In vivo white matter microstructure in adolescents with early-onset psychosis: a multi-site mega-analysis.

Emerging evidence suggests brain white matter alterations in adolescents with early-onset psychosis (EOP; age of onset <18 years). However, as neuroimaging methods vary and sample sizes are modest, results remain inconclusive. Using harmonized data processing protocols and a mega-analytic approach, we compared white matter microstructure in EOP and healthy controls using diffusion tensor imaging (DTI). Our sample included 321 adolescents with EOP (median age = 16.6 years, interquartile range (IQR) = 2.14, 46.4% females) and 265 adolescent healthy controls (median age = 16.2 years, IQR = 2.43, 57.7% females) pooled from nine sites. All sites extracted mean fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity (AD) for 25 white matter regions of interest per participant. ComBat harmonization was performed for all DTI measures to adjust for scanner differences. Multiple linear regression models were fitted to investigate case-control differences and associations with clinical variables in regional DTI measures. We found widespread lower FA in EOP compared to healthy controls, with the largest effect sizes in the superior longitudinal fasciculus (Cohen's d = 0.37), posterior corona radiata (d = 0.32), and superior fronto-occipital fasciculus (d = 0.31). We also found widespread higher RD and more localized higher MD and AD. We detected significant effects of diagnostic subgroup, sex, and duration of illness, but not medication status. Using the largest EOP DTI sample to date, our findings suggest a profile of widespread white matter microstructure alterations in adolescents with EOP, most prominently in male individuals with early-onset schizophrenia and individuals with a shorter duration of illness.

Face-down positioning or posturing after pars plana vitrectomy for macula-involving rhegmatogenous retinal detachments.

BACKGROUND: A macula-involving rhegmatogenous retinal detachment (RRD) is one of the most common ophthalmic surgical emergencies and causes significant visual morbidity. Pars plana vitrectomy (PPV) with gas tamponade is often performed to repair primary macula-involving RRDs with a high rate of anatomical retinal reattachment. It has been advocated by some ophthalmologists that face-down positioning after PPV and gas tamponade helps reduce postoperative retinal displacement. Retinal displacement can cause metamorphopsia and binocular diplopia. OBJECTIVES: The primary objective of this review is to determine whether face-down positioning reduces the risk of retinal displacement following PPV and gas tamponade for primary macula-involving RRDs. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (which contains the Cochrane Eyes and Vision Trials Register) (2022, Issue 11), MEDLINE (January 1946 to 28 November 2022), Embase.com (January 1947 to 28 November 2022), PubMed (1948 to 28 November 2022), Latin American and Caribbean Health Sciences Literature database (1982 to 28 November 2022), ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform. We did not use any date or language restrictions in the electronic search. We last searched the electronic databases on 28 November 2022. SELECTION CRITERIA: We included randomized controlled trials (RCTs) in which face-down positioning was compared with no positioning or another form of positioning following PPV and gas tamponade for primary macula-involving RRDs. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodology and assessed the certainty of the body of evidence for the prespecified outcomes using the GRADE approach. MAIN RESULTS: We identified three RCTs (369 eyes of 368 participants) that met the eligibility criteria. Two RCTs provided data on postoperative retinal displacement, one reported on postoperative distortion and quality of life outcomes, two on postoperative best-corrected visual acuity (BCVA) in logMAR, and two on postoperative ocular adverse events such as outer retinal folds. Study characteristics and risk of bias All the trials involved predominantly male participants (range: 68% to 72%). Only one trial provided race and ethnicity information, was registered on a trial registry, and reported funding sources. Using the RoB 2 tool, we assessed the risk of bias for proportion of eyes with retinal displacement, mean change in visual acuity, objective distortion scores, quality of life assessments, and ocular adverse events, with most domains judged to be at low risk of bias. Findings Immediate face-down positioning may result in a lower proportion of participants with postoperative retinal displacement compared with support-the-break positioning at six months (risk ratio [RR] 0.73, 95% confidence interval [CI] 0.54 to 0.99; 1 RCT; 239 eyes of 239 participants; very low certainty evidence). One study found no evidence of a difference in BCVA at three months when comparing postoperative face-up with face-down positioning with or without perfluorocarbon liquid (mean difference [MD] -0.03, 95% CI -0.09 to 0.02; I2 = 0; 56 eyes of 56 participants; very low certainty evidence). Immediate face-down positioning appears to have little to no effect on postoperative distortion scores at week 26 (MD 1.80, 95% CI -1.92 to 5.52; 1 RCT; 219 eyes of 219 participants; very low certainty evidence) and postoperative quality of life assessment scores at week 26 (MD -1.80, 95% CI -5.52 to 1.92; 1 RCT; 217 eyes of 217 participants; very low certainty evidence). Adverse events One study that enrolled 262 participants with macula-involving RRDs suggested that immediate face-down positioning after PPV and gas tamponade may reduce the ocular adverse event of postoperative outer retinal folds at six months (RR 0.39, 95% CI 0.17 to 0.90; 1 RCT; 262 eyes of 262 participants; very low certainty evidence) and binocular diplopia (RR 0.20, 95% CI 0.04 to 0.90; 1 RCT; 262 eyes of 262 participants; very low certainty evidence) compared with support-the-break positioning. Immediate face-down positioning may increase the ocular adverse event of elevated intraocular pressure compared with support-the-break positioning (RR 1.74, 95% CI 1.11 to 2.73; 1 RCT; 262 eyes of 262 participants; very low certainty evidence). Another study found no evidence of a difference in postoperative outer retinal folds when comparing face-down versus face-up positioning at one and three months (RR 1.00, 95% CI 0.50 to 2.02; RR 1.00, 95% CI 0.28 to 3.61; 1 RCT; 56 eyes of 56 participants; very low certainty evidence). No studies reported non-ocular adverse events. AUTHORS' CONCLUSIONS: Very low certainty evidence suggests that immediate face-down positioning after PPV and gas tamponade may result in a reduction in postoperative retinal displacement, outer retinal folds, and binocular diplopia, but may increase the chance of postoperative raised intraocular pressure compared with support-the-break positioning at six months. We identified two ongoing trials that compare face-down positioning with face-up positioning following PPV and gas tamponade in participants with primary macula-involving RRDs, whose results may provide relevant evidence for our stated objectives. Future trials should be rigorously designed, and investigators should analyze outcome data appropriately and report adequate information to provide evidence of high certainty. Quality of life and patient preferences should be examined in addition to clinical and adverse event outcomes.

Longitudinal Allometry of Sulcal Morphology in Health and Schizophrenia.

