Efficacy and Safety of Intravitreal Aflibercept Treat and Extend for Polypoidal Choroidal Vasculopathy in the ATLANTIC Study: A Randomized Clinical Trial

Aflibercept; Efficacy; Polypoidal choroidal vasculopathyAflibercept; Eficacia; Vasculopatía coroidea polipoideaAflibercept; Eficàcia; Vasculopatia coroidal polipoidalImportance: Polypoidal choroidal vasculopathy (PCV) is far less common and studied in a Caucasian population than in an Asian population, and the optimal treatment approach remains to be confirmed. Methods: A 52-week, double-masked, sham-controlled, phase 4, investigator-initiated randomized clinical trial (RCT) in naive symptomatic Caucasian patients with PCV treated with aflibercept in a treat-and-extend regimen (T&E) (intravitreal aflibercept injection [IVAI] T&E). Patients were randomized at week 16 to receive IVAI T&E plus either sham photodynamic therapy (PDT) or standard fluence PDT with verteporfin. The main outcome measures were changes in best-corrected visual acuity (BCVA) from baseline to 52 weeks and polyp occlusion at week 52. Data are presented as median (interquartile range [IQR]) for BCVA, number of IVAI, and change in central retinal thickness (CRT). Results: Of the 50 patients included in the study, 48 patients completed the 52 weeks of follow-up. During this period, a significant median (IQR) BCVA gain of 6 [2–12] Early Treatment Diabetic Retinopathy Study letters was observed for all patients (p < 0.001), after 8 (7–9) injections, with a significant reduction of −93.0 [−154.0, −44.0] µm in central macular thickness (p < 0.001). Using indocyanine green angiography, a complete occlusion of polypoidal lesions was documented in 72% of the cases. Still, no significant difference was detected between the sham PDT and the aflibercept PDT arms, at week 52, for BCVA change (6.5 [2–11] vs. 5 [2–13] letters (p = 0.98)), number of IVAIs (8.5 [7–9] vs. 8 [7–9] (p = 0.21)), change in CRT (−143 [−184; −47] vs. −89 [−123; −41.5] µm [p = 0.23]), and rates of complete polyp occlusion: 77 versus 68% (p = 0.53) or presence of fluid: 68 versus 57% (p = 0.56). No serious ocular adverse events were registered in the 2 arms. Conclusions and Relevance: To our knowledge, this is the first RCT to compare aflibercept T&E monotherapy with aflibercept T&E plus verteporfin PDT in a Caucasian population with PCV. Aflibercept monotherapy in a T&E showed to be effective and safe with a significant median BCVA improvement of 6 letters and a complete occlusion of polypoidal lesions in near 3 quarters of the eyes, at 1 year. As only 22% of the eyes underwent PDT treatment, the benefit of combined treatment for PCV in Caucasian patients could not be definitively elucidated from this study. Trial Registration: The clinical trial was registered in ClinicalTrials.gov Identifier NCT02495181 and the European Union Drug Regulating Authorities Clinical Trials Database EudraCT No. 2015-001368-20.Funding/support: This investigator-initiated study was financially supported by Bayer. Role of the funder/sponsor: Bayer had no role in the design and conduct of the study, collection, management, analysis, and interpretation of the data

Fundus flavimaculatus-like in myotonic dystrophy: a case report

Informe d'un cas; Fundus flavimaculatus; Distròfia miotònicaReporte de un caso; Fundus flavimaculatus; Distrofia miotónicaCase report; Fundus flavimaculatus; Myotonic dystrophyBackground Myotonic dystrophy is an inherited disease characterized by progressive muscle weakness and myotonia. It is a multisystemic disorder that affects different parts of the body, including the eye. Dysfunction of ocular muscles, ptosis and cataract are the most common ophthalmologic manifestations, but it can also present with pigmentary changes in the retina. This report presents and discusses an unusual case of a pigmented pattern dystrophy simulating a fundus flavimaculatus in a patient with myotonic dystrophy. Case presentation We present a case of a woman with a history of myotonic dystrophy and complaints of progressive vision loss who presented bilateral retinal pigmentary changes in posterior pole and midperiphery. The characteristics and distribution of pigmented deposits, as well as ancillary tests, showed a retinal phenotype compatible with a multifocal pattern dystrophy or a fundus flavimaculatus. Conclusions There are a few publications about retinal disorders in patients with myotonic dystrophy. When macular area is affected it tends to adopt a patterned-shape defined as butterfly dystrophy or reticular dystrophy. To our knowledge, this is the first report of a patient with myotonic dystrophy and multifocal pattern dystrophy or fundus flavimaculatus

