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Purpose: To develop a reliable algorithm for the automated identification, localization, and volume measurement of exudative manifestations in neovascular age-related macular degeneration (nAMD), including intraretinal (IRF), subretinal fluid (SRF), and pigment epithelium detachment (PED), using a deep-learning approach., Methods: One hundred seven spectral domain optical coherence tomography (OCT) cube volumes were extracted from nAMD eyes. Manual annotation of IRF, SRF, and PED was performed. Ninety-two OCT volumes served as training and validation set, and 15 OCT volumes from different patients as test set. The performance of our fluid segmentation method was quantified by means of pixel-wise metrics and volume correlations and compared to other methods. Repeatability was tested on 42 other eyes with five OCT volume scans acquired on the same day., Results: The fully automated algorithm achieved good performance for the detection of IRF, SRF, and PED. The area under the curve for detection, sensitivity, and specificity was 0.97, 0.95, and 0.99, respectively. The correlation coefficients for the fluid volumes were 0.99, 0.99, and 0.91, respectively. The Dice score was 0.73, 0.67, and 0.82, respectively. For the largest volume quartiles the Dice scores were >0.90. Including retinal layer segmentation contributed positively to the performance. The repeatability of volume prediction showed a standard deviations of 4.0 nL, 3.5 nL, and 20.0 nL for IRF, SRF, and PED, respectively., Conclusions: The deep-learning algorithm can simultaneously acquire a high level of performance for the identification and volume measurements of IRF, SRF, and PED in nAMD, providing accurate and repeatable predictions. Including layer segmentation during training and squeeze-excite block in the network architecture were shown to boost the performance., Translational Relevance: Potential applications include measurements of specific fluid compartments with high reproducibility, assistance in treatment decisions, and the diagnostic or scientific evaluation of relevant subgroups.

The standard treatment for neovascular age-related macular degeneration (nAMD) consists of intravitreal anti-vascular endothelial growth factors (VEGF). However, for some patients, even maximal anti-VEGF treatment does not entirely suppress exudative activity. The goal of this study was to identify molecular biomarkers in nAMD with incomplete response to anti-VEGF treatment. Aqueous humor (AH) samples were collected from three groups of patients: 17 patients with nAMD responding incompletely to anti-VEGF (18 eyes), 17 patients affected by nAMD with normal treatment response (21 eyes), and 16 control patients without any retinopathy (16 eyes). Proteomic and multiplex analyses were performed on these samples. Proteomic analyses showed that nAMD patients with incomplete anti-VEGF response displayed an increased inflammatory response, complement activation, cytolysis, protein-lipid complex, and vasculature development pathways. Multiplex analyses revealed a significant increase of soluble vascular cell adhesion molecule-1 (sVCAM-1) [  p = 0.001], interleukin-6 (IL-6) [  p = 0.009], bioactive interleukin-12 (IL-12p40) [  p = 0.03], plasminogen activator inhibitor type 1 (PAI-1) [  p = 0.004], and hepatocyte growth factor (HGF) [  p = 0.004] levels in incomplete responders in comparison to normal responders. Interestingly, the same biomarkers showed a high intercorrelation with r2 values between 0.58 and 0.94. In addition, we confirmed by AlphaLISA the increase of sVCAM-1 [  p < 0.0001] and IL-6 [  p = 0.043] in the incomplete responder group. Incomplete responders in nAMD are associated with activated angiogenic and inflammatory pathways. The residual exudative activity of nAMD despite maximal anti-VEGF treatment may be related to both angiogenic and inflammatory responses requiring specific adjuvant therapy. Data are available via ProteomeXchange with identifier PXD02247., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Mantel, Borgo, Guidotti, Forestier, Kirsch, Derradji, Waridel, Burdet, Mehl, Schweizer and Roduit.)

