Incident MA was assessed using proportional hazard ratios. Main outcomes measures MA incidence and progression over 4-years, association between treatment strategy, and number of injections. Results At baseline, MA was present in 24% and 20% of study eyes in T&E and PRN groups, respectively (p=0.32). At year-4, 27% (34/124) and 25% (20/81) eyes without baseline MA had detectable MA, in the T&E and PRN groups respectively. In those with MA at baseline, the mean square root area of MA progressed by a rate of 0.4±0.2 and 0.4±0.1mm/year in the T&E and PRN groups, respectively (p=0. 23). Multivariate analysis for baseline predictors of MA growth demonstrated older age, poorer baseline VA and presence of RAP, had a higher risk of greater MA progression (P=0.03). Regression analysis demonstrated no association between T&E and PRN treatment strategies with the risk of developing new MA during the four years of follow-up or the progression of pre-existing MA at year-4 (p=0.692). Conclusion Over four years, neither incidence nor progression of macular atrophy in eyes with nAMD treated with anti-VEGF injections was influenced by the treatment regimen and injection frequency. Eyes treated with a T&E regimen received more injections and had better visual outcomes compared to those treated with a PRN approach.

Objective Individuals with spinal cord injury (SCI) often present signs and symptoms of median nerve (MN) pathology. Preclinical signs identification of MN pathology might facilitate early intervention to prevent or delay carpal tunnel syndrome in SCI. We assessed if ultrasound parameters changed in response to upper extremity (UE) circuit training exercise in individuals with paraplegia and able-bodied individuals. Design Case-control study. Participants Adults (N=32) with paraplegia (n=16) and age- and sex-matched able-bodied controls (n=16). Intervention Circuit training exercise. Main Outcome Measures MN ultrasound evaluation at the pisiform and radius before and after UE exercise. Ultrasound parameters included cross-sectional area (CSA), and gray scale (GS). Data presented as mean ± SD. Results Pre-exercise CSAs were larger in SCI at the radius (12.0±2.9 vs 9.0±2.1; P=.003), but not the pisiform (9.8±3.1 vs 9.1±1.7; P=.431). There were no statistical differences in MN response to exercise between groups (all P≥.293). Across participants, CSA changes were inversely associated with their pre-exercise values at the pisiform (r=–0.648; P Conclusions CSA exercise response was more strongly related to pre-exercise MN values than presence or absence of SCI.

Age-related macular degeneration, diabetic retinopathy, cataract, and glaucoma remain the leading causes of visual impairment in developed nations, resulting in a substantial treatment burden on sufferers and health care systems. Despite significant advances in diagnostic testing and therapeutics, population-based strategies to reduce the burden of these diseases remain limited. However, there is some evidence that these diseases may share overlapping risk factors, particularly in regard to dietary intake and antioxidant status, and it is thus possible that dietary modification may reduce both the prevalence and severity of these conditions. In particular, dietary intake of green leafy vegetables, hyperglycemia/glycemia index, and omega-3 fatty acid intake, as well as overall dietary patterns, may affect risk of one or more of these conditions. In this review, we analyse the evidence for dietary intake and the association with these conditions, and provide insights into possible modifications that may thus simultaneously reduce the risk of visual impairment from multiple causes, including improving dietary intake of green leafy vegetables and reducing dietary glycemic index, both of which have been associated with a decreased risk of multiple causes of visual impairment.

Purpose To compare the efficacy and safety of abicipar every 8 weeks and quarterly (after initial doses) versus ranibizumab every 4 weeks in treatment-naive patients with neovascular age-related macular degeneration (AMD). Design Two randomized, multicenter, double-masked, parallel-group, active-controlled, phase 3 clinical trials (CEDAR, SEQUOIA) with identical protocols were conducted. Data from both trials were pooled for analysis. Participants Patients with active choroidal neovascularization secondary to AMD and best-corrected visual acuity (BCVA) of 24–73 Early Treatment Diabetic Retinopathy Study letters in the study eye were enrolled. Methods Patients (n = 1888) were randomized in a 1:1:1 ratio to study eye treatment with abicipar 2 mg every 8 weeks after 3 initial doses at baseline and weeks 4 and 8 (Q8), abicipar 2 mg every 12 weeks after 3 initial doses at baseline and weeks 4 and 12 (Q12), or ranibizumab 0.5 mg every 4 weeks (Q4). Main Outcome Measures The primary efficacy end point was proportion of patients with stable vision (defined as Results The proportion of patients with stable vision at week 52 was 93.2%, 91.3%, and 95.8% in the abicipar Q8, abicipar Q12, and ranibizumab Q4 groups, respectively, with both abicipar Q8 and Q12 noninferior to ranibizumab Q4. Week 52 mean change from baseline in BCVA was 7.5, 6.4, and 8.4 letters and in CRT was −144, −145, and −144 μm in the abicipar Q8, abicipar Q12, and ranibizumab Q4 groups, respectively. Incidence of intraocular inflammation (IOI) AEs was 15.4%, 15.3%, and 0.3%, respectively. The IOI AEs were typically mild or moderate in severity and treated with topical corticosteroids; 62 of 192 patients (32.3%) received oral and/or injectable corticosteroids. Conclusions Abicipar Q8 and Q12 were both noninferior to ranibizumab Q4 in the primary end point of stable vision at week 52. Intraocular inflammation was more frequent with abicipar. Quarterly and Q8 abicipar reduce nAMD disease and treatment burden compared with monthly treatment.

Optic disc pit is a rare congenital defect which appears as a circumscribed greyish depression in the lamina cribrosa. Serous macular detachment is one of the most visually debilitating complications of optic disc pit, affecting 25-75 per cent of patients. Although there is a wide variety of treatment modalities available with varying degrees of success, there is yet no consensus in the optimal management of optic disc pit-associated maculopathy. This review discusses the literature on the pathogenesis, clinical presentation, diagnosis and treatment options.