Scaling between subcomponents of folding and total brain volume (TBV) in healthy individuals (HIs) is allometric. It is unclear whether this is true in schizophrenia (SZ) or first-episode psychosis (FEP). This study confirmed normative allometric scaling norms in HIs using discovery and replication samples. Cross-sectional and longitudinal diagnostic differences in folding subcomponents were then assessed using an allometric framework. Structural imaging from a longitudinal (Sample 1: HI and SZ, nHI Baseline = 298, nSZ Baseline = 169, nHI Follow-up = 293, nSZ Follow-up = 168, totaling 1087 images, all individuals ≥ 2 images, age 16-69 years) and a cross-sectional sample (Sample 2: nHI = 61 and nFEP = 89, age 10-30 years), all human males and females, is leveraged to calculate global folding and its nested subcomponents: sulcation index (SI, total sulcal/cortical hull area) and determinants of sulcal area: sulcal length and sulcal depth. Scaling of SI, sulcal area, and sulcal length with TBV in SZ and FEP was allometric and did not differ from HIs. Longitudinal age trajectories demonstrated steeper loss of SI and sulcal area through adulthood in SZ. Longitudinal allometric analysis revealed that both annual change in SI and sulcal area was significantly stronger related to change in TBV in SZ compared with HIs. Our results detail the first evidence of the disproportionate contribution of changes in SI and sulcal area to TBV changes in SZ. Longitudinal allometric analysis of sulcal morphology provides deeper insight into lifespan trajectories of cortical folding in SZ.SIGNIFICANCE STATEMENT Psychotic disorders are associated with deficits in cortical folding and brain size, but we lack knowledge of how these two morphometric features are related. We leverage cross-sectional and longitudinal samples in which we decompose folding into a set of nested subcomponents: sulcal and hull area, and sulcal depth and length. We reveal that, in both schizophrenia and first-episode psychosis, (1) scaling of subcomponents with brain size is different from expected scaling laws and (2) caution is warranted when interpreting results from traditional methods for brain size correction. Longitudinal allometric scaling points to loss of sulcal area as a principal contributor to loss of brain size in schizophrenia. These findings advance the understanding of cortical folding atypicalities in psychotic disorders.

The Effect of Macular Hole Duration on Surgical Outcomes: An Individual Participant Data Study of Randomized Controlled Trials.

TOPIC: To define the effect of symptom duration on outcomes in people undergoing surgery for idiopathic full-thickness macular holes (iFTMHs) by means of an individual participant data (IPD) study of randomized controlled trials (RCTs). The outcomes assessed were primary iFTMH closure and postoperative best-corrected visual acuity (BCVA). CLINICAL RELEVANCE: Idiopathic full-thickness macular holes are visually disabling with a prevalence of up to 0.5%. Untreated BCVA is typically reduced to 20/200. Surgery can close holes and improve vision. Symptom duration is thought to affect outcomes with surgery, but the effect is unclear. METHODS: A systematic review identified eligible RCTs that included adults with iFTMH undergoing vitrectomy with gas tamponade in which symptom duration, primary iFTMH closure, and postoperative BCVA were recorded. Bibliographic databases were searched for articles published between 2000 and 2020. Individual participant data were requested from eligible studies. RESULTS: Twenty eligible RCTs were identified. Data were requested from all studies and obtained from 12, representing 940 eyes in total. Median symptom duration was 6 months (interquartile range, 3-10). Primary closure was achieved in 81.5% of eyes. There was a linear relationship between predicted probability of closure and symptom duration. Multilevel logistic regression showed each additional month of duration was associated with 0.965 times lower odds of closure (95% confidence interval [CI], 0.935-0.996, P = 0.026). Internal limiting membrane (ILM) peeling, ILM flap use, better preoperative BCVA, face-down positioning, and smaller iFTMH size were associated with increased odds of primary closure. Median postoperative BCVA in eyes achieving primary closure was 0.48 logarithm of the minimum angle of resolution (logMAR) (20/60). Multilevel logistic regression showed for eyes achieving primary iFTMH closure, each additional month of symptom duration was associated with worsening BCVA by 0.008 logMAR units (95% CI, 0.005-0.011, P < 0.001) (i.e., ∼1 Early Treatment Diabetic Retinopathy Study letter loss per 2 months). ILM flaps, intraocular tamponade using long-acting gas, better preoperative BCVA, smaller iFTMH size, and phakic status were also associated with improved postoperative BCVA. CONCLUSIONS: Symptom duration was independently associated with both anatomic and visual outcomes in persons undergoing surgery for iFTMH. Time to surgery should be minimized and care pathways designed to enable this.

Diabetic Macular Edema and Diode Subthreshold Micropulse Laser: A Randomized Double-Masked Noninferiority Clinical Trial.

PURPOSE: To determine clinical effectiveness, safety, and cost-effectiveness of subthreshold micropulse laser (SML), compared with standard laser (SL), for diabetic macular edema (DME) with central retinal thickness (CRT) < 400 µm. DESIGN: Pragmatic, multicenter, allocation-concealed, double-masked, randomized, noninferiority trial. PARTICIPANTS: Adults with center-involved DME < 400 µm and best-corrected visual acuity (BCVA) of > 24 Early Treatment Diabetic Retinopathy Study (ETDRS) letters in one/both eyes. METHODS: Randomization 1:1 to 577 nm SML or SL treatment. Retreatments were allowed. Rescue with intravitreal anti-vascular endothelial growth factor therapies or steroids was permitted if 10 or more ETDRS letter loss occurred, CRT increased > 400 µm, or both. MAIN OUTCOME MEASURES: Primary outcome was mean change in BCVA in the study eye at 24 months (noninferiority margin 5 ETDRS letters). Secondary outcomes were mean change from baseline to month 24 in binocular BCVA; CRT and mean deviation of Humphrey 10-2 visual field in the study eye; percentage meeting driving standards; EuroQoL EQ-5D-5L, 25-item National Eye Institute Visual Function Questionnaire (NEI-VFQ-25), and Vision and Quality of Life Index (VisQoL) scores; cost per quality-adjusted life-years (QALYs) gained; adverse effects; and number of laser and rescue treatments. RESULTS: The study recruited fully (n = 266); 87% of SML-treated and 86% of SL-treated patients had primary outcome data. Mean ± standard deviation BCVA change from baseline to month 24 was -2.43 ± 8.20 letters and -0.45 ± 6.72 letters in the SML and SL groups, respectively. Subthreshold micropulse laser therapy was deemed not only noninferior but also equivalent to SL therapy because the 95% confidence interval (CI; -3.9 to -0.04 letters) lay wholly within both upper and lower margins of the permitted maximum difference (5 ETDRS letters). No statistically significant difference was found in binocular BCVA (0.32 ETDRS letters; 95% CI, -0.99 to 1.64 ETDRS letters; P = 0.63); CRT (-0.64 µm; 95% CI, -14.25 to 12.98 µm; P = 0.93); mean deviation of the visual field (0.39 decibels (dB); 95% CI, -0.23 to 1.02 dB; P = 0.21); meeting driving standards (percentage point difference, 1.6%; 95% CI, -25.3% to 28.5%; P = 0.91); adverse effects (risk ratio, 0.28; 95% CI, 0.06-1.34; P = 0.11); rescue treatments (percentage point difference, -2.8%; 95% CI, -13.1% to 7.5%; P = 0.59); or EQ-5D, NEI-VFQ-25, or VisQoL scores. Number of laser treatments was higher in the SML group (0.48; 95% CI, 0.18-0.79; P = 0.002). Base-case analysis indicated no differences in costs or QALYs. CONCLUSIONS: Subthreshold micropulse laser therapy was equivalent to SL therapy, requiring slightly higher laser treatments.

Fenofibrate for diabetic retinopathy.