PRéCIS:: In this study, we report clinical results after implantation of an adjustable glaucoma drainage device. The intraocular pressure (IOP) profile was efficiently controlled postoperatively as the resistance to aqueous humor outflow was finely adjusted., Purpose: The main purpose of this study was to evaluate the safety and efficacy of the new adjustable glaucoma drainage device eyeWatch used in conjunction with a Baerveldt glaucoma implant in refractory glaucoma., Patients and Methods: This was a multicentric, prospective, noncomparative clinical trial. Patients older than 18 years of age suffering from refractory glaucoma after failed surgeries, with IOP of ≥20 mm Hg, in whom a further glaucoma procedure using an aqueous shunt was planned, were enrolled in this study. The primary outcome was the success rate, defined as an IOP≤18 mm Hg and reduction of >20% from baseline, IOP≥6 mm Hg. Secondary outcomes were mean IOP, visual acuity, number of antiglaucoma medications, number, and type of complications., Results: Fifteen patients were included. The mean follow-up time was 15.6±3.5 months. The mean baseline IOP decreased from 26.2±6.8 mm Hg before surgery to 11.9±2.8 mm Hg at 12 months (P<0.001). The mean number of glaucoma medications decreased from 3.0±0.7 before surgery to 0.8±0.9 at last visit (P<0.001). The success rate was 40% for complete success and 93% for overall success at last follow-up. Complication rate was 7%., Conclusions: The novel glaucoma device allows for perioperative and postoperative noninvasive adjustments of the resistance to aqueous humor outflow. This leads to better management of IOP during the early postoperative period, preventing ocular hypotony and eliminating the need for obstructive elements and reinterventions. The rate of complications was low, IOP was adequately controlled and lowered, with a substantial reduction in the number of antiglaucoma medication.

Purpose: The main purpose of this study was to compare the safety and efficacy of XEN gel implant surgery in patients with pseudoexfoliative glaucoma (PEXG) and primary open-angle glaucoma (POAG)., Setting: This was a prospective, interventional study in a tertiary glaucoma center., Methods: Fifty-seven eyes (43 patients) with POAG and 53 eyes (42 patients) with PEXG with uncontrolled intraocular pressure (IOP) despite medical treatment underwent combined XEN+cataract surgery or standalone XEN surgery. Mean IOP, mean number of medications at 1-year follow-up, needling rates, and incidence of adverse effects (AEs) were analyzed. Complete success, defined as an IOP <16 mm Hg without medications at 1 year, was also analyzed., Results: Combined XEN+cataract surgery was performed in 72% of POAG and 75% of PEXG eyes (P=0.674), the remainder underwent standalone XEN surgery. Patient characteristics were similar between the 2 groups except for higher age for the PEXG patients (78.5±8.5 vs. 71.3± 8.7 y; P<0.001). Mean medicated IOP was 19.8±5.8 (POAG) and 19.7±8.2 (PEXG) at baseline (P=0.98) and 13.9±4.6 (-29.8%) and 13.6±4.3 mm Hg (-31%) at 1 year (P=0.87), respectively (P<0.01). Mean medications dropped from 1.9±1.6 (POAG) and 2.0±1.3 (PEXG) preoperatively to 0.4±0.8 and 0.5±0.8, respectively at 1 year (P<0.001). A total of 42% (POAG) and 63% (PEXG) eyes achieved complete success (P=0.06) at 1 year. Needling was performed in 36.8% (POAG) versus 37.7% (PEXG) (P=0.923)., Conclusions: The XEN gel implant as a standalone or combined procedure demonstrated similar efficacy and safety results in PEXG and POAG eyes.

Purpose: To evaluate the safety and efficacy of XEN gel implant (Allergan Inc., Irvine) as a standalone versus combined XEN-Phacoemulsification surgery (XEN+cataract) in glaucoma patients., Methods: Prospective, interventional study. One-hundred forty-nine eyes (113 patients) with open-angle glaucoma and uncontrolled intraocular pressure (IOP) despite medical treatment were enrolled at a tertiary glaucoma center and followed up for a minimum of 1 year. Approximately two-thirds of patients underwent combined XEN+cataract surgery, while the remainder had XEN alone surgery. Primary outcome was a 20% or more decrease in IOP from medicated baseline at 1 year. Mean IOP, mean number of medications at last follow-up, and incidence of adverse effects were analyzed., Results: Of 149 enrolled eyes, data of 87 (58%) were available at 1 year. A total of 109 (73.2%) eyes underwent XEN+cataract surgery and 40 (26.8%) XEN alone surgery. Mean medicated IOP was 20.0±7.1 at baseline and 13.9±4.3 mm Hg at 1 year (P<0.01), a 31% IOP reduction. Mean medications dropped from 1.9±1.3 preoperatively to 0.5±0.8 at 1 year (P<0.001). In total, 62.1% of patients achieved a ≥20% IOP reduction; this proportion was higher in the XEN alone group. 57.7% of eyes achieved complete success (without any antiglaucoma medications) and 71.1% qualified success (with or without medications) when IOP<16 mm Hg was considered as the definition of success. In all, 37% of patients required needling intervention. Adverse effects included bleb revision in 5 eyes, choroidal detachment in 2 eyes, and second glaucoma surgery in 9 eyes., Conclusions: The XEN gel implant as a standalone procedure or combined with cataract surgery demonstrated safe and sustained IOP reduction after 1 year.