Tuberculosis immune reconstitution inflammatory syndrome (TB-IRIS) is an abnormal, excessive immune response against live or dead Mycobacteria tuberculosis that may occur during or even after completion of anti-TB therapy, commonly in HIV-infected patients. However, this has also been reported amongst HIV negative patients. We report a case of CNS TB-IRIS in a 57-year-old HIV negative man with miliary TB and tuberculoma. He first presented with 4 months of chronic constitutional symptoms. His symptoms improved on standard anti-TB (isoniazid, rifampicin, ethambutol, pyrazinamide) initially, but he developed worsening left hemiparesis after 1 month of treatment. He was restarted on tapering dose of dexamethasone, and anti-TB was intensified with intramuscular streptomycin for 2 months. His gained full muscle power 4 months later. Serial brain imaging subsequently showed slow treatment response with partial resolution of brain lesions. However, he developed another episode of left hemiparesis with facial asymmetry and slurred speech after 16 months of anti-TB treatment. Repeated MRI brain showed 2 large frontal ring enhancing lesions and lesions in cerebellar hemispheres and vermis regions. Due to diagnostic uncertainties and compressive nature of the brain lesions, craniotomy and excision biopsy of the right frontal lesion were performed. There were no evidence of drug resistant TB and no other brain pathologies were found. Moxifloxacin was added post operatively to achieve better CNS penetration. Patient eventually recovered and achieved full muscle strength of left upper and lower limbs.

Introduction: The treatment paradigm for neovascular age-related macular degeneration (nAMD) has had a profound shift over the past 15 years with the advent of anti-vascular endothelial growth fact...

Target vulnerability correlates the level of drug-target engagement required to generate a pharmacological response. High vulnerability targets are those that require only a relatively small fraction of occupancy to achieve the desired pharmacological outcome, whereas low vulnerability targets require high levels of engagement. Here we demonstrate that the slope of the correlation between drug-target residence time and the post-antibiotic effect (PAE) can be used to define the vulnerability of bacterial targets. For macrolides, a steep slope is observed between residence time on the E. coli ribosome and the PAE, indicating that the ribosome is a highly vulnerable drug target. Analysis of the residence time-PAE data for erythromycin, azithromycin, spiramycin, and telithromycin using a mechanistic pharmacokinetic-pharmacodynamic model that integrates drug-target kinetics into predictions of drug activity, lead to the successful prediction of the cellular PAE for tylosin which has the longest residence time (7.1 h) and PAE (5.8 h). Although the macrolide data support a connection between residence time, PAE and bactericidality, many bactericidal β-lactam antibiotics do not give a PAE illustrating the role of factors such as protein resynthesis in the expression of target vulnerability.

To report the outcomes of eyes receiving surgical management for traumatic macular holes. To describe the preoperative and postoperative optical coherence tomography features of traumatic macular holes and to explore associations between preoperative clinical and optical coherence tomography features, and visual outcome.Retrospective study of patients undergoing vitrectomy for traumatic macular hole and entered into the Australian and New Zealand Society of Retinal Specialists surgical registry. Preoperative clinical data, surgical details, and 3-month postoperative outcomes were recorded prospectively. Longer-term outcomes at 12 months were requested retrospectively, as were preoperative and postoperative optical coherence tomography scans.Hole closure was achieved in 91% (21/23) of patients with a single procedure. The average preoperative visual acuity was 20/120. At 3 months postoperatively, the mean visual acuity had improved to 20/70 (P0.001), 11/23 (48%) of eyes improved ≥15 letters, and the number of eyes with 20/40 acuity or better increased from 1/23 to 7/23. Eyes with worse visual outcomes (visual acuity20/80) had larger holes, worse preoperative acuity, and a greater extent of preoperative ellipsoid band attenuation than those with better postoperative visual acuity.Eyes receiving surgical management for traumatic macular hole achieved good anatomical results and approximately half had a substantial improvement in acuity. Ellipsoid band attenuation on preoperative optical coherence tomography and worse preoperative acuity were associated with poorer visual outcomes.

Purpose: The aim of this study was to examine 12-month outcomes of eyes switched from intravitreal ranibizumab or bevacizumab to aflibercept for cystoid macular edema due to retinal vein occlusion (RVO). Design: Retrospective, observation, case series. Methods: A retrospective study was performed assessing eyes with RVO switched to aflibercept for at least 12 months. To be included in the study, eyes had to have macular edema despite treatment for at least 6 months with bevacizumab and/or ranibizumab before the switch, central foveal thickness (CFT) ≥300 μm at time of switch, and visual acuity (VA) ≤60 early treatment of diabetic retinopathy score (ETDRS) letters (20/40 Snellen equivalent). Outcome measures included change in VA (in ETDRS letters), CFT, and interval between intravitreal injections. Results: 27 eyes of 27 patients were included in the analysis: 13 with branch RVO, and 14 with central RVO. Mean VA before switch was 54.2 ± 23.7 letters (20/80 Snellen equivalent) and mean CFT was 460.4 ± 178.2 μm. Mean number of previous anti-vascular endothelial growth factor (VEGF) injections was 29.5 ± 19.2. At 12 months, mean VA improved by 8.7 ± 13.2 letters (P

Purpose: Review and provide consensus recommendations on use of treat-and-extend (T&E) regimens for neovascular age-related macular degeneration (nAMD) and polypoidal choroidal vasculopathy (PCV) management with relevance for clinicians in the Asia-Pacific region. Methods: A systematic search of MEDLINE, EMBASE, and Cochrane databases, and abstract databases of the Asia-Pacific Vitreo-retina Society, European Society of Retina Specialists, American Academy of Ophthalmology, and Controversies in Ophthalmology: Asia-Australia congresses, was conducted to assess evidence for T&E regimens in nAMD. Only studies with ≥100 study eyes were included. An expert panel reviewed the results and key factors potentially influencing the use of T&E regimens in nAMD and PCV, and subsequently formed consensus recommendations for their application in the Asia-Pacific region. Results: Twenty-seven studies were included. Studies demonstrated that T&E regimens with aflibercept, ranibizumab, or bevacizumab in nAMD, and with aflibercept in PCV, were efficacious and safe. The recommendation for T&E is, after ≥3 consecutive monthly loading doses, treatment intervals can be extended by 2 to 4 weeks up to 12 to 16 weeks. When disease activity recurs, the recommendation is to reinject and shorten intervals by 2 to 4 weeks until fluid resolution, after which treatment intervals can again be extended. Intraretinal fluid should be treated until resolved; however, persistent minimal subretinal fluid after consecutive treatments may be tolerated with treatment intervals maintained or extended if the clinical condition is stable. Conclusions: T&E regimens are efficacious and safe for nAMD and PCV, can reduce the number of visits, and minimize the overall burden for clinicians and patients.