BACKGROUND: Diabetic retinopathy (DR) remains a major cause of sight loss worldwide, despite new therapies and improvements in the metabolic control of people living with diabetes. Therefore, DR creates a physical and psychological burden for people, and an economic burden for society. Preventing the development and progression of DR, or avoiding the occurrence of its sight-threatening complications is essential, and must be pursued to save sight. Fenofibrate may be a useful strategy to achieve this goal, by reversing diabetes' effects and reducing inflammation in the retina, as well as improving dyslipidaemia and hypertriglyceridaemia.  OBJECTIVES: To investigate the benefits and harms of fenofibrate for preventing the development and progression of diabetic retinopathy in people with type 1 (T1D) or type 2 diabetes (T2D), compared with placebo or observation. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, and three trials registers (February 2022). SELECTION CRITERIA: We included randomised controlled trials (RCTs) that included people with T1D or T2D, when these compared fenofibrate with placebo or with observation, and assessed the effect of fenofibrate on the development or progression of DR (or both). DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods for data extraction and analysis. Our primary outcome was progression of DR, a composite outcome of 1) incidence of overt retinopathy for participants who did not have DR at baseline, or 2) advancing two or more steps on the Early Treatment Diabetic Retinopathy Study (ETDRS) severity scale for participants who had any DR at baseline (or both), based on the evaluation of stereoscopic or non-stereoscopic fundus photographs, during the follow-up period. Overt retinopathy was defined as the presence of any DR observed on stereoscopic or non-stereoscopic colour fundus photographs. Secondary outcomes included the incidence of overt retinopathy, reduction in visual acuity of participants with a reduction in visual acuity of 10 ETDRS letters or more, proliferative diabetic retinopathy, and diabetic macular oedema; mean vision-related quality of life, and serious adverse events of fenofibrate. We used GRADE to assess the certainty of evidence. MAIN RESULTS: We included two studies and their eye sub-studies (15,313 participants) in people with T2D. The studies were conducted in the US, Canada, Australia, Finland, and New Zealand; follow-up period was four to five years. One was funded by the government, the other by industry. Compared to placebo or observation, fenofibrate likely results in little to no difference in progression of DR (risk ratio (RR) 0.86; 95% confidence interval (CI) 0.60 to 1.25; 1 study, 1012 participants; moderate-certainty evidence) in a population with and without overt retinopathy at baseline. Those without overt retinopathy at baseline showed little or no progression (RR 1.00, 95% CI 0.68 to 1.47; 1 study, 804 participants); those with overt retinopathy at baseline found that their DR progressed slowly (RR 0.21, 95% CI 0.06 to 0.71; 1 study, 208 people; test for interaction P = 0.02). Compared to placebo or observation, fenofibrate likely resulted in little to no difference in either the incidence of overt retinopathy (RR 0.91; 95% CI 0.76 to 1.09; 2 studies, 1631 participants; moderate-certainty evidence); or the incidence of diabetic macular oedema (RR 0.39; 95% CI 0.12 to 1.24; 1 study, 1012 participants; moderate-certainty evidence). The use of fenofibrate increased severe adverse effects (RR 1.55; 95% CI 1.05 to 2.27; 2 studies, 15,313 participants; high-certainty evidence). The studies did not report on incidence of a reduction in visual acuity of 10 ETDRS letters or more, incidence of proliferative diabetic retinopathy, or mean vision-related quality of life. AUTHORS' CONCLUSIONS: Current, moderate-certainty evidence suggests that in a mixed group of people with and without overt retinopathy, who live with T2D, fenofibrate likely results in little to no difference in progression of diabetic retinopathy. However, in people with overt retinopathy who live with T2D, fenofibrate likely reduces the progression. Serious adverse events were rare, but the risk of their occurrence was increased by the use of fenofibrate. There is no evidence on the effect of fenofibrate in people with T1D. More studies, with larger sample sizes, and participants with T1D are needed. They should measure outcomes that are important to people with diabetes, e.g. change in vision, reduction in visual acuity of 10 ETDRS letters or more, developing proliferative diabetic retinopathy; and evaluating the requirement of other treatments, e.g. injections of anti-vascular endothelial growth factor therapies, steroids.

Prognostic factors for the development and progression of proliferative diabetic retinopathy in people with diabetic retinopathy.

BACKGROUND: Diabetic retinopathy (DR) is characterised by neurovascular degeneration as a result of chronic hyperglycaemia. Proliferative diabetic retinopathy (PDR) is the most serious complication of DR and can lead to total (central and peripheral) visual loss. PDR is characterised by the presence of abnormal new blood vessels, so-called "new vessels," at the optic disc (NVD) or elsewhere in the retina (NVE). PDR can progress to high-risk characteristics (HRC) PDR (HRC-PDR), which is defined by the presence of NVD more than one-fourth to one-third disc area in size plus vitreous haemorrhage or pre-retinal haemorrhage, or vitreous haemorrhage or pre-retinal haemorrhage obscuring more than one disc area. In severe cases, fibrovascular membranes grow over the retinal surface and tractional retinal detachment with sight loss can occur, despite treatment. Although most, if not all, individuals with diabetes will develop DR if they live long enough, only some progress to the sight-threatening PDR stage.  OBJECTIVES: To determine risk factors for the development of PDR and HRC-PDR in people with diabetes and DR. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; which contains the Cochrane Eyes and Vision Trials Register; 2022, Issue 5), Ovid MEDLINE, and Ovid Embase. The date of the search was 27 May 2022. Additionally, the search was supplemented by screening reference lists of eligible articles. There were no restrictions to language or year of publication.  SELECTION CRITERIA: We included prospective or retrospective cohort studies and case-control longitudinal studies evaluating prognostic factors for the development and progression of PDR, in people who have not had previous treatment for DR. The target population consisted of adults (≥18 years of age) of any gender, sexual orientation, ethnicity, socioeconomic status, and geographical location, with non-proliferative diabetic retinopathy (NPDR) or PDR with less than HRC-PDR, diagnosed as per standard clinical practice. Two review authors independently screened titles and abstracts, and full-text articles, to determine eligibility; discrepancies were resolved through discussion. We considered prognostic factors measured at baseline and any other time points during the study and in any clinical setting. Outcomes were evaluated at three and eight years (± two years) or lifelong.  DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data from included studies using a data extraction form that we developed and piloted prior to the data collection stage. We resolved any discrepancies through discussion. We used the Quality in Prognosis Studies (QUIPS) tool to assess risk of bias. We conducted meta-analyses in clinically relevant groups using a random-effects approach. We reported hazard ratios (HR), odds ratios (OR), and risk ratios (RR) separately for each available prognostic factor and outcome, stratified by different time points. Where possible, we meta-analysed adjusted prognostic factors. We evaluated the certainty of the evidence with an adapted version of the GRADE framework.   MAIN RESULTS: We screened 6391 records. From these, we identified 59 studies (87 articles) as eligible for inclusion. Thirty-five were prospective cohort studies, 22 were retrospective studies, 18 of which were cohort and six were based on data from electronic registers, and two were retrospective case-control studies. Twenty-three studies evaluated participants with type 1 diabetes (T1D), 19 with type 2 diabetes (T2D), and 17 included mixed populations (T1D and T2D). Studies on T1D included between 39 and 3250 participants at baseline, followed up for one to 45 years. Studies on T2D included between 100 and 71,817 participants at baseline, followed up for one to 20 years. The studies on mixed populations of T1D and T2D ranged from 76 to 32,553 participants at baseline, followed up for four to 25 years.  We found evidence indicating that higher glycated haemoglobin (haemoglobin A1c (HbA1c)) levels (adjusted OR ranged from 1.11 (95% confidence interval (CI) 0.93 to 1.32) to 2.10 (95% CI 1.64 to 2.69) and more advanced stages of retinopathy (adjusted OR ranged from 1.38 (95% CI 1.29 to 1.48) to 12.40 (95% CI 5.31 to 28.98) are independent risk factors for the development of PDR in people with T1D and T2D. We rated the evidence for these factors as of moderate certainty because of moderate to high risk of bias in the studies.  There was also some evidence suggesting several markers for renal disease (for example, nephropathy (adjusted OR ranged from 1.58 (95% CI not reported) to 2.68 (2.09 to 3.42), and creatinine (adjusted meta-analysis HR 1.61 (95% CI 0.77 to 3.36)), and, in people with T1D, age at diagnosis of diabetes (< 12 years of age) (standardised regression estimate 1.62, 95% CI 1.06 to 2.48), increased triglyceride levels (adjusted RR 1.55, 95% CI 1.06 to 1.95), and larger retinal venular diameters (RR 4.28, 95% CI 1.50 to 12.19) may increase the risk of progression to PDR. The certainty of evidence for these factors, however, was low to very low, due to risk of bias in the included studies, inconsistency (lack of studies preventing the grading of consistency or variable outcomes), and imprecision (wide CIs). There was no substantial and consistent evidence to support duration of diabetes, systolic or diastolic blood pressure, total cholesterol, low- (LDL) and high- (HDL) density lipoproteins, gender, ethnicity, body mass index (BMI), socioeconomic status, or tobacco and alcohol consumption as being associated with incidence of PDR. There was insufficient evidence to evaluate prognostic factors associated with progression of PDR to HRC-PDR.  AUTHORS' CONCLUSIONS: Increased HbA1c is likely to be associated with progression to PDR; therefore, maintaining adequate glucose control throughout life, irrespective of stage of DR severity, may help to prevent progression to PDR and risk of its sight-threatening complications. Renal impairment in people with T1D or T2D, as well as younger age at diagnosis of diabetes mellitus (DM), increased triglyceride levels, and increased retinal venular diameters in people with T1D may also be associated with increased risk of progression to PDR. Given that more advanced DR severity is associated with higher risk of progression to PDR, the earlier the disease is identified, and the above systemic risk factors are controlled, the greater the chance of reducing the risk of PDR and saving sight.