Long-term probability of intraocular pressure elevation with the intravitreal dexamethasone implant in the real-world

Intraocular pressure; Intravitreal dexamethasonePressió intraocular; Dexametasona intravitreaPresión intraocular; Dexametasona intravítreaPURPOSE: To evaluate the long-term cumulative probability of intraocular pressure (IOP) elevation with the intravitreal dexamethasone implant (IDI) when used to treat different indications: diabetic macular edema, uveitis, retinal vein occlusion. METHODS: 705 IDI injections (429 eyes) were assessed and Kaplan-Meier graphs were generated to assess: the probability of different levels of IOP elevation (IOP≥21, ≥25 or ≥35 mmHg), IOP change ≥10 mmHg, initiation of IOP-lowering treatment, glaucoma surgery, IOP change with repeat injections and IOP elevation in eyes with glaucoma and ocular hypertension (OHT). RESULTS: The cumulative probability of IOP ≥21, ≥25 and ≥35 mmHg was 50%-60%, 25%-30% and 6%-7% at 12-24 months, respectively. The probability of initiating IOP-lowering medication was 31%-54% at 12-24 months. Glaucoma and OHT eyes had a higher probability of mild IOP elevation (≥21 mmHg, 65.1%, 75% and 57.8%, p = 0.01), yet a similar moderate (≥25 mmHg, 22.3%, 28% and 30.2%, p = 0.91) and severe elevation of IOP (≥35 mmHg, 3.7%, 7.1% and 4%, p = 0.71) as normal eyes. Glaucoma surgery was required in only 0.9% cases (4/429). At baseline, 8.8% of the treated eyes had glaucoma, 6.7% OHT and 16.9% were already on IOP-lowering medication. CONCLUSIONS: In the long-term (24 months), IOP elevation is common, generally mild (30% IOP, ≥25 mmHg) and well-tolerated, resolving with topical treatment (54%) and rarely requiring surgery (0.9%)

MAP4K4 impairs energy metabolism in endothelial cells and promotes insulin resistance in obesity

The blood vasculature responds to insulin, influencing hemodynamic changes in the periphery, which promotes tissue nutrient and oxygen delivery and thus metabolic function. The lymphatic vasculature regulates fluid and lipid homeostasis, and impaired lymphatic function can contribute to atherosclerosis and obesity. Recent studies have suggested a role for endothelial cell (EC) Mitogen activated protein kinase kinase kinase kinase 4 (Map4k4) in developmental angiogenesis and lymphangiogenesis as well as atherosclerosis. Here, we show that inducible EC Map4k4 deletion in adult mice ameliorates metabolic dysfunction in obesity despite the development of chylous ascites and a concomitant striking increase in adipose tissue lymphocyte content. Despite these defects, animals lacking endothelial Map4k4 were protected from skeletal muscle microvascular rarefaction in obesity, and primary ECs lacking Map4k4 displayed reduced senescence and increased metabolic capacity. Thus, endothelial Map4k4 has complex and opposing functions in the blood and lymphatic endothelium post-development. Whereas blood endothelial Map4k4 promotes vascular dysfunction and impairs glucose homeostasis in adult animals, lymphatic endothelial Map4k4 is required to maintain lymphatic vascular integrity and regulate immune cell trafficking in obesity

The Arg59Trp variant in ANGPTL8 (betatrophin) is associated with total and HDL-cholesterol in American Indians and Mexican Americans and differentially affects cleavage of ANGPTL3

We previously identified a locus linked to total cholesterol (TC) concentration in Pima Indians on chromosome 19p. To characterize this locus, we genotyped \u3e2000 SNPs in 1838 Pimas and assessed association with log(TC). We observed evidence for association with log(TC) with rs2278426 (3.5% decrease/copy of the T allele; P=5.045×10(-6)) in the ANGPTL8 (angiopoietin-like 8) gene. We replicated this association in 2413 participants of the San Antonio Mexican American Family Study (SAMAFS: 2.0% decrease per copy of the T allele; P=0.005842). In a meta-analysis of the combined data, we found the strongest estimated effect with rs2278426 (P=2.563×10(-7)). The variant T allele at rs2278426 predicts an Arg59Trp substitution and has previously been associated with LDL-C and HDL-C. In Pimas and SAMAFS participants, the T allele of rs2278426 was associated with reduced HDL-C levels (P=0.000741 and 0.00002, respectively), and the combined estimated effect for the two cohorts was -3.8% (P=8.526×10(-8)). ANGPTL8 transcript and protein levels increased in response to both glucose and insulin. The variant allele was associated with increased levels of cleaved ANGPTL3. We conclude that individuals with the variant allele may have lower TC and HDL-C levels due to increased activation of ANGPTL3 by ANGPTL8