Introduction: Glaucoma is a leading cause of blindness worldwide. Intraocular pressure (IOP) lowering is the only effective treatment strategy. Traditional glaucoma surgeries are generally considered to be unpredictable and associated with a high rate of complications. This has led to the development of a novel XEN Gel Implant, a type of minimally invasive glaucoma surgery (MIGS), lowering the IOP without extensive surgical dissection., Areas Covered: A literature search was undertaken on PubMed using the terms XEN glaucoma, gelatin microstent, and MIGS. All the articles and case reports on XEN Gel Implant and selected articles on MIGS were studied and reviewed. We have discussed the results of most studies on XEN Gel Implant related to its efficacy, safety and success., Expert Commentary: The XEN Gel Implant effectively lowers IOP and medication use, with a favorable safety profile. Long-term data on its success and cost-effectiveness are lacking. The studies have shown it to be without any serious adverse events and to have good safety profile encouraging future research on this novel implant. There is a need to correctly identify selection criteria for patients, who would benefit the most from the XEN Gel Implant.

Minimally invasive glaucoma surgery includes different devices which provide a less invasive and safer means of reducing intraocular pressure. The XEN Gel Stent (Allergan Inc., CA) is an ab interno procedure which creates a subconjunctival drainage pathway. It is a new surgical device and there is a paucity of data on complications and their management. We report a clinical case of a leaking bleb after XEN surgery managed by bleb revision, conjunctival suturing, and XEN replacement.

Isotope effects on fluorine chemical shifts induced by heteroatoms bonded covalently to a carbon atom bearing fluorine atoms were studied. For each compound, the isotope-induced chemical shifts 2delta19F(X) through two bonds were measured for the heteroatom (X = 29/28Si, 30/28Si, 34/32S and 80/77Se). The 1delta19F(13/12C) values for the carbon bonded to the fluorine atoms were also recorded. Examination of the 19F NMR data showed homogeneity of the isotope-induced chemical shifts along the rows of the periodic table and regularity down the columns (from 10 to 15 ppb per mass unit for the second row to 0.4 ppb for the fourth row). It became negligible for atoms of the fifth row., (Copyright 2004 John Wiley & Sons, Ltd.)

Liver repopulation constitutes an attractive approach for the treatment of liver disorders or of diseases requiring abundant secretion of an active protein. We have described previously a model of selective repopulation of a normal liver by Fas/CD95-resistant hepatocytes, in which we achieved up to 16% hepatocyte repopulation. In the present study, we investigated the therapeutic efficacy of this strategy. With this aim, apolipoprotein E (ApoE) knockout mice were transplanted with Fas/CD95-resistant hepatocytes which constitutively express ApoE. Transplanted mice were submitted to weekly injections of non-lethal doses of the Fas agonist antibody Jo2. After 8 weeks of treatment, we obtained up to 30% of the normal level of plasma ApoE. ApoE secretion was accompanied by a drastic and significant decrease in total plasma cholesterol, which even fell to normal levels. Moreover, this secretion was sufficient to markedly reduce the progression of atherosclerosis. These results demonstrate the efficacy of this repopulation approach for correcting a deficiency in a protein secreted by the liver.

Hepatocyte transplantation might represent a potential therapeutic alternative to liver transplantation in the future; however, transplanted cells have a limited capacity to repopulate the liver, as they do not proliferate under normal conditions. Recently, studies in urokinase (uPA) transgenic mice and in fumarylacetoacetate hydrolase (FAH)-deficient mice have shown that the liver can be repopulated by genetically engineered hepatocytes harboring a selective advantage over resident hepatocytes. We have reported that transgenic mice expressing human Bcl-2 in their hepatocytes are protected from Fas/CD95-mediated liver apoptosis. We now show that Bcl-2 transplanted hepatocytes selectively repopulate the liver of mice treated with nonlethal doses of the anti-Fas antibody Jo2. FK 506 immunosuppressed mice were transplanted by splenic injection with Bcl-2 hepatocytes. The livers of female recipients were repopulated by male Bcl-2 transgenic hepatocytes, as much as 16%, after 8 to 12 administrations of Jo2. This only occurred after anti-Fas treatment, confirming that resistance to Fas-induced apoptosis constituted the selective advantage of these transplanted hepatocytes. Thus, we have demonstrated a method for increasing genetic reconstitution of the liver through selective repopulation with modified transgenic hepatocytes, which will allow optimization of cell and gene therapy in the liver.