ANTECEDENTES: La retinopatía diabética (RD) se caracteriza por la degeneración neurovascular como consecuencia de la hiperglucemia crónica. La retinopatía diabética proliferativa (RDP) es la complicación más grave de la RD y puede provocar una pérdida total (central y periférica) de la visión. La RDP se caracteriza por la presencia de vasos sanguíneos de neoformación anormales, neovascularización, en la papila óptica (NVP) o en cualquier otra parte de la retina (NVE). La RDP puede evolucionar a una RDP con características de alto riesgo (RDP­CAR), que se define por la presencia de NVP de más de un cuarto a un tercio del área discal más hemorragia vítrea o prerretiniana, o hemorragia vítrea o prerretiniana que oscurece más de un área papilar. En los casos graves, crecen membranas fibrovasculares sobre la superficie retiniana y se puede producir un desprendimiento de retina por tracción con pérdida de la visión, a pesar del tratamiento. Aunque la mayoría de las personas con diabetes, si no todas, desarrollarán RD si viven lo suficiente, solo algunas llegan a la fase de RDP, que pone en peligro la vista. OBJETIVOS: Determinar los factores de riesgo de aparición de la RDP y RDP­CAR en personas con diabetes y RD. MÉTODOS DE BÚSQUEDA: Se hicieron búsquedas en el Registro Cochrane central de ensayos controlados (Cochrane Central Register of Controlled Trials, CENTRAL; que contiene el Registro de ensayos del Grupo Cochrane de Salud ocular y de la visión [Cochrane Eyes and Vision]; 2022, número 5), Ovid MEDLINE y Ovid Embase. La fecha de búsqueda fue el 27 de mayo de 2022. Además, la búsqueda se complementó con el cribado de las listas de referencias de los artículos elegibles. No hubo restricciones en cuanto al idioma ni al año de publicación. CRITERIOS DE SELECCIÓN: Se incluyeron estudios de cohortes prospectivos o retrospectivos y estudios longitudinales de casos y controles que evaluaran los factores pronósticos para la aparición y la progresión de la RDP, en personas que no habían recibido tratamiento previo para la RD. La población de interés estaba formada por adultos (≥18 años de edad) de cualquier sexo, orientación sexual, etnia, nivel socioeconómico y ubicación geográfica, con retinopatía diabética no proliferativa (RDNP) o RDP sin llegar a RDP­CAR, diagnosticada según la práctica clínica habitual. Dos autores de la revisión examinaron de forma independiente los títulos y resúmenes, así como los artículos completos, para determinar la elegibilidad; las discrepancias se resolvieron mediante debate. Se tuvieron en cuenta los factores pronósticos medidos al inicio del estudio y en cualquier otro punto temporal durante el estudio y en cualquier contexto clínico. Los desenlaces se evaluaron a los tres y ocho años (± dos años) o de por vida. OBTENCIÓN Y ANÁLISIS DE LOS DATOS: Dos autores de la revisión extrajeron de forma independiente los datos de los estudios incluidos mediante un formulario de extracción de datos que se desarrolló y evaluó antes de la etapa de obtención de datos. Las discrepancias se resolvieron mediante debate. Para evaluar el riesgo de sesgo se utilizó la herramienta Quality in Prognosis Studies (QUIPS). Se realizaron metanálisis en grupos clínicamente relevantes utilizando un enfoque de efectos aleatorios. Se proporcionaron los cociente de riesgos instantáneos (CRI), los odds ratios (OR) y las razones de riesgos (RR) por separado para cada factor pronóstico y desenlace disponibles, estratificados por diferentes puntos temporales. Cuando fue posible, se realizó un metanálisis de los factores pronósticos ajustados. La certeza de la evidencia se evaluó con una versión adaptada del método GRADE. RESULTADOS PRINCIPALES: Se han examinado 6391 registros. A partir de estos se identificaron 59 estudios (87 artículos) elegibles para inclusión. Treinta y cinco fueron estudios de cohortes prospectivos, 22 fueron estudios retrospectivos, 18 de los cuales fueron de cohortes y 6 se basaron en datos de registros electrónicos, y 2 fueron estudios retrospectivos de casos y controles. Veintitrés estudios evaluaron a participantes con diabetes tipo 1 (DT1), 19 con diabetes tipo 2 (DT2) y 17 incluyeron poblaciones mixtas (DT1 y DT2). Los estudios sobre la DT1 incluyeron entre 39 y 3250 participantes al inicio del estudio, con un seguimiento de 1 a 45 años. Los estudios sobre la DT2 incluyeron entre 100 y 71 817 participantes al inicio del estudio, con un seguimiento de 1 a 20 años. Los estudios sobre poblaciones mixtas de DT1 y DT2 variaron entre 76 y 32 553 participantes al inicio del estudio, con un seguimiento de 4 a 25 años. Se encontró evidencia que indicó que los niveles más altos de hemoglobina glucosilada (hemoglobina A1c [HbA1c]) (OR ajustado que varió de 1,11 [intervalo de confianza (IC) del 95%: 0,93 a 1,32] a 2,10 [IC del 95%: 1,64 a 2,69]) y los estadios más avanzados de retinopatía (OR ajustado que varió entre 1,38 [IC del 95%: 1,29 a 1,48] y 12,40 [IC del 95%: 5,31 a 28,98]) son factores de riesgo independientes para el desarrollo de RDP en personas con DT1 y DT2. La evidencia para estos factores se consideró de certeza moderada debido al riesgo moderado a alto de sesgo en los estudios. También hubo alguna evidencia que indicó varios marcadores de enfermedad renal (por ejemplo, nefropatía [OR ajustado que varió entre 1,58 (IC del 95% no proporcionado) y 2,68 (2,09 a 3,42)] y creatinina [metanálisis ajustado CRI 1,61 (IC del 95%: 0,77 a 3.36)]), y, en las personas con DT1, la edad en el momento del diagnóstico de la diabetes (< 12 años) (estimación de la regresión estandarizada 1,62; IC del 95%: 1,06 a 2,48), el aumento de los niveles de triglicéridos (RR ajustado 1,55; IC del 95%: 1,06 a 1,95) y los diámetros venulares retinianos mayores (RR 4,28; IC del 95%: 1,50 a 12,19) podrían aumentar el riesgo de progresión a RDP. Sin embargo, la certeza de la evidencia para estos factores fue de baja a muy baja, debido al riesgo de sesgo en los estudios incluidos, la inconsistencia (falta de estudios que impide la calificación de consistencia o desenlaces variables) y la imprecisión (IC amplios). No hubo evidencia importante ni consistente que apoyara que la duración de la diabetes, la presión arterial sistólica o diastólica, el colesterol total, las lipoproteínas de baja (LDL) y alta (HDL) densidad, el sexo, el origen étnico, el índice de masa corporal (IMC), el nivel socioeconómico o el consumo de tabaco y alcohol estuvieran asociados con la incidencia de RDP. No hubo evidencia suficiente para evaluar los factores pronósticos asociados con la progresión de la RDP a RDP­CAR. CONCLUSIONES DE LOS AUTORES: Es probable que el aumento de la HbA1c se asocie con la progresión a la RDP; por lo tanto, mantener un control adecuado de la glucosa durante toda la vida, independientemente del estadio de gravedad de la RD, podría ayudar a prevenir la progresión a la RDP y el riesgo de sus complicaciones que ponen en peligro la vista. La insuficiencia renal en personas con DT1 o DT2, así como una menor edad en el momento del diagnóstico de la diabetes mellitus (DM), el aumento de los niveles de triglicéridos y el aumento de los diámetros venulares retinianos en personas con DT1 también se podrían asociar con un mayor riesgo de progresión a RDP. Dado que la gravedad más avanzada de la RD se asocia con un mayor riesgo de progresión a RDP, cuanto antes se identifique la enfermedad y se controlen los factores de riesgo sistémicos mencionados, mayores serán las posibilidades de reducir el riesgo de RDP y conservar la vista.