Objective Developmental dyslexia is a reading disorder that features difficulties in perceiving and tracking rhythmic regularities in auditory streams, such as speech and music. Studies on typical healthy participants have shown that power fluctuations of neural oscillations in beta band (15–25 Hz) reflect an essential mechanism for tracking rhythm or entrainment and relate to predictive timing and attentional processes. Here we investigated whether adults with dyslexia have atypical beta power fluctuation. Methods The electroencephalographic activities of individuals with dyslexia (n = 13) and typical control participants (n = 13) were measured while they passively listened to an isochronous tone sequence (2 Hz presentation rate). The time–frequency neural activities generated from auditory cortices were analyzed. Results The phase of beta power fluctuation at the 2 Hz stimulus presentation rate differed and appeared opposite between individuals with dyslexia and controls. Conclusions Atypical beta power fluctuation might reflect deficits in perceiving and tracking auditory rhythm in dyslexia. Significance These findings extend our understanding of atypical neural activities for tracking rhythm in dyslexia and could inspire novel methods to objectively measure the benefits of training, and predict potential benefit of auditory rhythmic rehabilitation programs on an individual basis.

We performed multiplex immunofluorescence (mIF) using an array of myeloid and lymphoid markers on primary tumor samples from 122 patients with RCC. Regions of interest (ROIs) were selected from three distinct tumor zones: the tumor-core, stroma, and tumor-stroma interface. Digital pathologic imaging analysis was leveraged to quantify the geospatial location and distribution of immune cells within the TIME, and these findings were correlated with a variety of tumor molecular profiles. For patients with ccRCC, as clinical stage increased, immunosuppressive M2-like CD163+ TAMs migrated from the tumor compartment and into the stroma at the tumor-stroma interface and became increasingly co-localized with CD8+ T-cells. Furthermore, high CD163+ TAM clustering into the stromal compartment and high CD8+/CD163+ stromal co-localization were independently associated with worse OS and cancer-specific survival (CSS), while accounting for clinical stage. Overall, this data suggests that the pro-tumor effect of M2-like TAMs and their effect on CD8+ T-cells may be dependent on their specific geospatial location and distribution within the TIME -- namely, that M2-like TAMs exert their pro-tumor effect and interact with CD8+ T-cells most effectively from the stromal compartment at the tumor-stroma interface.

Endophthalmitis is a sight-threatening condition, and its timely and appropriate management is essential in preventing permanent vision loss. Recent changes in clinical practice in endophthalmitis and advances in modern vitreoretinal surgery may limit the applicability of established randomised clinical trial evidence to current management. This review discusses the epidemiology, pathophysiology, changing patient presentation, diagnosis and advances in the management of endophthalmitis, presenting the existing literature on this topic and results from Sydney Eye Hospital. Supplementary Information The online version contains supplementary material available at 10.1007/s40123-021-00406-6.

A profound characteristic of field cancerization is alterations in chromatin packing. This study aimed to quantify these alterations using electron microscopy image analysis of buccal mucosa cells of laryngeal, esophageal, and lung cancer patients. Analysis was done on normal-appearing mucosa, believed to be within the cancerization field, and not tumor itself. Large-scale electron microscopy (nanotomy) images were acquired of cancer patients and controls. Within the nuclei, the chromatin packing of euchromatin and heterochromatin was characterized. Furthermore, the chromatin organization was quantified through chromatin packing density scaling. A significant difference was found between the cancer and control groups in the chromatin packing density scaling parameter for length scales below the optical diffraction limit (200 nm) in both the euchromatin (p = 0.002) and the heterochromatin (p = 0.006). The chromatin packing scaling analysis also indicated that the chromatin organization of cancer patients deviated significantly from the control group. They might allow for novel strategies for cancer risk stratification and diagnosis with high sensitivity. This could aid clinicians in personalizing screening strategies for high-risk patients and follow-up strategies for treated cancer patients.

Previous studies indicate that temporal predictability can enhance timing and intensity perception, but it is not known whether it also enhances pitch perception, despite pitch being a fundamental perceptual attribute of sound. Here we investigate this in the context of rhythmic regularity, a form of predictable temporal structure common in sound streams, including music and speech. It is known that neural oscillations in low (delta: 1–3 Hz) and high (beta: 15–25 Hz) frequency bands entrain to rhythms in phase and power, respectively, but it is not clear why both low and high frequency bands entrain to external rhythms, and whether they and their coupling serve different perceptual functions. Participants discriminated near-threshold pitch deviations (targets) embedded in either rhythmic (regular/isochronous) or arrhythmic (irregular/non-isochronous) tone sequences. Psychophysically, we found superior pitch discrimination performance for target tones in rhythmic compared to arrhythmic sequences. Electroencephalography recordings from auditory cortex showed that delta phase, beta power modulation, and delta-beta coupling were all modulated by rhythmic regularity. Importantly, trial-by-trial neural-behavioural correlational analyses showed that, prior to a target, the depth of U-shaped beta power modulation predicted pitch discrimination sensitivity whereas cross-frequency coupling strength predicted reaction time. These novel findings suggest that delta phase might reflect rhythmic temporal expectation, beta power temporal attention, and delta-beta coupling auditory-motor communication. Together, low and high frequency auditory neural oscillations reflect different perceptual functions that work in concert for tracking rhythmic regularity and proactively facilitate pitch perception.

