Interferon-mediated reprogramming of membrane cholesterol to evade bacterial toxins.

Plasma membranes of animal cells are enriched for cholesterol. Cholesterol-dependent cytolysins (CDCs) are pore-forming toxins secreted by bacteria that target membrane cholesterol for their effector function. Phagocytes are essential for clearance of CDC-producing bacteria; however, the mechanisms by which these cells evade the deleterious effects of CDCs are largely unknown. Here, we report that interferon (IFN) signals convey resistance to CDC-induced pores on macrophages and neutrophils. We traced IFN-mediated resistance to CDCs to the rapid modulation of a specific pool of cholesterol in the plasma membrane of macrophages without changes to total cholesterol levels. Resistance to CDC-induced pore formation requires the production of the oxysterol 25-hydroxycholesterol (25HC), inhibition of cholesterol synthesis and redistribution of cholesterol to an esterified cholesterol pool. Accordingly, blocking the ability of IFN to reprogram cholesterol metabolism abrogates cellular protection and renders mice more susceptible to CDC-induced tissue damage. These studies illuminate targeted regulation of membrane cholesterol content as a host defense strategy.

Limiting Cholesterol Biosynthetic Flux Spontaneously Engages Type I IFN Signaling.

Cellular lipid requirements are achieved through a combination of biosynthesis and import programs. Using isotope tracer analysis, we show that type I interferon (IFN) signaling shifts the balance of these programs by decreasing synthesis and increasing import of cholesterol and long chain fatty acids. Genetically enforcing this metabolic shift in macrophages is sufficient to render mice resistant to viral challenge, demonstrating the importance of reprogramming the balance of these two metabolic pathways in vivo. Unexpectedly, mechanistic studies reveal that limiting flux through the cholesterol biosynthetic pathway spontaneously engages a type I IFN response in a STING-dependent manner. The upregulation of type I IFNs was traced to a decrease in the pool size of synthesized cholesterol and could be inhibited by replenishing cells with free cholesterol. Taken together, these studies delineate a metabolic-inflammatory circuit that links perturbations in cholesterol biosynthesis with activation of innate immunity.

IL-10 constrains sphingolipid metabolism to limit inflammation.

Interleukin-10 (IL-10) is a key anti-inflammatory cytokine that can limit immune cell activation and cytokine production in innate immune cell types1. Loss of IL-10 signalling results in life-threatening inflammatory bowel disease in humans and mice-however, the exact mechanism by which IL-10 signalling subdues inflammation remains unclear2-5. Here we find that increased saturated very long chain (VLC) ceramides are critical for the heightened inflammatory gene expression that is a hallmark of IL-10 deficiency. Accordingly, genetic deletion of ceramide synthase 2 (encoded by Cers2), the enzyme responsible for VLC ceramide production, limited the exacerbated inflammatory gene expression programme associated with IL-10 deficiency both in vitro and in vivo. The accumulation of saturated VLC ceramides was regulated by a decrease in metabolic flux through the de novo mono-unsaturated fatty acid synthesis pathway. Restoring mono-unsaturated fatty acid availability to cells deficient in IL-10 signalling limited saturated VLC ceramide production and the associated inflammation. Mechanistically, we find that persistent inflammation mediated by VLC ceramides is largely dependent on sustained activity of REL, an immuno-modulatory transcription factor. Together, these data indicate that an IL-10-driven fatty acid desaturation programme rewires VLC ceramide accumulation and aberrant activation of REL. These studies support the idea that fatty acid homeostasis in innate immune cells serves as a key regulatory node to control pathologic inflammation and suggests that 'metabolic correction' of VLC homeostasis could be an important strategy to normalize dysregulated inflammation caused by the absence of IL-10.

Acceptability of prenatal diagnosis and prenatal treatment of haemophilia using cell and gene therapies within US haemophilia community.