PREDICTIVE FACTORS ASSOCIATED WITH ANATOMICAL AND FUNCTIONAL OUTCOMES AFTER PANRETINAL PHOTOCOAGULATION IN PEOPLE WITH PROLIFERATIVE DIABETIC RETINOPATHY.

PURPOSE: To determine effects of baseline characteristics and laser type performed on outcomes in people with proliferative diabetic retinopathy (PDR) undergoing panretinal photocoagulation (PRP). METHODS: Medical records of all consecutive patients with PDR naïve to PRP, identified using an electronic database, evaluated at the Macula Clinic, Belfast Health and Social Care Trust, receiving their first PRP between January 1, 2016, and June 30, 2017, and followed for a minimum of 6 months after stabilization of PDR, were retrospectively reviewed. Outcomes included time to stabilization after PRP, progression of PDR, and mean change in the best-corrected visual acuity from baseline to the last follow-up. Cox regression was used to estimate hazard ratios (HRs) for the effect of baseline characteristics and type of laser on outcomes after treatment. RESULTS: One hundred and fourteen patients (135 eyes) with a mean age of 56.9 (SD: 12.9) years were included, 67% males. People receiving pattern or mixed laser had a statistically significantly delayed stabilization (HR: 0.57, P = 0.020; and HR: 0.44, P ≤ 0.001, respectively) and increased risk of progression (HR: 1.87, P = 0.045; and HR: 1.96, P = 0.028, respectively) when compared with those receiving standard laser. Among other potential predictors in multivariable regression analysis, only vitreous hemorrhage and fibrosis or traction at baseline increased the risk of progression (HR: 1.58, P = 0.047; and HR: 4.29, P ≤ 0.001, respectively). Baseline characteristics and type of laser had no statistically significant effect on vision. CONCLUSION: These findings should be considered when selecting laser treatment, planning surveillance, and counselling patients with PDR undergoing PRP.

Evaluation of a New Model of Care for People with Complications of Diabetic Retinopathy: The EMERALD Study.

PURPOSE: The increasing diabetes prevalence and advent of new treatments for its major visual-threatening complications (diabetic macular edema [DME] and proliferative diabetic retinopathy [PDR]), which require frequent life-long follow-up, have increased hospital demands markedly. Subsequent delays in patient's evaluation and treatment are causing sight loss. Strategies to increase capacity are needed urgently. The retinopathy (EMERALD) study tested diagnostic accuracy, acceptability, and costs of a new health care pathway for people with previously treated DME or PDR. DESIGN: Prospective, multicenter, case-referent, cross-sectional, diagnostic accuracy study undertaken in 13 hospitals in the United Kingdom. PARTICIPANTS: Adults with type 1 or 2 diabetes previously successfully treated DME or PDR who, at the time of enrollment, had active or inactive disease. METHODS: A new health care pathway entailing multimodal imaging (spectral-domain OCT for DME, and 7-field Early Treatment Diabetic Retinopathy Study [ETDRS] and ultra-widefield [UWF] fundus images for PDR) interpreted by trained nonmedical staff (ophthalmic graders) to detect reactivation of disease was compared with the current standard care (face-to-face examination by ophthalmologists). MAIN OUTCOME MEASURES: Primary outcome: sensitivity of the new pathway. SECONDARY OUTCOMES: specificity; agreement between pathways; costs; acceptability; proportions requiring subsequent ophthalmologist assessment, unable to undergo imaging, and with inadequate images or indeterminate findings. RESULTS: The new pathway showed sensitivity of 97% (95% confidence interval [CI], 92%-99%) and specificity of 31% (95% CI, 23%-40%) to detect DME. For PDR, sensitivity and specificity using 7-field ETDRS images (85% [95% CI, 77%-91%] and 48% [95% CI, 41%-56%], respectively) or UWF images (83% [95% CI, 75%-89%] and 54% [95% CI, 46%-61%], respectively) were comparable. For detection of high-risk PDR, sensitivity and specificity were higher when using UWF images (87% [95% CI, 78%-93%] and 49% [95% CI, 42%-56%], respectively, for UWF versus 80% [95% CI, 69-88%] and 40% [95% CI, 34%-47%], respectively, for 7-field ETDRS images). Participants preferred ophthalmologists' assessments; in their absence, they preferred immediate feedback by graders, maintaining periodic ophthalmologist evaluations. When compared with the current standard of care, the new pathway could save £1390 per 100 DME visits and between £461 and £1189 per 100 PDR visits. CONCLUSIONS: The new pathway has acceptable sensitivity and would release resources. Users' suggestions should guide implementation.

The importance of the epithelial fibre cell interface to lens regeneration in an in vivo rat model and in a human bag-in-the-lens (BiL) sample.

Human lens regeneration and the Bag-in-the-Lens (BIL) surgical treatment for cataract both depend upon lens capsule closure for their success. Our studies suggest that the first three days after surgery are critical to their long-term outcomes. Using a rat model of lens regeneration, we evidenced lens epithelial cell (LEC) proliferation increased some 50 fold in the first day before rapidly declining to rates observed in the germinative zone of the contra-lateral, un-operated lens. Cell multi-layering at the lens equator occurred on days 1 and 2, but then reorganised into two discrete layers by day 3. E- and N-cadherin expression preceded cell polarity being re-established during the first week. Aquaporin 0 (AQP0) was first detected in the elongated cells at the lens equator at day 7. Cells at the capsulotomy site, however, behaved very differently expressing the epithelial mesenchymal transition (EMT) markers fibronectin and alpha-smooth muscle actin (SMA) from day 3 onwards. The physical interaction between the apical surfaces of the anterior and posterior LECs from day 3 after surgery preceded cell elongation. In the human BIL sample fibre cell formation was confirmed by both histological and proteome analyses, but the cellular response is less ordered and variable culminating in Soemmerring's ring (SR) formation and sometimes Elschnig's pearls. This we evidence for lenses from a single patient. No bow region or recognisable epithelial-fibre cell interface (EFI) was evident and consequently the fibre cells were disorganised. We conclude that lens cells require spatial and cellular cues to initiate, sustain and produce an optically functional tissue in addition to capsule integrity and the EFI.