Aim The incidence and prevalence of diabetes mellitus (DM) in Australia is increasing. Thus, it is essential that practitioners appreciate the impending effect that increasing incidence of diabetes has on patients and the wider community. Accordingly, this study examines the humanistic burden of intravitreal injections for the treatment of diabetic macular oedema (DMO) among several health variables. Methods Survey data from a representative sample of Australian adults undergoing treatment for DMO were examined. Respondents participated via an online survey recruited by means of a national online consumer panel and the New South Wales and Victorian Diabetes Foundations. The online survey included questions relating to the humanistic burden of disease, such as the emotional and physical impact of intravitreal injection therapy; the practical impacts of injection therapy; and to identify potential improvements to treatment regimens. Results Sixty-five participants took part in the online survey. Of these, 49% had their most recent injection

Background Retinal pigment epithelium (RPE) is known to secrete factors important for retinal homeostasis. How this secretome changes in diabetic eyes treated with anti-vascular endothelial growth factor (VEGF) inhibitors is unclear. Methods Diabetic conditions were simulated in vitro using ARPE-19 cell-line culture, with high glucose (25 mM) culture media, and hypoxia was chemically induced using cobalt chloride. Stress was assessed using cell viability assays as well as Western blots and enzyme-linked immunosorbent assay (ELISA) for production of HIF-1a and VEGF-A. Production of neurotrophic factors was quantified once conditions were established using ELISA under stress with and without the addition of VEGF inhibitors. Changes were analysed with one-way ANOVA. Results Hypoxia downregulated pigment epithelium-derived factor (PEDF) expression. The addition of bevacizumab, ranibizumab and aflibercept in normoxic conditions all led to a significant downregulation of PEDF. Glucose concentration had no effect on secretion of PEDF. Brain-derived neurotrophic factor (BDNF) secretion was downregulated in high glucose and was upregulated in hypoxia. Placental growth factor (PlGF) secretion by ARPE-19 was undetectable by ELISA. Conclusions We found that hypoxia, high glucose or VEGF inhibitors affected secretion of neurotrophic factors. This variation under different conditions may influence neuron and photoreceptor survival in the diabetic state and VEGF inhibitor treated eyes.

Purpose: We report a case of a male patient with chronic ocular pain that resolved completely following peripheral nerve blocks. Observations: A 66-year-old male presented with a seven-year history of severe left eye pain and photophobia. The pain began after retinal detachment repair with scleral buckle placement. Previous treatments included topical (autologous serum tears, corticosteroids, diclofenac, cyclosporine) and oral (gabapentin, diclofenac) therapies with no pain relief. The patient's pain was so severe that he requested enucleation. After discussion, the decision was made to perform periocular nerve blocks. Prior to the procedure, the patient reported an average pain intensity of 8 out of 10 and photophobia daily. Following left supraorbital, supratrochlear, infraorbital and infratrochlear injections with bupivacaine and methylprednisolone, pain intensity and photophobia improved to 1–2 out of 10. One week later, repeat infraorbital and infratrochlear nerve blocks were given, after which time the patient reported complete resolution of symptoms that lasted for 7 months. Repeat nerve blocks were administered with repeat resolution of pain. There were no complications associated with the procedures. Conclusions and Importance: Chronic ocular pain can be a debilitating condition. Periorbital nerve blocks can provide pain relief and should be considered as a potential treatment option after medical management has failed. Keywords: Chronic ocular pain, Periocular nerve blocks, Neuropathic ocular pain

Purpose To test the hypothesis that tolerating some subretinal fluid (SRF) in patients with neovascular age-related macular degeneration (nAMD) treated with ranibizumab using a treat-and-extend (TE intensive arm: SRF intolerant) or resolution of all IRF only (relaxed arm: SRF tolerant except for SRF >200 μm at the foveal center) before extending treatment intervals. A 5-letter noninferiority margin was applied to the primary outcome. Main Outcome Measures Mean change in best-corrected VA (BCVA), and central subfield thickness and number of injections from baseline to month 24. Results Of the 349 participants randomized (intensive arm, n = 174; relaxed arm, n = 175), 279 (79.9%) completed the month 24. The mean change in BCVA from baseline to month 24 was 3.0 letters (standard deviation, 16.3 letters) in the intensive group and 2.6 letters (standard deviation, 16.3 letters) in the relaxed group, demonstrating noninferiority of the relaxed compared with the intensive treatment (P = 0.99). Similar proportions of both groups achieved 20/40 or better VA (53.5% and 56.6%, respectively; P = 0.92) and 20/200 or worse VA (8.7% and 8.1%, respectively; P = 0.52). Participants in the relaxed group received fewer ranibizumab injections over 24 months (mean, 15.8 [standard deviation, 5.9]) than those in the intensive group (mean, 17 [standard deviation, 6.5]; P = 0.001). Significantly more participants in the intensive group never extended beyond 4-week treatment intervals (13.5%) than in the relaxed group (2.8%; P = 0.003), and significantly more participants in the relaxed group extended to and maintained 12-week treatment intervals (29.6%) than the intensive group (15.0%; P = 0.005). Conclusions Patients treated with a ranibizumab T&E protocol who tolerated some SRF achieved VA that is comparable, with fewer injections, with that achieved when treatment aimed to resolve all SRF completely.

Introduction The Movement Disorder Society’s Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) is the current gold standard means of assessing disease state in Parkinson’s disease (PD). Objective measures in the form of wearable sensors have the potential to improve our ability to monitor symptomology in PD, but numerous methodological challenges remain, including integration into the MDS-UPDRS. We applied a structured video coding scheme to temporally quantify clinical, scripted, motor tasks in the MDS-UPDRS for the alignment and integration of objective measures collected in parallel. Methods 25 PD subjects completed two video-recorded MDS-UPDRS administrations. Visual cues of task performance reliably identifiable in video recordings were used to construct a structured video coding scheme. Postural transitions were also defined and coded. Videos were independently coded by two trained non-expert coders and a third expert coder to derive indices of inter-rater agreement. Results 50 videos of MDS-UPDRS performance were fully coded. Non-expert coders achieved a high level of agreement (Cohen’s κ > 0.8) on all postural transitions and scripted motor tasks except for Postural Stability (κ = 0.617); this level of agreement was largely maintained even when more stringent thresholds for agreement were applied. Durations coded by non-expert coders and expert coders were significantly different (p Conclusions Non-expert coders consistently and accurately quantified discrete behavioral components of the MDS-UPDRS using a structured video coding scheme; this represents a novel, promising approach for integrating objective and clinical measures into unified, longitudinal datasets.