BACKGROUND: The overall burden of disease in persons with haemophilia continues to be high despite the latest advancements in therapeutics. Clinical trials testing prenatal treatments for several genetic disorders are underway or are recruiting subjects, attesting to the much-needed change in paradigm of how patients with monogenic disorders can be treated. Here we investigate the overall attitude towards prenatal diagnosis, preferences on types of prenatal therapies for haemophilia, the level of 'acceptable' risk tolerated, and which social and moral pressures or disease personal experiences may predict willingness of individuals to consider foetal therapy in a future pregnancy. RESULTS: A multidisciplinary team designed the survey, and the study was carried out using REDCap, and publicized through the National Haemophilia Foundation. Subjects ≥18 years of age were eligible to participate in the study. We assessed participants' attitudes towards prenatal therapy and their level of 'acceptable' risk towards the procedure and therapy. The survey was completed by 67 adults, the majority females. Respondents were willing to undergo prenatal diagnosis, and their main concerns related to the well-being of the pregnant woman and the foetus regarding lasting therapeutic efficacy, side effects of the therapy, and procedural risks, but they were likely to accept a wide range of prenatal therapeutic options, particularly if the foetal therapy proved to be long-lasting and safe. CONCLUSIONS: These data demonstrate the willingness of persons with haemophilia, and the haemophilia community, to explore new treatment options beyond the currently offered approaches.

Precarious Employment and Well-Being: Insights from the COVID-19 Pandemic.

While precarious employment is not a new concept, it has been brought to the center of scholarly and public discourse worldwide by the unprecedented COVID-19 pandemic. This essay delineates how precarious employment shapes well-being and situates that relationship in the context of the COVID-19 pandemic. The essay also provides an overview of how the nine articles boldly investigate how these two layers of global risk-precarious employment and the pandemic-interact to shape individuals' well-being. In addition to advancing theoretical and empirical knowledge by analyzing timely data from diverse sources and populations, these articles call for more efforts on worker protection reforms and government financial support.

Cognitive ageing is premature among a community sample of optimally treated people living with HIV.

OBJECTIVES: Evidence of premature cognitive ageing amongst people living with HIV (PLHIV) remains controversial due to previous research limitations including underpowered studies, samples with suboptimal antiretroviral access, varying rate of virological control, high rate of AIDS, over-representation of non-community samples, and inclusion of inappropriate controls. The current study addresses these limitations, while also considering mental health and non-HIV comorbidity burden to determine whether PLHIV showed premature cognitive ageing compared with closely comparable HIV-negative controls. METHODS: This study enrolled 254 PLHIV [92% on antiretroviral therapy; 84% with HIV RNA < 50 copies/mL; 15% with AIDS) and 72 HIV-negative gay and bisexual men [mean (SD) age = 49 (10.2) years] from a single primary care clinic in Sydney, Australia. Neurocognitive function was evaluated with the Cogstate Computerized Battery (CCB) at baseline and 6 months after. Linear mixed-effects (LME) models examined main and interaction effects of HIV status and chronological age on the CCB demographically uncorrected global neurocognitive z-score (GZS), adjusting for repeated testing, and then adjusting sequentially for HIV disease markers, mental health and comorbidities. RESULTS: HIV status and age interacted with a lower GZS (ß = -0.43, P < 0.05). Higher level of anxiety symptoms (ß = -0.11, P < 0.01), historical AIDS (ß = -0.12, P < 0.05) and historical HIV brain involvement (ß = -0.12, P < 0.05) were associated with lower GZS. CONCLUSIONS: We found a robust medium-sized premature ageing effect on cognition in a community sample with optimal HIV care. Our study supports routine screening of cognitive and mental health among PLHIV aged ≥ 50 years.

Regulation of Lipid Membrane Partitioning of Tamoxifen by Ionic Strength and Cholesterol.