Enhanced Function of Induced Pluripotent Stem Cell-Derived Endothelial Cells Through ESM1 Signaling.

The mortality rate for (cardio)-vascular disease is one of the highest in the world, so a healthy functional endothelium is of outmost importance against vascular disease. In this study, human induced pluripotent stem (iPS) cells were reprogrammed from 1 ml blood of healthy donors and subsequently differentiated into endothelial cells (iPS-ECs) with typical EC characteristics. This research combined iPS cell technologies and next-generation sequencing to acquire an insight into the transcriptional regulation of iPS-ECs. We identified endothelial cell-specific molecule 1 (ESM1) as one of the highest expressed genes during EC differentiation, playing a key role in EC enrichment and function by regulating connexin 40 (CX40) and eNOS. Importantly, ESM1 enhanced the iPS-ECs potential to improve angiogenesis and neovascularisation in in vivo models of angiogenesis and hind limb ischemia. These findings demonstrated for the first time that enriched functional ECs are derived through cell reprogramming and ESM1 signaling, opening the horizon for drug screening and cell-based therapies for vascular diseases. Therefore, this study showcases a new approach for enriching and enhancing the function of induced pluripotent stem (iPS) cell-derived ECs from a very small amount of blood through ESM1 signaling, which greatly enhances their functionality and increases their therapeutic potential. Stem Cells 2019;37:226-239.

Visual cycle modulators versus placebo or observation for the prevention and treatment of geographic atrophy due to age-related macular degeneration.

BACKGROUND: Age-related macular degeneration (AMD) is a highly prevalent condition in an ever-increasing elderly population. Although insidious in the early stages, advanced AMD (neovascular and atrophic forms) can cause significant visual disability and economic burden on health systems worldwide. The most common form, geographic atrophy, has no effective treatment to date, whereas neovascular AMD can be treated with intravitreal anti-vascular endothelial growth factor (anti-VEGF) injections. Geographic atrophy has a slow disease progression and patients tend to have preserved central vision until the final stages. This tendency, coupled with the use of modern imaging modalities, provides a large window of opportunity to intervene with validated methods to assess treatment efficacy. As geographic atrophy is an increasingly common condition with no effective intervention, many treatments are under investigation, one of which is visual cycle modulators. These medications have been shown to reduce lipofuscin accumulation in pre-clinical studies that have led to several clinical trials, reviewed herein. OBJECTIVES: To assess the efficacy and safety of visual cycle modulators for the prevention and treatment of geographic atrophy secondary to AMD. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Trials Register) (2020, Issue 1); MEDLINE Ovid; Embase Ovid; Web of Science Core Collection; Scopus; Association for Research in Vision and Ophthalmology (ARVO) website; ClinicalTrials.gov and the WHO ICTRP to 11 January 2020 with no language restrictions. We also searched using the reference lists of reviews and existing studies and the Cited Reference Search function in Web of Science to identify further relevant studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi-randomised clinical studies (if available) that compared visual cycle modulators to placebo or no treatment (observation) in people diagnosed with AMD (early, intermediate or geographic atrophy). DATA COLLECTION AND ANALYSIS: Two authors independently assessed risk of bias in the included studies and extracted data. Both authors entered data into RevMan 5. We resolved discrepancies through discussion. We graded the certainty of the evidence using the GRADE approach. MAIN RESULTS: We included three RCTs from the USA; one of these had clinical sites in Germany. Two studies compared emixustat to placebo while the other compared fenretinide to placebo. All assigned one study eye per participant and, combined, have a total of 821 participants with a majority white ethnicity (97.6%). All participants were diagnosed with geographic atrophy due to AMD based on validated imaging modalities. All three studies have high risk of attrition bias mainly due to ocular adverse effects of emixustat and fenretinide. We considered only one study to be adequately conducted and reported with high risk of bias in only one domain (attrition bias). We considered the other two studies to be poorly reported and to have high risk of attrition bias and reporting bias. People with geographic atrophy treated with emixustat may not experience a clinically important change in best-corrected visual acuity (BCVA) between baseline and 24 months compared to people treated with placebo (mean difference (MD) 1.9 Early Treatment Diabetic Retinopathy Study (ETDRS) letters, 95% confidence interval (CI) -2.34 to 6.14, low-certainty evidence). Emixustat may also result in little or no difference in loss of 15 ETDRS letters or more of BCVA compared with placebo at 24 months (16.4% versus 18%) (risk ratio (RR) 0.91, 95% CI 0.59 to 1.4, low-certainty evidence). In terms of disease progression, emixustat may result in little or no difference in the annual growth rate of geographic atrophy compared with placebo (mean difference MD 0.09 mm2/year (95% CI -0.26 to 0.44, low-certainty evidence). All three studies reported adverse events of both drugs (emixustat: moderate-certainty evidence; fenretinide: low-certainty evidence). The main adverse events were ocular in nature and associated with the mechanism of action of the drugs. Delayed dark adaptation (emixustat: 54.5%; fenretinide: 39.3%) and chromatopsia (emixustat: 22.6%; fenretinide: 25.2%) were the most common adverse events reported, and were the most prevalent reasons for study dropout in emixustat trials. These effects were dose-dependent and resolved after drug cessation. No specific systemic adverse events were considered related to emixustat; only pruritus and rash were considered to be due to fenretinide. One emixustat study reported six deaths, none deemed related to the drug. None of the included RCTs reported the other pre-specified outcomes, including proportion of participants losing 10 letters or more, and mean change in macular sensitivity. We planned to investigate progression to advanced AMD (geographic atrophy or neovascular AMD) in prevention studies, including participants with early or intermediate AMD, but we identified no such studies. Two of the included studies reported an additional outcome - incidence of choroidal neovascularisation (CNV) - that was not in our published protocol. CNV onset may be reduced in those treated with emixustat but the evidence was uncertain (risk ratio (RR) 0.67, 95% CI 0.27 to 1.65, low-certainty evidence), or fenretinide (RR 0.5, 95% CI 0.26 to 0.98, low-certainty evidence) compared to placebo. A dose-dependent relationship was observed with emixustat. AUTHORS' CONCLUSIONS: There is limited evidence to support the use of visual cycle modulators (emixustat and fenretinide) for the treatment of established geographic atrophy due to AMD. The possible reduction in the incidence of CNV observed with fenretinide, and to a lesser extent, emixustat, requires formal assessment in focused studies.

PRAGMATISM OF RANDOMIZED CLINICAL TRIALS ON RANIBIZUMAB FOR THE TREATMENT OF DIABETIC MACULAR EDEMA: Impact on Clinical Outcomes.