Cancer-associated fibroblasts (CAF) are highly prevalent cells in the tumor microenvironment in clear cell renal cell carcinoma (ccRCC). CAFs exhibit a pro-tumor effect in vitro and have been implicated in tumor cell proliferation, metastasis, and treatment resistance. Our objective is to analyze the geospatial distribution of CAFs with proliferating and apoptotic tumor cells in the ccRCC tumor microenvironment and determine associations with survival and systemic treatment. Pre-treatment primary tumor samples were collected from 96 patients with metastatic ccRCC. Three adjacent slices were obtained from 2 tumor-core regions of interest (ROI) per patient, and immunohistochemistry (IHC) staining was performed for αSMA, Ki-67, and caspase-3 to detect CAFs, proliferating cells, and apoptotic cells, respectively. H-scores and cellular density were generated for each marker. ROIs were aligned, and spatial point patterns were generated, which were then used to perform spatial analyses using a normalized Ripley’s K function at a radius of 25 μm (nK(25)). The survival analyses used an optimal cut-point method, maximizing the log-rank statistic, to stratify the IHC-derived metrics into high and low groups. Multivariable Cox regression analyses were performed accounting for age and International Metastatic RCC Database Consortium (IMDC) risk category. Survival outcomes included overall survival (OS) from the date of diagnosis, OS from the date of immunotherapy initiation (OS-IT), and OS from the date of targeted therapy initiation (OS-TT). Therapy resistance was defined as progression-free survival (PFS) &lt, 6 months, and therapy response was defined as PFS &gt, 9 months. CAFs exhibited higher cellular clustering with Ki-67+ cells than with caspase-3+ cells (nK(25): Ki-67 1.19, caspase-3 1.05, p = 0.04). The median nearest neighbor (NN) distance from CAFs to Ki-67+ cells was shorter compared to caspase-3+ cells (15 μm vs. 37 μm, respectively, p &lt, 0.001). Multivariable Cox regression analyses demonstrated that both high Ki-67+ density and H-score were associated with worse OS, OS-IT, and OS-TT. Regarding αSMA+CAFs, only a high H-score was associated with worse OS, OS-IT, and OS-TT. For caspase-3+, high H-score and density were associated with worse OS and OS-TT. Patients whose tumors were resistant to targeted therapy (TT) had higher Ki-67 density and H-scores than those who had TT responses. Overall, this ex vivo geospatial analysis of CAF distribution suggests that close proximity clustering of tumor cells and CAFs potentiates tumor cell proliferation, resulting in worse OS and resistance to TT in metastatic ccRCC.

Andrew Chang,1 John Stokes,2,3 Lindy Priestman,4 Connor Holmes,4 Peter Said5 1Sydney Retina Clinic, Sydney Institute of Vision Science, Save Sight Institute, University of Sydney, Sydney, New South Wales, Australia; 2Inservio, Sydney, New South Wales, Australia; 3Department of Biomedical Sciences, Charles Sturt University, Orange, New South Wales, Australia; 4Atlantis Healthcare Pty Ltd, Sydney, New South Wales, Australia; 5Medical Affairs, Bayer Australia Ltd, Sydney, New South Wales, AustraliaCorrespondence: Andrew ChangSydney Retina Clinic, 187 Macquarie Street, Sydney, New South Wales, 2000, AustraliaTel + 61 2 92213755Fax + 61 2 92211637Email achang@sydneyretina.com.auPurpose: This study aimed to compare persistence between patients prescribed intravitreal aflibercept (IVT-AFL) for neovascular age-related macular degeneration (nAMD) in Australia enrolled on a patient support program (PSP) with that of a sample of patients from the Australian Pharmaceutical Benefits Scheme (PBS) dataset (10% PBS sample); explore predictors of persistence; describe changes in patient beliefs over the course of their enrollment in a PSP for patients treated with IVT-AFL for nAMD; and assess patient satisfaction.Participants and Methods: Participants prescribed IVT-AFL for the treatment of nAMD were invited to participate in the PSP. The PSP provided tailored support to patients through provision of a welcome pack, structured telephone calls, and information booklets. Persistence was defined in the PSP as the time from the start date in the program, until discontinuation from the program; and as the time from initial prescription until 6-months after the date of last prescription in the 10% PBS set. Persistence on the program and risk of discontinuation were modeled using Kaplan-Meier methods and Cox proportional hazards. In addition, persistence was compared between patients on the PSP and a 10% PBS sample of patients prescribed IVT-AFL for nAMD.Results: Persistence on treatment at 24 months was significantly higher in patients enrolled on the PSP compared to the PBS cohort (88% vs 64%, p< 0.05). The risk of discontinuation in patients enrolled on the PSP was higher in patients identified at screening as “high-risk”, those who were younger, or those with significant distance to travel for treatment. During the PSP, patients reported significant increase in their belief that they had control over their condition (6.1 ± 3.5 to 6.8 ± 3.7; p=0.0034) and a reduction in concerns about treatment. Satisfaction with the PSP was high.Conclusion: Patients provided with access to a PSP showed better persistence on treatment and improved beliefs about nAMD disease and its treatment compared to those in the PBS sample. Improved persistence rates may translate into better outcomes for the patient and the healthcare system, however, further research is required to determine which elements of the program are most beneficial, particularly to those at high risk of discontinuation.Keywords: intravitreal aflibercept, patient satisfaction, illness perceptions, medication beliefs, neovascular macular degeneration, persistence

PurposeTo compare the efficacy and safety of brolucizumab versus aflibercept in eyes with polypoidal choroidal vasculopathy (PCV) over 96 weeks in the HAWK study.DesignHAWK was a global, 2-year, randomised, double-masked, multicentre phase III trial in participants with neovascular age-related macular degeneration.MethodsOf the Japanese participants with PCV, 39 received brolucizumab 6 mg and 30 received aflibercept 2 mg. After 3 monthly loading doses, brolucizumab-treated eyes received an injection every 12 weeks (q12w) but were adjusted to q8w if disease activity was detected. Aflibercept-treated eyes received fixed q8w dosing. Mean change in best-corrected visual acuity (BCVA), the proportion of participants on q12w, retinal thickness, retinal fluid changes and safety were assessed to Week 96.ResultsMean change in BCVA (early treatment diabetic retinopathy study (ETDRS) letters) from baseline to week 48/week 96 was+10.4/+11.4 for brolucizumab and +11.6/+11.1 for aflibercept. For brolucizumab-treated eyes, the probability of only q12w dosing after loading through week 48 was 76%, and 68% through week 96. Fluid resolution was greater with brolucizumab than aflibercept: respective proportions of eyes with intraretinal fluid and/or subretinal fluid were 7.7% and 30% at week 48% and 12.8% and 16.7% at week 96. Brolucizumab exhibited an overall well-tolerated safety profile despite a higher rate of intraocular inflammation compared with aflibercept.ConclusionIn Japanese eyes with PCV, brolucizumab q12w/q8w monotherapy resulted in robust and consistent BCVA gains that were comparable to q8w aflibercept dosing. Anatomical outcomes favoured brolucizumab over aflibercept, with 76% of brolucizumab participants maintained on q12w dosing after loading to week 48.