PURPOSE: The purpose of this study was to inspect the interactions between an anti-breast cancer, TAM, with model of lipid membranes composed of either zwitterionic DPPC LUVs or anionic DPPG LUVs and how they depend on ionic strength and cholesterol. METHODS: The Kp of TAM into DPPC and DPPG LUVs were determined at three different NaCl concentrations by second derivative UV-Vis spectrophotometry. The effect of cholesterol incorporated into these LUVs on TAM's Kp was also assessed. The ATR-FTIR measurements were carried out to verify structural changes within the acyl chain and head group regions of the liposomes upon TAM partitioning. RESULTS: Increasing salt concentration produced negligible impact on the partitioning of TAM into DPPC bilayer as its Kp remained unaffected whilst induced outstanding reduction of TAM's Kp into DPPG liposomes. Furthermore, TAM was found to disorder the lipids' acyl chains, which could result in an increase in the membrane fluidity, a necessary piece of information to refer to when prescribing TAM dosage for administration. Additionally, cholesterol showed astoundingly opposite contribution to the partitioning of TAM into the LUVs, as its Kp value reduced in DPPC/Chol bilayer yet increased in DPPG/Chol liposomes. CONCLUSION: Ionic strength and cholesterol play a noteworthy role in regulation of TAM partitioning into lipid membranes as they could obstruct or promote such action.

Employment insecurity and sleep disturbance: Evidence from 31 European countries.

For nearly half a century, jobs have become increasingly characterized by employment insecurity. We examined the implications for sleep disturbance with cross-sectional data from the European Working Conditions Survey (2010). A group of 24,553 workers between the ages of 25 and 65 years in 31 European countries were asked to indicate whether they suffered from "insomnia or general sleep difficulties" in the past 12 months. We employed logistic regression to model the association between employment insecurity and sleep disturbance for all countries combined and each individual country. For all countries combined, employment insecurity increased the odds of reporting insomnia or general sleep difficulties in the past 12 months. Each unit increase in employment insecurity elevated the odds of sleep disturbance by approximately 47%. This finding was remarkably consistent across 27 of 31 European countries, including Albania, Austria, Belgium, Bulgaria, Croatia, Cyprus, Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Ireland, Italy, Latvia, Lithuania, Luxembourg, the Netherlands, Norway, Slovakia, Slovenia, Spain, Sweden, Turkey and UK. These results persisted with adjustments for age, gender, immigrant status, household size, partnership status, number of children, child care, elder care, education, earner status, precarious employment status, workplace sector, workplace tenure and workplace size. Employment insecurity was unrelated to sleep disturbance in four European countries: Malta, Poland, Portugal and Romania. Our research continues recent efforts to reveal the human costs associated with working in neoliberal postindustrial labour markets. Our analyses contribute to the external validity of previous research by exploring the impact of employment insecurity across European countries.

New therapies in development for the management of non-infectious uveitis: A review.

Uveitis is a spectrum of inflammatory disorders characterized by ocular inflammation and is one of the leading causes of preventable visual loss. The main aim of the treatment of uveitis is to control the inflammation, prevent recurrences of the disease and preserve vision while minimizing the adverse effects associated with the therapeutic agents. Initial management of uveitis relies heavily on the use of corticosteroids. However, monotherapy with high-dose corticosteroids is associated with side effects and cannot be maintained long term. Therefore, steroid-sparing agents are needed to decrease the burden of steroid therapy. Currently, the therapeutic approach for non-infectious uveitis (NIU) consists of a step-ladder strategy with the first-line option being corticosteroids in various formulations followed by the use of first-, second- and third-line agents in cases with suboptimal steroid response. Unfortunately, the agents currently at our disposal have limitations such as having a narrow therapeutic window along with their own individual potential side-effect profiles. Therefore, research has been targeted to identify newer drugs as well as new uses for older drugs that target specific pathways in the inflammatory response. Such efforts are made in order to provide targeted and safer therapy with reduced side effects and greater efficacy. Several specially designed molecular antibodies are currently in various phases of investigations that can potentially halt the inflammation in patients with NIU. In the review, we have provided a comprehensive overview of the current and upcoming therapeutic options for patients with NIU.

Epidemiology and clinical features of inflammatory retinal vascular occlusions: pooled data from two tertiary-referral institutions.