Protein Kinase Mitogen-activated Protein Kinase Kinase Kinase Kinase 4 (MAP4K4) Promotes Obesity-induced Hyperinsulinemia

Previous studies revealed a paradox whereby mitogen-activated protein kinase kinase kinase kinase 4 (Map4k4) acted as a negative regulator of insulin sensitivity in chronically obese mice, yet systemic deletion of Map4k4 did not improve glucose tolerance. Here, we report markedly reduced glucose-responsive plasma insulin and C-peptide levels in whole body Map4k4-depleted mice (M4K4 iKO) as well as an impaired first phase of insulin secretion from islets derived from M4K4 iKO mice ex vivo After long-term high fat diet (HFD), M4K4 iKO mice pancreata also displayed reduced beta cell mass, fewer proliferating beta cells and reduced islet-specific gene mRNA expression compared with controls, although insulin content was normal. Interestingly, the reduced plasma insulin in M4K4 iKO mice exposed to chronic (16 weeks) HFD was not observed in response to acute HFD challenge or short term treatment with the insulin receptor antagonist S961. Furthermore, the improved insulin sensitivity in obese M4K4 iKO mice was abrogated by high exogenous insulin over the course of a euglycemic clamp study, indicating that hypoinsulinemia promotes insulin sensitivity in chronically obese M4K4 iKO mice. These results demonstrate that protein kinase Map4k4 drives obesity-induced hyperinsulinemia and insulin resistance in part by promoting insulin secretion from beta cells in mice

Adipocyte-specific Hypoxia-inducible gene 2 promotes fat deposition and diet-induced insulin resistance

OBJECTIVE: Adipose tissue relies on lipid droplet (LD) proteins in its role as a lipid-storing endocrine organ that controls whole body metabolism. Hypoxia-inducible Gene 2 (Hig2) is a recently identified LD-associated protein in hepatocytes that promotes hepatic lipid storage, but its role in the adipocyte had not been investigated. Here we tested the hypothesis that Hig2 localization to LDs in adipocytes promotes adipose tissue lipid deposition and systemic glucose homeostasis. METHOD: White and brown adipocyte-deficient (Hig2fl/fl x Adiponection cre+) and selective brown/beige adipocyte-deficient (Hig2fl/fl x Ucp1 cre+) mice were generated to investigate the role of Hig2 in adipose depots. Additionally, we used multiple housing temperatures to investigate the role of active brown/beige adipocytes in this process. RESULTS: Hig2 localized to LDs in SGBS cells, a human adipocyte cell strain. Mice with adipocyte-specific Hig2 deficiency in all adipose depots demonstrated reduced visceral adipose tissue weight and increased glucose tolerance. This metabolic effect could be attributed to brown/beige adipocyte-specific Hig2 deficiency since Hig2fl/fl x Ucp1 cre+ mice displayed the same phenotype. Furthermore, when adipocyte-deficient Hig2 mice were moved to thermoneutral conditions in which non-shivering thermogenesis is deactivated, these improvements were abrogated and glucose intolerance ensued. Adipocyte-specific Hig2 deficient animals displayed no detectable changes in adipocyte lipolysis or energy expenditure, suggesting that Hig2 may not mediate these metabolic effects by restraining lipolysis in adipocytes. CONCLUSIONS: We conclude that Hig2 localizes to LDs in adipocytes, promoting adipose tissue lipid deposition and that its selective deficiency in active brown/beige adipose tissue mediates improved glucose tolerance at 23 degrees C. Reversal of this phenotype at thermoneutrality in the absence of detectable changes in energy expenditure, adipose mass, or liver triglyceride suggests that Hig2 deficiency triggers a deleterious endocrine or neuroendocrine pathway emanating from brown/beige fat cells

Preventative services offered by veterinarians on sheep farms in England and Wales: opinions and drivers for proactive flock health planning