Objectives: We aim at reporting the functional and oncological outcomes in men with localized prostate cancer who underwent individualized partial gland cryoablation of the prostate by using validated quality-of-life instruments. Methods: We retrospectively reviewed our cryosurgery database between July 2003 and September 2019 for men who were treated with individualized partial gland cryoablation of the prostate at our tertiary care center. Baseline and periodic urinary and sexual function surveys were administered throughout the post-treatment period. Results: A total of 82 men were included in the study. Median follow-up was 28 months (interquartile range: 10.5-59.3 months). A total of 71 men underwent primary individualized partial gland cryoablation, whereas 11 men underwent salvage partial gland ablation. Failure-free survival at 1 to 5 years was 98%, 89%, 84%, 75%, and 75% in the primary therapy group, and 100%, 80%, and 40% in the salvage group at 1 to 3 years, respectively. In the primary therapy group, all 71 patients remained free of pads at 3 months and throughout the follow-up period. Men who had undergone primary focal cryoablation had a higher post-treatment International Index of Erectile Function (IIEF) score, followed by men treated with primary hemi-cryoablation and primary subtotal cryoablation. The American Urological Association (AUA) symptom scores decreased regardless of the type of partial gland ablation performed, with subtotal ablation having the lowest score compared with hemiablation and focal cryoablation. No patient developed a fistula in the primary group, and 1 (9%) patient developed a fistula in the salvage group. Conclusion: Individualized partial gland cryoablation of the prostate is able to achieve excellent oncological and functional outcomes in select men with localized prostate cancer.

Accurate time perception is crucial for hearing (speech, music) and action (walking, catching). Motor brain regions are recruited during auditory time perception. Therefore, the hypothesis was tested that children (age 6-7) at risk for developmental coordination disorder (rDCD), a neurodevelopmental disorder involving motor difficulties, would show nonmotor auditory time perception deficits. Psychophysical tasks confirmed that children with rDCD have poorer duration and rhythm perception than typically developing children (N = 47, d = 0.95-1.01). Electroencephalography showed delayed mismatch negativity or P3a event-related potential latency in response to duration or rhythm deviants, reflecting inefficient brain processing (N = 54, d = 0.71-0.95). These findings are among the first to characterize perceptual timing deficits in DCD, suggesting important theoretical and clinical implications.

To investigate the reliability and comparability of retinal measurements obtained with spectral-domain optical coherence tomography (OCT), optical coherence tomography angiography (OCTA), confocal scanning laser ophthalmoscopy (cSLO) colour images, and fundus autofluorescence (FAF) between two multimodal imaging platforms in eyes with macular pathology and normal, healthy volunteers. This cross-sectional, multi-centre, instrument validation study recruited 94 consecutive subjects. All participants underwent a dilated examination and were scanned consecutively on the Heidelberg Spectralis (Heidelberg Engineering, Heidelberg, Germany) and Nidek Mirante (Nidek Co. Ltd., Gamagori, Japan) devices. Agreement between device images were evaluated from measures of the central retinal thickness (CRT), presence of segmentation and fixation imaging artefacts (IA), foveal avascular zone (FAZ) measurements; as well as sensitivity and specificity values from the detection of atrophy on fundus autofluorescence (FAF), drusen, subretinal drusenoid deposits, geographic atrophy, epiretinal membrane, fibrosis and haemorrhage on multicolour imaging, and agreement between devices and groups. Compared with reference clinical examination, sensitivity values for the identification of retinal features using sole device images ranged from 100% for epiretinal membranes to 66.7% for subretinal drusenoid deposits (SSD). Mean absolute difference for CRT between OCT devices was 3.78 μm (95% confidence interval [CI]: − 21.39 to 28.95, P = 0.809). Differences in the superficial and deep capillary plexus FAZ area on OCTA between devices were not statistically significant (P = 0.881 and P = 0.595, respectively). IAs were significantly increased in the presence of macular pathology. Comparison of retinal measurements between the OCT devices did not differ significantly. Common ultrastructural biomarkers of multiple macular pathologies were identified with high sensitivities and specificities, with good agreement between graders, indicating that they can be identified with comparable confidence in retinal imaging between the two devices.