IMPORTANCE: In a subset of patients with retinal vasculitis, there is occlusion of blood flow through the retinal vessels. These eyes are at high risk of sight-threatening complications. BACKGROUND: To characterize epidemiology, clinical course, treatment and outcomes of occlusive retinal vasculitis (ORV). DESIGN: Retrospective study PARTICIPANTS: Seventy-seven uveitis patients with ORV at two large tertiary-care institutions (the USA and India). METHODS: Out of 2438 patients screened, 346 patients were diagnosed with retinal vasculitis of which 77 patients (96 eyes) were diagnosed with ORV. Patients with ORV (capillary, arteriolar and/or venular) were further analysed. Diagnostic criteria for occlusive vasculitis included (i) absence of blood flow in vessels (arterioles, venules and/or capillaries), (ii) capillary non-perfusion areas and/or arteriolar-venous anastomosis and (iii) intraretinal haemorrhages, cotton-wool spots or vitreous haemorrhage. MAIN OUTCOME MEASURES: Best-corrected visual acuity, treatment and complications. RESULTS: The mean age was 32.09 ± 13.51 years. Most common aetiologies were tuberculosis and Adamantiades-Behçet's disease in India and systemic lupus erythematosus in the USA. Best-corrected visual acuity improved from 0.38 ± 0.30 logMAR (20/48 Snellen equivalent) (baseline) to 0.25 ± 0.30 (20/35 Snellen equivalent) at final visit (P < 0.0001). Vitreous haemorrhage was seen in 31.08% eyes. Pars plana vitrectomy was performed in 12.16% eyes. Therapy with systemic steroids was required in 78.48% patients. In addition, 46.75% patients required immunomodulators and/or biologics. CONCLUSIONS: Occlusive retinal vasculitis is caused by heterogeneous group of uveitides depending upon the geographic location. It is imperative to identify eyes with ORV as they are predisposed to complications requiring aggressive therapy.

Intravitreal Aflibercept for Diabetic Macular Edema: 148-Week Results from the VISTA and VIVID Studies.

PURPOSE: To compare efficacy and safety of intravitreal aflibercept injection (IAI) with macular laser photocoagulation for diabetic macular edema (DME) over 3 years. DESIGN: Two similarly designed phase 3 trials: VISTADME and VIVIDDME. PARTICIPANTS: Patients (eyes; n = 872) with central-involved DME. METHODS: Eyes received IAI 2 mg every 4 weeks (2q4), IAI 2 mg every 8 weeks after 5 monthly doses (2q8), or laser control. From week 24, if rescue treatment criteria were met, IAI patients received active laser, and laser control patients received IAI 2q8. From week 100, laser control patients who had not received IAI rescue treatment received IAI as needed per retreatment criteria. MAIN OUTCOME MEASURES: The primary end point was the change from baseline in best-corrected visual acuity (BCVA) at week 52. We report the 148-week results. RESULTS: Mean BCVA gain from baseline to week 148 with IAI 2q4, IAI 2q8, and laser control was 10.4, 10.5, and 1.4 letters (P < 0.0001) in VISTA and 10.3, 11.7, and 1.6 letters (P < 0.0001) in VIVID, respectively. The proportion of eyes that gained ≥15 letters from baseline at week 148 was 42.9%, 35.8%, and 13.6% (P < 0.0001) in VISTA and 41.2%, 42.2%, and 18.9% (P < 0.0001) in VIVID, respectively. Greater proportions of eyes treated with IAI 2q4 and IAI 2q8 versus those treated with laser control had an improvement of ≥2 steps in the Diabetic Retinopathy Severity Scale (DRSS) score in both VISTA (29.9% and 34.4% vs. 20.1% [P = 0.0350, IAI 2q4; P = 0.0052, IAI 2q8]) and VIVID (44.3% and 47.8% vs. 17.4% [P < 0.0001 for both]). In an integrated safety analysis, the most frequent ocular serious adverse event was cataract (3.1%, 2.1%, 0.3% for 2q4, 2q8, and control). CONCLUSIONS: Visual improvements observed with both IAI regimens (over laser control) at weeks 52 and 100 were maintained at week 148, with similar overall efficacy in the IAI 2q4 and IAI 2q8 groups. Treatment with IAI also had positive effects on the DRSS score. Over 148 weeks, the incidence of adverse events was consistent with the known safety profile of IAI.

In Vitro Evaluation of Inhalable Verapamil-Rifapentine Particles for Tuberculosis Therapy.

