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Technology is changing money and this book looks at where it might be taking us. Technology has transformed money from physical objects to intangible information. With the arrival of smart cards, mobile phones and Bitcoin it has become easier than ever to create new forms of money. Crucially, money is also inextricably connected with our identities. Your card or phone is a security device that can identify you - and link information about you to your money. Dave Birch looks back over the history of money, spanning thousands of years. He sees in the past, both recent and ancient, evidence for several possible futures. Looking further back to a world before cash and central banks, there were multiple 'currencies' operating at the level of communities, and the use of barter for transactions. Perhaps technology will take us back to the future, a future that began back in 1971, when money became a claim backed by reputation rather than by physical commodities of any kind. Since then, money has been bits. The author shows that these phenomena are not only possible in the future, but already upon us. We may well want to make transactions in Tesco points, Air Miles, Manchester United pounds, Microsoft dollars, Islamic e-gold or Cornish e-tin. The use of cash is already in decline, and is certain to vanish from polite society. The newest technologies will take money back to its origins: a substitute for memory, a record of mutual debt obligations within multiple overlapping communities. This time though, money will be smart. It will be money that reflects the values of the communities that produced it. Future money will know where it has been, who has been using it and what they have been using it for. -- Provided by publisher.

Inherited retinal diseases (IRDs) are a group of rare, heterogenous eye disorders caused by gene mutations that result in degeneration of the retina. There are currently limited treatment options for IRDs; however, retinal gene therapy holds great promise for the treatment of different forms of inherited blindness. One such IRD for which gene therapy has shown positive initial results is choroideremia, a rare, X-linked degenerative disorder of the retina and choroid. Mutation of the CHM gene leads to an absence of functional Rab escort protein 1 (REP1), which causes retinal pigment epithelium cell death and photoreceptor degeneration. The condition presents in childhood as night blindness, followed by progressive constriction of visual fields, generally leading to vision loss in early adulthood and total blindness thereafter. A recently developed adeno-associated virus-2 (AAV2) vector construct encoding REP1 (AAV2-REP1) has been shown to deliver a functional version of the CHM gene into the retinal pigment epithelium and photoreceptor cells. Phase 1 and 2 studies of AAV2-REP1 in patients with choroideremia have produced encouraging results, suggesting that it is possible not only to slow or stop the decline in vision following treatment with AAV2-REP1, but also to improve visual acuity in some patients.

There is no treatment available for vision loss associated with advanced dry age-related macular degeneration (AMD) or geographic atrophy (GA). In a pilot, proof of concept phase 2 study, we evaluated ciliary neurotrophic factor (CNTF) delivered via an intraocular encapsulated cell technology implant for the treatment of GA. We designed a multicenter, 1-y, double-masked, sham-controlled dose-ranging study. Patients with GA were randomly assigned to receive a high-or low-dose implant or sham surgery. The primary endpoint was the change in best corrected visual acuity (BCVA) at 12 mo. CNTF treatment resulted in a dose-dependent increase in retinal thickness. This change was followed by visual acuity stabilization (loss of less than 15 letters) in the high-dose group (96.3%) compared with low-dose (83.3%) and sham (75%) group. A subgroup analysis of those with baseline BCVA at 20/63 or better revealed that 100% of patients in the high-dose group lost <15 letters compared with 55.6% in the combined low-dose/sham group (P = 0.033). There was a 0.8 mean letter gain in the high-dose group compared with a 9.7 mean letter loss in the combined low-dose/sham group (P = 0.0315). Both the implant and the implant procedure were well-tolerated. These findings suggest that CNTF delivered by the encapsulated cell technology implant appears to slow the progression of vision loss in GA, especially in eyes with 20/63 or better vision at baseline.