BACKGROUND: Evidence is accumulating that coronavirus disease 2019 increases the risk of hospitalization and mechanical ventilation in pregnant patients and for preterm delivery. However, the impact on maternal mortality and whether morbidity is differentially affected by disease severity at delivery and trimester of infection are unknown. OBJECTIVE: This study aimed to describe disease severity and outcomes of severe acute respiratory syndrome coronavirus 2 infections in pregnancy across the Washington State, including pregnancy complications and outcomes, hospitalization, and case fatality. STUDY DESIGN: Pregnant patients with a polymerase chain reaction-confirmed severe acute respiratory syndrome coronavirus 2 infection between March 1, 2020, and June 30, 2020, were identified in a multicenter retrospective cohort study from 35 sites in Washington State. Sites captured 61% of annual state deliveries. Case-fatality rates in pregnancy were compared with coronavirus disease 2019 fatality rates in similarly aged adults in Washington State using rate ratios and rate differences. Maternal and neonatal outcomes were compared by trimester of infection and disease severity at the time of delivery. RESULTS: The principal study findings were as follows: (1) among 240 pregnant patients in Washington State with severe acute respiratory syndrome coronavirus 2 infections, 1 in 11 developed severe or critical disease, 1 in 10 were hospitalized for coronavirus disease 2019, and 1 in 80 died; (2) the coronavirus disease 2019-associated hospitalization rate was 3.5-fold higher than in similarly aged adults in Washington State (10.0% vs 2.8%; rate ratio, 3.5; 95% confidence interval, 2.3-5.3); (3) pregnant patients hospitalized for a respiratory concern were more likely to have a comorbidity or underlying conditions including asthma, hypertension, type 2 diabetes mellitus, autoimmune disease, and class III obesity; (4) 3 maternal deaths (1.3%) were attributed to coronavirus disease 2019 for a maternal mortality rate of 1250 of 100,000 pregnancies (95% confidence interval, 257-3653); (5) the coronavirus disease 2019 case fatality in pregnancy was a significant 13.6-fold (95% confidence interval, 2.7-43.6) higher in pregnant patients than in similarly aged individuals in Washington State with an absolute difference in mortality rate of 1.2% (95% confidence interval, -0.3 to 2.6); and (6) preterm birth was significantly higher among women with severe or critical coronavirus disease 2019 at delivery than for women who had recovered from coronavirus disease 2019 (45.4% severe or critical coronavirus disease 2019 vs 5.2% mild coronavirus disease 2019; P

Low back pain with radicular symptoms is a common cause of disability in the adult population in the USA. Lumbar transforaminal epidural steroid injection (TFESI) is one of the most frequently used intervention for lumbar radiculitis. The purpose of this review is to evaluate complications associated with lumbar TFESI. Based on the literature review, the reported rate of minor complications was between 2.4 and 9.6%. The major complications including spinal abscess, spinal cord infarct, and epidural hematoma were documented as case reports. Some patients with spinal cord infarct had permanent neurologic deficits, while the other patients had recovery of neurological function after surgical or medical intervention. This review identifies both the minor and major complications related to lumbar transforaminal epidural steroid injections. According to this review, most complications are minor. Lumbar TFESI can be considered a safe treatment in the management of lumbar radicular pain. However, pain specialists should be aware of the potentially devastating major complications. Early recognition and treatment of complications are crucial for improving the outcome.

To report the 2-year efficacy and safety of abicipar every 8 weeks and quarterly (after initial doses) compared with monthly ranibizumab in patients with treatment-naïve neovascular age-related macular degeneration (nAMD).Two multicenter, randomized, phase 3 clinical trials with identical protocols (CEDAR and SEQUOIA). Analyses used pooled trial data.The trials enrolled 1888 patients (1 eye/patient) with active choroidal neovascularization secondary to age-related macular degeneration and best-corrected visual acuity (BCVA) of 24 to 73 Early Treatment Diabetic Retinopathy Study letters.At enrollment, patients were assigned to study eye treatment with abicipar 2 mg every 8 weeks after initial doses at baseline and weeks 4 and 8 (abicipar Q8, n = 630), abicipar 2 mg every 12 weeks after initial doses at baseline and weeks 4 and 12 (abicipar Q12, n = 628), or ranibizumab 0.5 mg every 4 weeks (ranibizumab Q4, n = 630).Efficacy measures included stable vision (15-letter loss in BCVA from baseline) and change from baseline in BCVA and central retinal thickness (CRT). Safety measures included adverse events (AEs).For patients who completed the study, efficacy of abicipar after initial doses was maintained through week 104. At week 104, the proportion of patients with stable vision was 93.0% (396/426), 89.8% (379/422), and 94.4% (470/498); mean change in BCVA from baseline was +7.8 letters, +6.1 letters, and +8.5 letters, and mean change in CRT from baseline was -147 μm, -146 μm, and -142 μm in the abicipar Q8 (14 injections), abicipar Q12 (10 injections), and ranibizumab Q4 (25 injections) groups, respectively. The overall incidence of intraocular inflammation (IOI) AEs was 15.4%, 15.3%, and 0.3% from baseline through week 52 and 16.2%, 17.6%, and 1.3% from baseline through week 104 in the abicipar Q8, abicipar Q12, and ranibizumab Q4 groups, respectively.Two-year results show efficacy of abicipar Q8 and Q12 in nAMD. First onset of IOI events with abicipar was much reduced in the second year and comparable with ranibizumab (0.8% and 2.3% vs. 1.0%). The extended duration of effect of abicipar allows for quarterly dosing and reduced treatment burden.

Cervical interlaminar epidural steroid injection is a common intervention in the management of cervical radiculitis. Given the large number of injections done annually, it is important to assess the potential complications associated with this procedure. Based on current published studies, the overall complication rate varies. The vast majority are minor complications. However, this review also identified potentially catastrophic complications following cervical interlaminar epidural steroid injections. Based upon our review, cervical epidural steroid injection is considered a safe intervention. Nevertheless, catastrophic complications such as spinal cord injuries from needle placement, infections, and epidural hematoma can occur. It is prudent to take appropriate measures to minimize these complications.

Background Hyperthermia (heating to 43 °C) activates the innate immune system and improves bladder cancer chemosensitivity. Objective To evaluate the tissue penetration and safety of convective hyperthermia combined with intravesical mitomycin C (MMC) pharmacokinetics in live porcine bladder models using the Combat bladder recirculation system (BRS). Methods Forty 60 kg-female swine were anesthetized and catheterized with a 3-way, 16 F catheter. The Combat device was used to heat the bladders to a target temperature of 43 °C with recirculating intravesical MMC at doses of 40, 80, and 120 mg. Dwell-heat time varied from 30–180 min. Rapid necropsy with immediate flash freezing of tissues, blood and urine occurred. MMC concentrations were measured by liquid chromatography tandem-mass spectrometry. Results The Combat BRS system was able to achieve target range temperature (42–44 °C) in 12 mins, and this temperature was maintained as long as the device was running. Two factors increased tissue penetration of MMC in the bladder: drug concentration, and the presence of heat. In the hyperthermia arm, MMC penetration saturated at 80 mg, suggesting that with heating, drug absorption may saturate and not require higher doses to achieve the maximal biological effect. Convective hyperthermia did not increase the MMC concentration in the liver, heart, kidney, spleen, lung, and lymph node tissue even at the 120 mg dose. Conclusions Convective bladder hyperthermia using the Combat BRS device is safe and the temperature can be maintained at 43 °C. Hyperthermia therapy may increase MMC penetration into the bladder wall but does not result in an increase of MMC levels in other organs.