Recent studies have demonstrated that efflux pumps of Mycobacterium tuberculosis (M. tb) provide a crucial mechanism in the development of drug resistant to antimycobacterial drugs. Drugs that inhibit these efflux pumps, such as verapamil, have shown the potential in enhancing the treatment success. We therefore hypothesized that the combined inhaled administration of verapamil and a first-line rifamycin antibiotic will further improve the treatment efficacy. An inhalable dry powder consisting of amorphous verapamil and crystalline rifapentine with l-leucine as an excipient was produced by spray drying. The in vitro aerosol characteristic of the powder, its microbiological activity and stability were assessed. When the powder was dispersed by an Osmohaler, the total fine particle fraction (FPFtotal, wt % of particles in aerosol <5 µm) of verapamil and rifapentine was 77.4 ± 1.1% and 71.5 ± 2.0%, respectively. The combination drug formulation showed a minimum inhibitory concentration (MIC90) similar to that of rifapentine alone when tested against both M. tb H37Ra and M. tb H37Rv strains. Importantly, the combination resulted in increased killing of M. tb H37Ra within the infected macrophage cells compared to either verapamil or rifapentine alone. In assessing cellular toxicity, the combination exhibited an acceptable half maximal inhibitory concentration (IC50) values (62.5 µg/mL) on both human monocytic (THP-1) and lung alveolar basal epithelial (A549) cell lines. Finally, the powder was stable after 3 months storage in 0% relative humidity at 20 ± 3 °C.

Asterless is a scaffold for the onset of centriole assembly.

Centrioles are found in the centrosome core and, as basal bodies, at the base of cilia and flagella. Centriole assembly and duplication is controlled by Polo-like-kinase 4 (Plk4): these processes fail if Plk4 is downregulated and are promoted by Plk4 overexpression. Here we show that the centriolar protein Asterless (Asl; human orthologue CEP152) provides a conserved molecular platform, the amino terminus of which interacts with the cryptic Polo box of Plk4 whereas the carboxy terminus interacts with the centriolar protein Sas-4 (CPAP in humans). Drosophila Asl and human CEP152 are required for the centrosomal loading of Plk4 in Drosophila and CPAP in human cells, respectively. Depletion of Asl or CEP152 caused failure of centrosome duplication; their overexpression led to de novo centriole formation in Drosophila eggs, duplication of free centrosomes in Drosophila embryos, and centrosome amplification in cultured Drosophila and human cells. Overexpression of a Plk4-binding-deficient mutant of Asl prevented centriole duplication in cultured cells and embryos. However, this mutant protein was able to promote microtubule organizing centre (MTOC) formation in both embryos and oocytes. Such MTOCs had pericentriolar material and the centriolar protein Sas-4, but no centrioles at their core. Formation of such acentriolar MTOCs could be phenocopied by overexpression of Sas-4 in oocytes or embryos. Our findings identify independent functions for Asl as a scaffold for Plk4 and Sas-4 that facilitates self-assembly and duplication of the centriole and organization of pericentriolar material.

Liposuction for Advanced Lymphedema: A Multidisciplinary Approach for Complete Reduction of Arm and Leg Swelling.