Tay-Sachs disease (TSD) is a lysosomal storage disease due to hexosaminidase A deficiency caused by mutations in the gene for alpha-chain (Hex alpha). A human Hex alpha cDNA was subcloned into the adenoviral plasmid pAdRSV. Hex alpha. Replication-deficient adenovirus was generated by homologous recombination in 293 cells. Human fibroblasts from a patient suffering from TSD were infected with the recombinant adenovirus. TSD fibroblasts expressing the recombinant alpha-chain had an enzyme activity on the natural substrate ranging from 40 to 84% of the normal. The corrected cells secreted up to 25 times more Hex alpha than control fibroblasts. The Hex alpha encoded by the adenovirus was shown to be correctly transported into the lysosomes and to normalize the impaired degradation of GM2 ganglioside in TSD fibroblasts.

In hereditary neurological diseases, gene transfer into neurons is made difficult by: the nature of the cells (postmitotic cells, that cannot be cultured, genetically modified ex vivo, then retransplanted), sometimes, their widespread localization, the blood-brain barrier. However, three viral vectors derived from adenovirus, Herpes simplex virus and adeno-associated virus have been shown to be very efficient in transferring DNA into brain cells. All of these vectors can infect resting cells, especially neurons, and are efficient in vivo. Retroviral vectors which can infect dividing cells only are mainly used for ex vivo genetic modification of cells (neural progenitor cells, myoblasts, fibroblasts) followed by intracerebral transplantation. Alternatively, genetically modified cells can be transplanted in a peripheral site if the transgene product is able to cross the blood-brain barrier or to be transported retrogradely from the nerve terminals. We have especially investigated the potential interest of adenoviral vectors to transfer foreign genes into brain cells and to treat animal models of neurological diseases. These vectors allowed us to transfer the lacZ gene into any neural cell type, including neurons, glia, photoreceptors and olfactory receptors, ex vivo, in cell culture, and in vivo, by stereotactic administration. In addition, axonal transport of adenoviral vectors has been demonstrated, e.g. in the substantia nigra after injection into the striatum, in the olfactory bulb after intranasal instillation and in spinal motor neurons after intramuscular injection. After intracerebroventricular injection, ependymal cells are massively infected and express the transgene for several months, as this is also observed in neurons. Through the spinal canal and cerebrospinal fluid, the vector can diffuse to a considerable distance from the injection point, e.g. to the lumbar spinal cord after injection in the suboccipital region. To test the biological function of transgenes transferred through adenoviral vectors, we have constructed vectors with cDNAs or genes for various neutrophic factors: CNTF, NT3, BDNF and GDNF. These vectors were biologically active on target cells, ex vivo and in vivo. In the pmn mouse model of progressive motor neuronal degeneration, some of these vectors, alone or combined, allowed for prolongation of life of homozygous animals by more than two fold, and for decrease in the demyelination of phrenic nerve axons. Finally, we have also constructed an adenoviral vector carrying the alpha-hexosaminidase cDNA, encoding the enzyme subunit deficient in Tay Sachs patients. This vector permitted to normalize ganglioside metabolism in Tay Sachs fibroblasts and is currently tested in knock out mice deficient in hexosaminidase A. In spite of all these encouraging results, we are nevertheless aware that progress in vector design and delivery strategies will be needed before gene therapy can become a realistic therapeutical strategy in humans.

Mortality is high in unrecognized pulmonary embolism (PE), but the diagnosis is difficult to establish, especially in patients with coexisting cardiopulmonary disorders. We describe a group of 14 patients with pulmonary thromboemboli in whom transesophageal echocardiography (TEE) performed for coexisting cardiopulmonary conditions established the clinical diagnosis of PE not suspected prior to TEE. The patients had initial clinical diagnoses of heart failure (eight patients), cardiogenic shock (two patients), atrial septal defect (two patients), aortic dissection (one patient), and pneumonia (one patient). Thirteen patients had risk factors for PE. Transthoracic echocardiography (TTE) demonstrated right heart strain in eight patients but did not visualize PE in any of the patients. The TEE diagnosis of occult central pulmonary artery thromboembolism changed treatment in all 14 patients. Ten of the 14 patients were successfully discharged from the hospital. We conclude that occult central pulmonary artery thromboemboli are not uncommon in patients presenting with acute cardiopulmonary disorders and the presence of risk factors for PE and right heart strain on TTE should alert the physician to suspect PE. If and when TEE is performed in patients with acute cardiopulmonary disorders with risk factors for PE and right heart strain, the physician should evaluate the main pulmonary artery and its branches for central pulmonary artery thromboemboli.