Purpose To evaluate functional and anatomical outcomes after a switch from intravitreal bevacizumab to aflibercept in patients with persistent diabetic macular edema. Methods Prospective, single-arm, open-label clinical trial of patients with persistent diabetic macular edema, despite previous treatment with bevacizumab. Five loading doses of intravitreal aflibercept were administered every 4 weeks with subsequent injections administered every 8 weeks. Patients were reviewed every 4 weeks, and best-corrected visual acuity and central macular thickness were recorded. Primary outcome measures included change in central macular thickness and best-corrected visual acuity at week 48 compared with baseline. Paired t-tests were used to assess change between baseline and follow-up visits. Results At baseline, 43 eyes from 43 patients were recruited with a median (interquartile range) of 12 (7-24) previous intravitreal anti-vascular endothelial growth factor injections over a period of 18 (8-34) months. Mean ± SD central macular thickness reduced by 59 ± 114 μm (P = 0.002), and best-corrected visual acuity improved by 3.9 ± 7.0 letters (P = 0.001) after 48 weeks in the 41 patients who completed the trial. Best-corrected visual acuity improvements were more marked in patients who gained ≥5 letters after the first injection (8.9 ± 5.7 vs. 1.8 ± 6.5 letter gain at 48 weeks, P = 0.002), a difference which remained significant after regression analysis with baseline best-corrected visual acuity . Vision gains and central macular thickness reduction were similar in 9 fellow eyes eligible for inclusion being concurrently treated for diabetic macular edema with bevacizumab. Conclusion Intravitreal aflibercept was effective in improving anatomical and visual outcomes among patients with an incomplete response to intravitreal bevacizumab with 48 weeks of follow-up. Patients with a good early response subsequent to switching had a better improvement in vision at 48 weeks.

Purpose: The current body of evidence on the efficacy and safety of anti-VEGFs for macular oedema secondary to branch retinal vein occlusion (BRVO) is steadily growing as large clinical trials and observational studies are continually completed. The aim of this meta-analysis is to analyse anatomical and functional outcomes in response to anti-VEGF therapy using evidence generated from a pooled analysis of current clinical trials and observational studies. Methods: The current meta-analysis includes treatment of BRVO with aflibercept, bevacizumab and ranibizumab from randomised controlled trials and observational studies. Inclusion criteria included peer-reviewed publications with at least a 12-month follow-up period. On literature review using multiple electronic databases (PubMed, Embase and Cochrane), 22 studies met the inclusion criteria. Baseline patient characteristics, study design, sample size and 12- and 24-month change in best corrected visual acuity (BCVA) and central foveal thickness (CFT) as measured on optical coherence tomography imaging were pooled in a meta-analysis. Data were then stratified by study design and anti-VEGF therapy in subgroup analyses. Results: A total of 1,236 eyes from 22 studies were included in this meta-analysis. Mean baseline BCVA ranged from 66 ETDRS letters (20/50 Snellen equivalent) to 35 letters (20/200 Snellen). Mean baseline CFT ranged from 406.0 to 681.0 µm. Anti-VEGF treatment demonstrated an overall mean improvement in BCVA at 12 months of 14 letters (95% CI 12.0 to 16.2, p < 0.001) and CFT reduction of 228 µm (95% CI –278.9 to –176.1, p < 0.001). The BCVA gains at 12 months were maintained to month 24 with a mean gain of 12.5 letters (95% CI 6.3 to 18.8, p < 0.001), as well as reduction of CFT of 238 µm (95% CI –336.0 to –140.2, p < 0.001). No cases of endophthalmitis or glaucoma were reported in any study. Conclusion: This meta-analysis confirms the comparable safety and efficacy of anti-VEGF therapies for patients with cystoid macular oedema secondary to BRVO. There is a need for randomised prospective comparative trials of anti-VEGF agents for BRVO.

The proposed doses of chloroquine (CQ) and hydroxychloroquine (HCQ) for treatment of COVID-19 (1000 mg/day for 10 days, CQ; 800 mg first day then 400 mg/day for 5 days, HCQ) in many guidelines worldwide, are considerably higher than the maximum recommended daily safe doses of both agents (≤2.3 mg/kg/day, CQ; ≤5.0 mg/kg/day, HCQ) for development of retinal toxicity. Irreversible retinal damage can occur if the exposure to the safe doses is >5 years. It is not known whether exposure to high doses over a short period of time can also cause the damage. We recommend that before prescribing CQ or HCQ, history of ocular disease should be obtained to avoid the prescription if appropriate. If either agent is to be used, routine baseline ocular examination is not absolutely necessary. Patients who do not have ocular disease should also be informed about the potential risk of retinal toxicity. Both agents, however, have not yet been proven to be beneficial to COVID-19.

Vitreous floaters are a common cause for presentation to ophthalmologists, and may significantly affect visual function. In the absence of some more serious underlying pathology such as uveitis, many patients may not experience significant persistent visual impairment from floaters. For some patients, the symptomatic effects of floaters may persist. For these patients, treatment options are available, of which the most commonly reported is vitrectomy. Other treatment modalities have also become more common, notably YAG vitreolysis. Selection of appropriate patients for surgery is often difficult, in part due to the relative lack of objective outcomes with which to measure both visual impairment and improvement post-procedure. Although well-tolerated, vitrectomy does carry with it risks, including iatrogenic retinal breaks, retinal detachment, and in phakic patients, subsequent cataract formation. Techniques such as small gauge vitrectomy, intraoperative examination and treatment of breaks or other worrying lesions, and careful consideration of the need for posterior vitreous detachment induction may help limit the incidence of these adverse events. For other treatment options such as YAG vitreolysis, research and clinical experience remain more limited, and as such the long-term efficacy and risks of these therapies are still unclear. Here, we review the evidence surrounding the role of vitrectomy and YAG vitreolysis in the treatment of vitreous floaters and potential means to minimize therapeutic complications.