PURPOSE: This research describes and evaluates a liposuction surgery and multidisciplinary rehabilitation approach for advanced lymphedema of the upper and lower extremities. METHODS: A prospective clinical study was conducted at an Advanced Lymphedema Assessment Clinic (ALAC) comprised of specialists in plastic surgery, rehabilitation, imaging, oncology, and allied health, at Macquarie University, Australia. Between May 2012 and 31 May 2014, a total of 104 patients attended the ALAC. Eligibility criteria for liposuction included (i) unilateral, non-pitting, International Society of Lymphology stage II/III lymphedema; (ii) limb volume difference greater than 25 %; and (iii) previously ineffective conservative therapies. Of 55 eligible patients, 21 underwent liposuction (15 arm, 6 leg) and had at least 3 months postsurgical follow-up (85.7 % cancer-related lymphedema). Liposuction was performed under general anesthesia using a published technique, and compression garments were applied intraoperatively and advised to be worn continuously thereafter. Limb volume differences, bioimpedance spectroscopy (L-Dex), and symptom and functional measurements (using the Patient-Specific Functional Scale) were taken presurgery and 4 weeks postsurgery, and then at 3, 6, 9, and 12 months postsurgery. RESULTS: Mean presurgical limb volume difference was 45.1 % (arm 44.2 %; leg 47.3 %). This difference reduced to 3.8 % (arm 3.6 %; leg 4.3 %) by 6 months postsurgery, a mean percentage volume reduction of 89.6 % (arm 90.2 %; leg 88.2 %) [p < 0.001]. All patients had improved symptoms and function. Bioimpedance spectroscopy showed reduced but ongoing extracellular fluid, consistent with the underlying lymphatic pathology. CONCLUSIONS: Liposuction is a safe and effective option for carefully selected patients with advanced lymphedema. Assessment, treatment, and follow-up by a multidisciplinary team is essential.

Scatter Photocoagulation Does Not Reduce Macular Edema or Treatment Burden in Patients with Retinal Vein Occlusion: The RELATE Trial.

PURPOSE: To determine whether scatter and grid laser photocoagulation (laser) adds benefit to ranibizumab injections in patients with macular edema from retinal vein occlusion (RVO) and to compare 0.5-mg with 2.0-mg ranibizumab. DESIGN: Randomized, double-masked, controlled clinical trial. PARTICIPANTS: Thirty-nine patients with central RVO (CRVO) and 42 with branch RVO (BRVO). METHODS: Subjects were randomized to 0.5 mg or 2.0 mg ranibizumab every 4 weeks for 24 weeks and re-randomized to pro re nata ranibizumab plus laser or ranibizumab alone. MAIN OUTCOME MEASURES: Mean change from baseline best-corrected visual acuity (BCVA) at week 24 for BCVA at weeks 48, 96, and 144 for second randomization. RESULTS: Mean improvement from baseline BCVA at week 24 was 15.5 and 15.8 letters in the 0.5-mg and 2.0-mg CRVO groups, and 12.1 and 14.6 letters in the 0.5-mg and 2.0-mg BRVO groups. For CRVO, but not BRVO, there was significantly greater reduction from baseline mean central subfield thickness (CST) in the 2.0-mg versus 0.5-mg group (396.1 vs. 253.5 µm; P = 0.03). For the second randomization in CRVO patients, there was no significant difference from week 24 BCVA in the ranibizumab plus laser versus the ranibizumab only groups at week 48 (-3.3 vs. 0.0 letters), week 96 (+0.69 vs. -1.6 letters), or week 144 (+0.4 vs. -6.7 letters), and a significant increase from week 24 mean CST at week 48 (+94.7 vs. +15.2 µm; P = 0.05) but not weeks 96 or 144. For BRVO, there was a significant reduction from week 24 mean BCVA in ranibizumab plus laser versus ranibizumab at week 48 (-7.5 vs. +2.8; P < 0.01) and week 96 (-2.0 vs. +4.8; P < 0.03), but not week 144, and there were no differences in mean CST change from week 24 at weeks 48, 96, or 144. Laser failed to increase edema resolution or to reduce the ranibizumab injections between weeks 24 and 144. CONCLUSIONS: In patients with macular edema resulting from RVO, there was no short-term clinically significant benefit from monthly injections of 2.0-mg versus 0.5-mg ranibizumab injections and no long-term benefit in BCVA, resolution of edema, or number of ranibizumab injections obtained by addition of laser treatment to ranibizumab.

Intravitreal Aflibercept for Diabetic Macular Edema: 100-Week Results From the VISTA and VIVID Studies.