PURPOSE: To evaluate the pragmatism and generalizability of randomized clinical trials (RCTs) on ranibizumab for diabetic macular edema and determine whether clinical outcomes would differ based on whether or not patients fulfill the eligibility criteria of these RCTs. METHODS: Pragmatism and generalizability of three RCTs on ranibizumab for diabetic macular edema (DRCRnet Protocols I and T, and RESTORE) were rated using the PRECIS-2 tool. A cohort of consecutive patients with diabetic macular edema was assessed to determine whether clinical outcomes differed based on whether or not patients met the RCT eligibility criteria. Univariable and multivariable regression analyses, adjusted for baseline best-corrected visual acuity, central retinal thickness and number of injections received, were used. RESULTS: All RCTs were rated as being more pragmatic than explanatory, with DRCRnet trials being the most pragmatic. Of the 216 eyes (176 patients) included in the cohort, 63% would have met eligibility criteria for Protocol T, 61% for Protocol I, and 56% for RESTORE. When adjusted for best-corrected visual acuity, central retinal thickness, and number of ranibizumab injections received, there were no statistically significant differences in best-corrected visual acuity or central retinal thickness found between "eligible" and "ineligible" patients. CONCLUSION: Randomized clinical trials evaluating ranibizumab for diabetic macular edema were more pragmatic than explanatory. "Ineligible" patients still benefited from ranibizumab therapy.

FIRST FAILED MACULAR HOLE SURGERY OR REOPENING OF A PREVIOUSLY CLOSED HOLE: Do We Gain by Reoperating?-A Systematic Review and Meta-analysis.

PURPOSE: To evaluate repeated surgery for idiopathic full-thickness macular hole that failed to close (FTC) after first surgery or reopened (RO) once originally closed. METHODS: Systematic review and meta-analysis. Pubmed.gov and Cochrane Library were searched for studies in English presenting outcomes of idiopathic full-thickness macular hole that FTC or RO (case reports/series of <5 cases excluded). OUTCOME MEASURES: Anatomical closure, postoperative best-corrected visual acuity, intraoperative/postoperative complications, and patient-reported outcomes. Meta-analysis was performed on aggregate and available individual participant data sets using the metafor package in R. RESULTS: Twenty-eight eligible studies were identified. After reoperation, pooled estimates for anatomical closure were 78% (95% confidence interval 71-84%) and 80% (95% confidence interval 66-89%) for FTC and RO groups, respectively. On average, best-corrected visual acuity improved in both groups. However, only 15% (28 of 189 eyes) of FTC eyes achieved best-corrected visual acuity of ≥6/12. The pooled estimated probability of ≥2-line best-corrected visual acuity improvement was 58% in the FTC group (95% confidence interval 45-71%); meta-analysis was not possible in the RO group. The most common complication was cataract. CONCLUSION: Reoperation for FTC or RO idiopathic full-thickness macular hole achieved a clinically meaningful visual acuity improvement in more than half of patients; high levels of vision (≥6/12), however, were uncommon.

IMPACT OF RETINAL ISCHEMIA ON FUNCTIONAL AND ANATOMICAL OUTCOMES AFTER ANTI-VASCULAR ENDOTHELIAL GROWTH FACTOR THERAPY IN PATIENTS WITH RETINAL VEIN OCCLUSION.

PURPOSE: To compare the impact of the classification of retinal vein occlusion (RVO) into ischemic or nonischemic forms on outcomes after anti-vascular endothelial growth factor therapy. METHODS: Retrospective review of consecutive patients with RVO evaluated at the Belfast Health and Social Care Trust between July 1, 2014, and December 31, 2015. Outcomes, including gain of ≥10 and ≥15 letters at 12 months, mean change in best-corrected visual acuity from baseline to 12 months, resolution of macular edema at 12 months, and development of neovascular complications and epiretinal membrane after anti-vascular endothelial growth factor therapy, were compared between ischemic and nonischemic eyes using regression models. RESULTS: One hundred and seventeen eyes (115 patients), 58 with central RVO and 59 with branch RVO, were included. A greater proportion of eyes with ischemic branch RVO gained ≥10 and ≥15 letters at 12 months than those with nonischemic branch RVO (P = 0.005 and P = 0.016, respectively). No statistically significant differences in visual outcomes were observed between ischemic and nonischemic central RVO. Retinal vein occlusion classification was not associated with anatomical outcomes after treatment. CONCLUSION: Findings support the use of anti-vascular endothelial growth factors in ischemic and nonischemic forms of RVO.

STAT3 activation in circulating myeloid-derived cells contributes to retinal microvascular dysfunction in diabetes.

BACKGROUND: Leukostasis is a key patho-physiological event responsible for capillary occlusion in diabetic retinopathy. Circulating monocytes are the main cell type entrapped in retinal vessels in diabetes. In this study, we investigated the role of the signal transducer and activator of transcription 3 (STAT3) pathway in diabetes-induced immune cell activation and its contribution to retinal microvascular degeneration. METHODS: Forty-one patients with type 1 diabetes (T1D) [mild non-proliferative diabetic retinopathy (mNPDR) (n = 13), active proliferative DR (aPDR) (n = 14), inactive PDR (iPDR) (n = 14)] and 13 age- and gender-matched healthy controls were recruited to the study. C57BL/6 J WT mice, SOCS3fl/fl and LysMCre/+SOCS3fl/fl mice were rendered diabetic by Streptozotocin injection. The expression of the phosphorylated human and mouse STAT3 (pSTAT3), mouse LFA-1, CD62L, CD11b and MHC-II in circulating immune cells was evaluated by flow cytometry. The expression of suppressor of cytokine signalling 3 (SOCS3) was examined by real-time RT-PCR. Mouse plasma levels of cytokines were measured by Cytometric Beads Array assay. Retinal leukostasis was examined following FITC-Concanavalin A perfusion and acellular capillary was examined following Isolectin B4 and Collagen IV staining. RESULTS: Compared to healthy controls, the expression of pSTAT3 in circulating leukocytes was statistically significantly higher in mNPDR but not aPDR and was negatively correlated with diabetes duration. The expression of pSTAT3 and its inhibitor SOCS3 was also significantly increased in leukocytes from diabetic mice. Diabetic mice had higher plasma levels of IL6 and CCL2 compared with control mice. LysMCre/+SOCS3fl/fl mice and SOCS3fl/fl mice developed comparative levels of diabetes, but leukocyte activation, retinal leukostasis and number of acellular capillaries were statistically significantly increased in LysMCre/+SOCS3fl/fl diabetic mice. CONCLUSION: STAT3 activation in circulating immune cells appears to contribute to retinal microvascular degeneration and may be involved in DR initiation in T1D.

Polarized retinal pigment epithelium generates electrical signals that diminish with age and regulate retinal pathology.

The transepithelial potential difference (TEP) across the retinal pigment epithelial (RPE) is dependent on ionic pumps and tight junction "seals" between epithelial cells. RPE cells release neurotrophic growth factors such as pigment epithelial derived factor (PEDF), which is reduced in age-related macular degeneration (AMD). The mechanisms that control the secretion of PEDF from RPE cells are not well understood. Using the CCL2/CX3CR1 double knockout mouse model (DKO), which demonstrates RPE damage and retinal degeneration, we uncovered an interaction between PEDF and the TEP which is likely to play an important role in retinal ageing and in the pathogenesis of AMD. We found that: (a) the expression of ATP1B1 (the Na+ /K+ -ATPase ß1 subunit) was reduced significantly in RPE from aged mice, in patients with CNV (Choroidal Neovascularization) and in DKO mice; (b) the expression of PEDF also was decreased in aged persons and in DKO mice; (c) the TEP across RPE was reduced markedly in RPE cells from DKO mice and (d) an applied electric field (EF) of 50-100 mV/mm, used to mimic the natural TEP, increased the expression and secretion of PEDF in primary RPE cells. In conclusion, the TEP across the RPE depends on the expression of ATP1B1 and this regulates the secretion of PEDF by RPE cells and so may regulate the onset of retinal disease. Increasing the expression of PEDF using an applied EF to replenish a disease or age-reduced TEP may offer a new way of preventing or reversing retinal dysfunction.

Different lasers and techniques for proliferative diabetic retinopathy.