Recent independent UK government reports and studies have highlighted the importance, but lack, of flock health services provided by veterinarians. Qualitative interviews were analysed by thematic analysis to construct belief statements to understand veterinarians' opinions on preventative advice and drivers for current services to sheep farmers. A postal questionnaire was sent to 515 sheep practices registered with the Royal College of Veterinary Surgeon (RCVS) in England and Wales in 2012 to gather quantitative data on these belief statements and to gather demographic information and current services provided by the veterinarian. Exploratory factor analysis with heuristic approaches was conducted on the respondents' belief statements to identify common factors of veterinarian beliefs. Three main factors were identified: motivation for proactiveness, perceived capability to offer preventative services and perceived opportunity to deliver these services. A beta regression model was built to identify the factors significantly associated with the time veterinarians spent in an advisory role. The relative proportion of time increased by 10% (1.01-1.19), 16% (1.03-1.30) and 29% (CI: 1.09-1.53) for each unit increase in score for factor 1 motivation, factor 2 capability and factor 3 opportunity respectively, indicating that these latent factors explained time veterinarians spent in an advisory role with sheep clients. There was a significant correlation between these factors suggesting influence of the associated beliefs between factors. This study provides insight into the nature and drivers of veterinarians' current behaviour and beliefs. These results could be further tested in behaviour intervention studies and help in designing efficient strategies aiming at promoting proactive health services offered by veterinarians on sheep farms in England and Wales

Differential response to intravitreal dexamethasone implant in naïve and previously treated diabetic macular edema eyes

Background: To identify different response patterns to intravitreal dexamethasone implants (IDI) in naïve and previously treated (PT) diabetic macular edema (DME) eyes in a real-life setting. Methods: 342 IDI injections (203 DME eyes) were included. Number of IDI injections, percentage (%) of eyes with 1, 2, 3 and ≥ 4 injections, time to reinjections, visual acuity (VA), intraocular pressure (IOP) and central retinal thickness (CRT) were evaluated for naïve and PT DME eyes over 24 months. Results: Mean number of injections was significantly lower in naïve vs PT DME eyes (1.40 ± 0.9 vs 1.82 ± 0.9, p < 0.001). The percentage of eyes receiving 1 injection was significantly higher in naïve vs PT DME eyes (76.1 vs 47.7), (p < 0.001). However, it was significantly lower for 2 (16.4 vs 29.4), or 3 injections (1.4 vs 17.6) (both p < 0.001), with no differences in eyes receiving ≥4 injections (5.9 vs 5.1 respectively, p = 0.80). Mean time to reinjection was not significantly different between both groups for the second, third and fourth injection (9.6 ± 4.0 vs 10.0 ± 5.5, p = 0.75, 13.2 ± 4.0 vs 16.0 ± 3.5, p = 0.21 and 21.7 ± 3.8 vs 19.7 ± 5.8, p = 0.55). VA scores were consistently better in naïve vs PT DME eyes at all studied timepoints, with no significant differences in CRT reduction or adverse effect rates. Conclusion: Naïve DME eyes received lower number of IDI injections and showed better VA levels than PT DME eyes for 24 months in a real-world setting. This data supports the IDI use in early DME stages and provide further evidence of better IDI response when used as first-line therapy

An update of the evolving epidemic of blaKPC carrying Klebsiella pneumoniae in Sicily, Italy, 2014: Emergence of multiple Non-ST258 Clones

Background: In Italy, Klebsiella pneumoniae carbapenemase producing K. pneumoniae (KPC-Kp) strains are highly endemic and KPC producing CC258 is reported as the widely predominating clone. In Palermo, Italy, previous reports have confirmed this pattern. However, recent preliminary findings suggest that an epidemiological change is likely ongoing towards a polyclonal KPC-Kp spread. Here we present the results of molecular typing of 94 carbapenem non susceptible K. pneumoniae isolates detected during 2014 in the three different hospitals in Palermo, Italy. Methods and Results: Ninety-four consecutive, non replicate carbapenem non susceptible isolates were identified in the three largest acute general hospitals in Palermo, Italy, in the six-month period March-August 2014. They were characterized by PCR for β-lactam, aminoglycoside and plasmid mediated fluoroquinolone resistance genetic determinants. The mgrB gene of the colistin resistant isolates was amplified and sequenced. Clonality was assessed by pulsed field gel electrophoresis and multilocus sequence typing. Eight non-CC258 sequence types (STs) were identified accounting for 60% of isolates. In particular, ST307 and ST273 accounted for 29% and 18% of isolates. CC258 isolates were more frequently susceptible to gentamicin and non-CC258 isolates to amikacin. Colistin non susceptibility was found in 42% of isolates. Modifications of mgrB were found in 32 isolates. Conclusions: Concurrent clonal expansion of some STs and lateral transmission of genetic resistance determinants are likely producing a thorough change of the KPC-Kp epidemiology in Palermo, Italy. In our setting mgrB inactivation proved to substantially contribute to colistin resistance. Our findings suggest the need to continuously monitor the KPC-Kp epidemiology and to assess by a nationwide survey the possible shifting towards a polyclonal epidemic