PURPOSE: To compare efficacy and safety of 2 dosing regimens of intravitreal aflibercept injection (IAI) with macular laser photocoagulation for diabetic macular edema (DME). DESIGN: Two similarly designed, randomized, phase 3 trials, VISTA(DME) and VIVID(DME). PARTICIPANTS: Patients (eyes; n=872) with type 1 or 2 diabetes mellitus who had DME with central involvement. METHODS: Eyes received IAI 2 mg every 4 weeks (2q4), IAI 2 mg every 8 weeks after 5 monthly doses (2q8), or laser control. MAIN OUTCOME MEASURES: The primary end point was mean change from baseline in best-corrected visual acuity (BCVA) at week 52. This report presents the 100-week results including mean change from baseline in BCVA, proportion of eyes that gained ≥15 letters, and proportion of eyes with a ≥2-step improvement in the Diabetic Retinopathy Severity Scale (DRSS) score. RESULTS: Mean BCVA gain from baseline to week 100 with IAI 2q4, IAI 2q8, and laser control was 11.5, 11.1, and 0.9 letters (P < 0.0001) in VISTA and 11.4, 9.4, and 0.7 letters (P < 0.0001) in VIVID, respectively. The proportion of eyes that gained ≥15 letters from baseline at week 100 was 38.3%, 33.1%, and 13.0% (P < 0.0001) in VISTA and 38.2%, 31.1%, and 12.1% (P ≤ 0.0001) in VIVID. The proportion of eyes that lost ≥15 letters at week 100 was 3.2%, 0.7%, and 9.7% (P ≤ 0.0220) in VISTA and 2.2%, 1.5%, and 12.9% (P ≤ 0.0008) in VIVID. Significantly more eyes in the IAI 2q4 and 2q8 groups versus those in the laser control group had a ≥2 step improvement in the DRSS score in both VISTA (37.0% and 37.1% vs. 15.6%; P < 0.0001) and VIVID (29.3% and 32.6% vs. 8.2%; P ≤ 0.0004). In an integrated safety analysis, the most frequent serious ocular adverse event was cataract (2.4%, 1.0%, and 0.3% for 2q4, 2q8, and control). CONCLUSIONS: In both VISTA and VIVID, the 52-week visual and anatomic superiority of IAI over laser control was sustained through week 100, with similar efficacy in the 2q4 and 2q8 groups. Safety in these studies was consistent with the known safety profile of IAI.

What have we learnt about the management of diabetic macular edema in the antivascular endothelial growth factor and corticosteroid era?

PURPOSE OF REVIEW: To summarize the outcomes of the use of antivascular endothelial growth factor (anti-VEGF) agents and corticosteroids on the treatment paradigm for diabetic macular edema (DME). RECENT FINDINGS: Favorable efficacy data along with acceptable long-term safety results of anti-VEGF agents have made them the standard first-line therapy in the management of DME. Level I evidence from large, multicenter clinical trials has established the beneficial role of anti-VEGF agents and intravitreal steroids. In addition, the role of anti-VEGF agents in the treatment of diabetic retinopathy has also been recently recognized. However, concerns such as suboptimal response, VEGF resistance, and long-term effects on retinal layers and vasculature have also been highlighted recently. SUMMARY: The use of anti-VEGF agents and corticosteroids has revolutionized the management of DME. Despite the advantages including ease of administration, low incidence of adverse events, and concomitant improvement in retinopathy status, limitations of this therapeutic approach have been recognized. The current review will focus on the lessons learnt in the management of DME in the anti-VEGF and steroid era.

Intravitreal aflibercept for diabetic macular edema.