PurposePreviously, we have shown the capability of a hybrid deep learning (DL) model that combines a U-Net and a sliding-window (SW) convolutional neural network (CNN) for automatic segmentation of retinal layers from OCT scan images in retinitis pigmentosa (RP). We found that one of the shortcomings of the hybrid model is that it tends to underestimate ellipsoid zone (EZ) width or area, especially when EZ extends toward or beyond the edge of the macula. In this study, we trained the model with additional data which included more OCT scans having extended EZ. We evaluated its performance in automatic measurement of EZ area on SD-OCT volume scans obtained from the participants of the RUSH2A natural history study by comparing the model’s performance to the reading center’s manual grading.Materials and MethodsDe-identified Spectralis high-resolution 9-mm 121-line macular volume scans as well as their EZ area measurements by a reading center were transferred from the management center of the RUSH2A study under the data transfer and processing agreement. A total of 86 baseline volume scans from 86 participants of the RUSH2A study were included to evaluate two hybrid models: the original RP240 model trained on 480 mid-line B-scans from 220 patients with retinitis pigmentosa (RP) and 20 participants with normal vision from a single site, and the new RP340 model trained on a revised RP340 dataset which included RP240 dataset plus an additional 200 mid-line B-scans from another 100 patients with RP. There was no overlap of patients between training and evaluation datasets. EZ and apical RPE in each B-scan image were automatically segmented by the hybrid model. EZ areas were determined by interpolating the discrete 2-dimensional B-scan EZ-RPE layer over the scan area. Dice similarity, correlation, linear regression, and Bland-Altman analyses were conducted to assess the agreement between the EZ areas measured by the hybrid model and by the reading center.ResultsFor EZ area > 1 mm2, average dice coefficients ± SD between the EZ band segmentations determined by the DL model and the manual grading were 0.835 ± 0.132 and 0.867 ± 0.105 for RP240 and RP340 hybrid models, respectively ( p < 0.0005; n = 51). When compared to the manual grading, correlation coefficients (95% CI) were 0.991 (0.987–0.994) and 0.994 (0.991–0.996) for RP240 and RP340 hybrid models, respectively. Linear regression slopes (95% CI) were 0.918 (0.896–0.940) and 0.995 (0.975–1.014), respectively. Bland-Altman analysis revealed a mean difference ± SD of -0.137 ± 1.131 mm2 and 0.082 ± 0.825 mm2, respectively.ConclusionAdditional training data improved the hybrid model’s performance, especially reducing the bias and narrowing the range of the 95% limit of agreement when compared to manual grading. The close agreement of DL models to manual grading suggests that DL may provide effective tools to significantly reduce the burden of reading centers to analyze OCT scan images. In addition to EZ area, our DL models can also provide the measurements of photoreceptor outer segment volume and thickness to further help assess disease progression and to facilitate the study of structure and function relationship in RP.

Essential fatty acids are structural components of all tissues and are indispensable for cell membrane synthesis; the brain, retina and other neural tissues are particularly rich in long‐chain polyunsaturated fatty acids (LC‐PUFA). These fatty acids serve as specific precursors for eicosanoids, which regulate numerous cell and organ functions. Recent human studies support the essential nature of n‐3 fatty acids in addition to the well‐established role of n−6 essential fatty acids in humans, particularly in early life. The main findings are that light sensitivity of retinal rod photoreceptors is significantly reduced in newborns with n−3 fatty acid deficiency, and that docosahexaenoic acid (DHA) significantly enhances visual acuity maturation and cognitive functions. DHA is a conditionally essential nutrient for adequate neurodevelopment in humans. Comprehensive clinical studies have shown that dietary supplementation with marine oil or single‐cell oil sources of LC‐PUFA results in increased blood levels of DHA and arachidonic acid, as well as an associated improvement in visual function in formula‐fed infants matching that of human breast‐fed infants. The effect is mediated not only by the known effects on membrane biophysical properties, neurotransmitter content, and the corresponding electrophysiological correlates but also by a modulating gene expression of the developing retina and brain. Intracellular fatty acids or their metabolites regulate transcriptional activation of gene expression during adipocyte differentiation and retinal and nervous system development. Regulation of gene expression by LC‐PUFA occurs at the transcriptional level and may be mediated by nuclear transcription factors activated by fatty acids. These nuclear receptors are part of the family of steroid hormone receptors. DHA also has significant effects on photoreceptor membranes and neurotransmitters involved in the signal transduction process; rhodopsin activation, rod and cone development, neuronal dendritic connectivity, and functional maturation of the central nervous system.