BACKGROUND: Diabetic retinopathy (DR) is a chronic progressive disease of the retinal microvasculature associated with prolonged hyperglycaemia. Proliferative DR (PDR) is a sight-threatening complication of DR and is characterised by the development of abnormal new vessels in the retina, optic nerve head or anterior segment of the eye. Argon laser photocoagulation has been the gold standard for the treatment of PDR for many years, using regimens evaluated by the Early Treatment of Diabetic Retinopathy Study (ETDRS). Over the years, there have been modifications of the technique and introduction of new laser technologies. OBJECTIVES: To assess the effects of different types of laser, other than argon laser, and different laser protocols, other than those established by the ETDRS, for the treatment of PDR. We compared different wavelengths; power and pulse duration; pattern, number and location of burns versus standard argon laser undertaken as specified by the ETDRS. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Trials Register) (2017, Issue 5); Ovid MEDLINE; Ovid Embase; LILACS; the ISRCTN registry; ClinicalTrials.gov and the ICTRP. The date of the search was 8 June 2017. SELECTION CRITERIA: We included randomised controlled trials (RCTs) of pan-retinal photocoagulation (PRP) using standard argon laser for treatment of PDR compared with any other laser modality. We excluded studies of lasers that are not in common use, such as the xenon arc, ruby or Krypton laser. DATA COLLECTION AND ANALYSIS: We followed Cochrane guidelines and graded the certainty of evidence using the GRADE approach. MAIN RESULTS: We identified 11 studies from Europe (6), the USA (2), the Middle East (1) and Asia (2). Five studies compared different types of laser to argon: Nd:YAG (2 studies) or diode (3 studies). Other studies compared modifications to the standard argon laser PRP technique. The studies were poorly reported and we judged all to be at high risk of bias in at least one domain. The sample size varied from 20 to 270 eyes but the majority included 50 participants or fewer.Nd:YAG versus argon laser (2 studies): very low-certainty evidence on vision loss, vision gain, progression and regression of PDR, pain during laser treatment and adverse effects.Diode versus argon laser (3 studies): very-low certainty evidence on vision loss, vision gain, progression and regression of PDR and adverse effects; moderate-certainty evidence that diode laser was more painful (risk ratio (RR) troublesome pain during laser treatment (RR 3.12, 95% CI 2.16 to 4.51; eyes = 202; studies = 3; I2 = 0%).0.5 second versus 0.1 second exposure (1 study): low-certainty evidence of lower chance of vision loss with 0.5 second compared with 0.1 second exposure but estimates were imprecise and compatible with no difference or an increased chance of vision loss (RR 0.42, 95% CI 0.08 to 2.04, 44 eyes, 1 RCT); low-certainty evidence that people treated with 0.5 second exposure were more likely to gain vision (RR 2.22, 95% CI 0.68 to 7.28, 44 eyes, 1 RCT) but again the estimates were imprecise . People given 0.5 second exposure were more likely to have regression of PDR compared with 0.1 second laser PRP again with imprecise estimate (RR 1.17, 95% CI 0.92 to 1.48, 32 eyes, 1 RCT). There was very low-certainty evidence on progression of PDR and adverse effects.'Light intensity' PRP versus classic PRP (1 study): vision loss or gain was not reported but the mean difference in logMAR acuity at 1 year was -0.09 logMAR (95% CI -0.22 to 0.04, 65 eyes, 1 RCT); and low-certainty evidence that fewer patients had pain during light PRP compared with classic PRP with an imprecise estimate compatible with increased or decreased pain (RR 0.23, 95% CI 0.03 to 1.93, 65 eyes, 1 RCT).'Mild scatter' (laser pattern limited to 400 to 600 laser burns in one sitting) PRP versus standard 'full' scatter PRP (1 study): very low-certainty evidence on vision and visual field loss. No information on adverse effects.'Central' (a more central PRP in addition to mid-peripheral PRP) versus 'peripheral' standard PRP (1 study): low-certainty evidence that people treated with central PRP were more likely to lose 15 or more letters of BCVA compared with peripheral laser PRP (RR 3.00, 95% CI 0.67 to 13.46, 50 eyes, 1 RCT); and less likely to gain 15 or more letters (RR 0.25, 95% CI 0.03 to 2.08) with imprecise estimates compatible with increased or decreased risk.'Centre sparing' PRP (argon laser distribution limited to 3 disc diameters from the upper temporal and lower margin of the fovea) versus standard 'full scatter' PRP (1 study): low-certainty evidence that people treated with 'centre sparing' PRP were less likely to lose 15 or more ETDRS letters of BCVA compared with 'full scatter' PRP (RR 0.67, 95% CI 0.30 to 1.50, 53 eyes). Low-certainty evidence of similar risk of regression of PDR between groups (RR 0.96, 95% CI 0.73 to 1.27, 53 eyes). Adverse events were not reported.'Extended targeted' PRP (to include the equator and any capillary non-perfusion areas between the vascular arcades) versus standard PRP (1 study): low-certainty evidence that people in the extended group had similar or slightly reduced chance of loss of 15 or more letters of BCVA compared with the standard PRP group (RR 0.94, 95% CI 0.70 to 1.28, 270 eyes). Low-certainty evidence that people in the extended group had a similar or slightly increased chance of regression of PDR compared with the standard PRP group (RR 1.11, 95% CI 0.95 to 1.31, 270 eyes). Very low-certainty information on adverse effects. AUTHORS' CONCLUSIONS: Modern laser techniques and modalities have been developed to treat PDR. However there is limited evidence available with respect to the efficacy and safety of alternative laser systems or strategies compared with the standard argon laser as described in ETDRS.

Vitreomacular interface abnormalities in patients with diabetic macular oedema and their implications on the response to anti-VEGF therapy.

PURPOSE: To determine whether the presence of vitreomacular interface abnormalities (VMIA) in patients with diabetic macular oedema (DMO) modifies the response to ranibizumab. METHODS: Medical records and spectral-domain optical coherence tomography (SD-OCT) scans of consecutive patients with centre-involving DMO initiating therapy with ranibizumab between December 2013 and March 2014 at the Belfast Health and Social Care Trust were reviewed. Patients were identified through an electronic database. Demographics; systemic baseline characteristics; history of previous ocular surgery/laser; best-corrected visual acuity (BCVA), central retinal thickness (CRT) and stage of retinopathy at presentation; and BCVA, CRT and presence/absence of fluid at the last follow-up were recorded. OCT scans were reviewed by a masked investigator who graded them for the presence/absence of VMIA at baseline and during follow-up and for the change in the posterior hyaloid face during follow-up. The association between (1) VMIA at baseline and (2) the change in the posterior hyaloid face during the follow-up and functional/anatomical outcomes was evaluated. RESULTS: One hundred forty-six eyes of 100 patients (mean age 63.5 years) followed for a mean of 9 months (range 2-14 months; only 9/146 dropped to follow-up before month 6) were included. Statistically significant differences were observed at baseline in BCVA (p = 0.007), previous macular laser and panretinal photocoagulation (PRP) (p = 0.006) and previous cataract surgery (p = 0.01) between eyes with and without VMIA, with better levels of vision, higher frequency of macular laser and lower frequency of PRP in eyes where no VMIA was present. Multivariable regression analysis did not disclose any statistically significant associations between VMIA at baseline or change in the posterior hyaloid face during the follow-up and functional and anatomical outcomes following treatment. CONCLUSION: VMIA are associated with worse presenting vision in patients with DMO; VMIA or change in the posterior hyaloid face during the follow-up did not modify the response to ranibizumab in this study.