PURPOSE: A head-to-head comparison was performed between vascular endothelial growth factor blockade and laser for treatment of diabetic macular edema (DME). DESIGN: Two similarly designed, double-masked, randomized, phase 3 trials, VISTA(DME) and VIVID(DME). PARTICIPANTS: We included 872 patients (eyes) with type 1 or 2 diabetes mellitus who presented with DME with central involvement. METHODS: Eyes received either intravitreal aflibercept injection (IAI) 2 mg every 4 weeks (2q4), IAI 2 mg every 8 weeks after 5 initial monthly doses (2q8), or macular laser photocoagulation. MAIN OUTCOME MEASURES: The primary efficacy endpoint was the change from baseline in best-corrected visual acuity (BCVA) in Early Treatment Diabetic Retinopathy Study (ETDRS) letters at week 52. Secondary efficacy endpoints at week 52 included the proportion of eyes that gained ≥ 15 letters from baseline and the mean change from baseline in central retinal thickness as determined by optical coherence tomography. RESULTS: Mean BCVA gains from baseline to week 52 in the IAI 2q4 and 2q8 groups versus the laser group were 12.5 and 10.7 versus 0.2 letters (P < 0.0001) in VISTA, and 10.5 and 10.7 versus 1.2 letters (P < 0.0001) in VIVID. The corresponding proportions of eyes gaining ≥ 15 letters were 41.6% and 31.1% versus 7.8% (P < 0.0001) in VISTA, and 32.4% and 33.3% versus 9.1% (P < 0.0001) in VIVID. Similarly, mean reductions in central retinal thickness were 185.9 and 183.1 versus 73.3 µm (P < 0.0001) in VISTA, and 195.0 and 192.4 versus 66.2 µm (P < 0.0001) in VIVID. Overall incidences of ocular and nonocular adverse events and serious adverse events, including the Anti-Platelet Trialists' Collaboration-defined arterial thromboembolic events and vascular deaths, were similar across treatment groups. CONCLUSIONS: At week 52, IAI demonstrated significant superiority in functional and anatomic endpoints over laser, with similar efficacy in the 2q4 and 2q8 groups despite the extended dosing interval in the 2q8 group. In general, IAI was well-tolerated.

Clinical features and incidence rate of ocular complications in punctate inner choroidopathy.

PURPOSE: To study the clinical features and incidence rate of ocular complications in patients with punctate inner choroidopathy. METHODS: This is a retrospective cohort study conducted in a single-center academic practice setting. Patients diagnosed with punctate inner choroidopathy at the Wilmer Eye Institute, Johns Hopkins University from 1984 to 2012 were identified. Demographics and clinical features including the presence of choroidal neovascularization (CNV) and structural complications were collected. Main outcome measures, including visual impairment and incidence rate of ocular complications, were analyzed. RESULTS: Thirty-one patients (59 eyes) were included in the study. Follow-up data were available for 24 patients (47 eyes) with a mean follow-up time of 3.4 years (range, 2 months to 8.7 years). In the affected eyes with follow-up, the incidence rate of visual impairment to 20/50 or worse was 0.06 per eye-year (EY) (95% confidence interval, 0.022/EY-0.114/EY). The incidence rate of visual loss to 20/200 or worse was 0.006/EY (95% confidence interval, 0.0001/EY-0.034/EY). Thirty-six eyes (77%) had an ultimate visual acuity of 20/40 or better. All of the 13 patients with more than ≥ 3 years of follow-up had a visual acuity of ≥ 20/40 in at least 1 eye at 3 years after presentation. Two thirds of the follow-up patients (67%) on immunomodulatory drug therapy did not have new or recurrent CNV. However, this was not a statistically significant difference. Three eyes with follow-up had recurrence of CNV for an incidence rate of 0.04/EY (95% confidence interval, 0.008/EY-0.12/EY). Two eyes developed new CNV during follow-up for an incidence rate of 0.02/EY (95% confidence interval, 0.002/EY-0.066/EY). CONCLUSION: The visual prognosis in most cases of punctate inner choroidopathy is very good. The incidence rate of new CNV and recurrent CNV was 0.02/EY and 0.04/EY, respectively.

Incidental Breast Hemangioma on Breast MRI: A Case Report.

Vascular tumors of the breast are rare, but benign hemangiomas are the most common type. Capillary hemangiomas are a subset of benign vascular tumors that involve smaller vessel sizes. They are difficult to diagnose with mammography and ultrasound, as they lack pathognomonic features and are frequently not seen. MRI is the most sensitive imaging tool. The lesions appear similar to angiosarcoma or ductal carcinoma in situ on imaging, which further complicates the diagnosis. A biopsy of the lesions is required for a definitive diagnosis. In this report, a 49-year-old female with newly diagnosed breast cancer is incidentally found to have a capillary hemangioma on staging breast MRI that was confirmed with a biopsy and excised along with the primary breast cancer with a partial mastectomy. The imaging findings of breast hemangioma on mammography, ultrasound, and MRI are also reviewed and described in this report.