Mutations in RPGR account for over 70% of X-linked retinitis pigmentosa (XlRP), characterized by retinal degeneration and eventual blindness. The clinical consequences of RPGR mutations are highly varied, even among individuals with the same mutation: males demonstrate a wide range of clinical severity, and female carriers may or may not be affected. This study describes the phenotypic diversity in a cohort of 98 affected males from 56 families with RPGR mutations, and demonstrates the contribution of genetic factors (i.e., allelic heterogeneity and genetic modifiers) to this diversity. Patients were categorized as grade 1 (mild), 2 (moderate) or 3 (severe) according to specific clinical criteria. Patient DNAs were genotyped for coding SNPs in 4 candidate modifier genes with products known to interact with RPGR protein: RPGRIP1, RPGRIP1L, CEP290, and IQCB1. Family-based association testing was performed using PLINK. A wide range of clinical severity was observed both between and within families. Patients with mutations in exons 1-14 were more severely affected than those with ORF15 mutations, and patients with predicted null alleles were more severely affected than those predicted to make RPGR protein. Two SNPs showed association with severe disease: the minor allele (N) of I393N in IQCB1 (p = 0.044) and the common allele (R) of R744Q in RPGRIP1L (p = 0.049). These data demonstrate that allelic heterogeneity contributes to phenotypic diversity in XlRP and suggest that this may depend on the presence or absence of RPGR protein. In addition, common variants in 2 proteins known to interact with RPGR are associated with severe disease in this cohort.

Significance Knowledge of the molecules that guide retinal interneuron formation is incomplete. We showed that PRDI-BF1 and RIZ homology domain containing 8 (PRDM8) is required for the development of rod bipolar cells and OFF-cone bipolar subtypes as well as amacrine cell identity. Although bipolar cells were specified in Prdm8 -null mice, rod bipolar cell differentiation was impaired, leading to their death and near absence from adult retina. This defect disrupts postphotoreceptor signal transduction, as shown by nonprogressive b-wave deficits in electroretinograms. Our findings suggest PRDM8 as a candidate gene for human congenital stationary night blindness. They also establish PRDM8 as a component of the regulatory network governing bipolar cell development and amacrine cell diversity, aiding efforts to generate these essential interneurons in vitro. Retinal bipolar (BP) cells mediate the earliest steps in image processing in the visual system, but the genetic pathways that regulate their development and function are incompletely known. We identified PRDI-BF1 and RIZ homology domain containing 8 (PRDM8) as a highly conserved transcription factor that is abundantly expressed in mouse retina. During development and in maturity, PRDM8 is expressed strongly in BP cells and a fraction of amacrine and ganglion cells. To determine whether Prdm8 is essential to BP cell development or physiology, we targeted the gene in mice. Prdm8 ᴱᴳFᴾ/ᴱᴳFᴾ mice showed nonprogressive b-wave deficits on electroretinograms, consistent with compromised BP cell function or circuitry resembling the incomplete form of human congenital stationary night blindness (CSNB). BP cell specification was normal in Prdm8 ᴱᴳFᴾ/ᴱᴳFᴾ retina as determined by VSX2 ⁺ cell numbers and retinal morphology at postnatal day 6. BP subtype differentiation was impaired, however, as indicated by absent or diminished expression of BP subtype-specific markers, including the putative PRDM8 regulatory target PKCα ( Prkca ) and its protein. By adulthood, rod bipolar (RB) and type 2 OFF-cone bipolar (CB) cells were nearly absent from Prdm8 -null mice. Although no change was detected in total amacrine cell (AC) numbers, increased PRKCA ⁺ and cholinergic ACs and decreased GABAergic ACs were seen, suggesting an alteration in amacrine subtype identity. These findings establish that PRDM8 is required for RB and type 2 OFF-CB cell survival and amacrine subtype identity, and they present PRDM8 as a candidate gene for human CSNB.

Inherited retinal diseases (IRDs) are a genetically and phenotypically heterogeneous group of genetic eye disorders. There are more than 300 disease entities, and together this group of disorders affects millions of people globally and is a frequent cause of blindness or low-vision certification. However, each type is rare or ultra-rare. Characteristically, the impaired vision in IRDs is due to retinal photoreceptor dysfunction and loss resulting from mutation in a gene that codes for a retinal protein. Historically, IRDs have been considered incurable and individuals living with these blinding conditions could be offered only supportive care. However, the treatment landscape for IRDs is beginning to evolve. Progress is being made, driven by improvements in understanding of genotype–phenotype relationships, through advances in molecular genetic testing and retinal imaging. Alongside this expanding knowledge of IRDs, the current era of precision medicine is fueling a growth in targeted therapies. This has resulted in the first treatment for an IRD being approved. Several other therapies are currently in development in the IRD space, including RNA-based therapies, gene-based therapies (such as augmentation therapy and gene editing), cell therapy, visual prosthetics, and optogenetics. RNA-based therapies are a novel approach within precision medicine that have demonstrated success, particularly in rare diseases. Three antisense oligonucleotides (AONs) are currently in development for the treatment of specific IRD subtypes. These RNA-based therapies bring several key advantages in the setting of IRDs, and the potential to bring meaningful vision benefit to individuals living with inherited blinding disorders. This review will examine the increasing breadth and relevance of RNA-based therapies in clinical medicine, explore the key features that make AONs suitable for treating genetic eye diseases, and provide an overview of the three-leading investigational AONs in clinical trials.

To evaluate retinal sensitivity (RS) by mesopic and scotopic microperimetry (MP-1S) in an elderly Amish population with age-related macular degeneration (AMD). Mesopic and scotopic microperimetric testing was performed in 148 eyes of 77 elderly Amish subjects (age > 50 years) from Pennsylvania using a retinal function analyzer. Scotopic testing was performed using a 2.0 log unit neutral density filter following 30 minutes of dark adaptation. All subjects underwent complete ophthalmic examinations, including spectral-domain optical coherence tomography, fundus autofluorescence, infrared reflectance imaging, and flash color fundus photography. Certified graders at Doheny Image Reading Center identified subjects with evidence of AMD as defined by the Beckman classification and quantified drusen volume. RS in subjects with and without AMD was compared. Correlations between RS and drusen burden were analyzed. Ten eyes with incomplete MP-1S exams were excluded from the final analysis. Among the 138 eyes from 77 subjects included in the final analysis, 42 eyes from 29 subjects had evidence of early or intermediate AMD. The mean age of subjects with AMD was 69.65 years ± 13.81 years versus 63.04 years ± 12.69 years in those without AMD (P = .06). Mesopic RS was 18.8 dB ± 2.1 dB in subjects with AMD and 19.6 dB ± 1.4 dB in those without AMD (P = .07). Scotopic RS was significantly lower (P = .04) in subjects with AMD (15.9 dB ± 2.9 dB) compared with those without AMD (17.3 dB ± 2.4 dB). There was no relationship between mesopic RS and either drusen area (r = -0.06; P = .32) or drusen volume (r = -0.08; P = .30). There was a trend for an association between scotopic RS and both drusen area (r = -0.39; P = .24) and drusen volume (r = -0.36; P = .30). In an elderly Amish population, eyes with early or intermediate AMD show a greater reduction in scotopic RS than mesopic RS, suggesting that rod function is more severely affected than cone function. Drusen area and volume measurements better correlated with scotopic RS. [Ophthalmic Surg Lasers Imaging Retina. 2019;50:e236-e241.].

Background/AimsStargardt disease is a rare, inherited, degenerative disease of the retina that is the most common type of hereditary macular dystrophy. Currently, no approved treatments for the disease exist. The purpose of this study was to characterise the pharmacodynamics of emixustat, an orally available small molecule that targets the retinal pigment epithelium–specific 65 kDa protein (RPE65), in subjects with macular atrophy secondary to Stargardt disease.MethodsIn this multicentre study conducted at six study sites in the USA, 23 subjects with macular atrophy secondary to Stargardt disease were randomised to one of three doses of daily emixustat (2.5 mg, 5 mg or 10 mg) and treated for 1 month. The primary outcome was the suppression of the rod b-wave recovery rate on electroretinography after photobleaching, which is an indirect measure of RPE65 inhibition.ResultsSubjects who received 10 mg emixustat showed near-complete suppression of the rod b-wave amplitude recovery rate postphotobleaching (mean=91.86%, median=96.69%), whereas those who received 5 mg showed moderate suppression (mean=52.2%, median=68.0%). No effect was observed for subjects who received 2.5 mg emixustat (mean=−3.31%, median=−12.23%). The adverse event profile was consistent with prior studies in other patient populations and consisted primarily of ocular adverse events likely related to RPE65 inhibition.ConclusionThis study demonstrated dose-dependent suppression of rod b-wave amplitude recovery postphotobleaching, confirming emixustat’s biological activity in patients with Stargardt disease. These findings informed dose selection for a 24-month phase 3 trial (SeaSTAR Study) that is now comparing emixustat to placebo in the treatment of Stargardt disease-associated macular atrophy.