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Funding: This work was performed by funding from The University of Sydney (CIA Jenkins) and funds provided by the National Health and Medical Research Council (Australia) APP1147897. Purpose: Robust, affordable plasma proteomic biomarker workflows are needed for large-scale clinical studies. We evaluated aspects of sample preparation to allow LC-MS analysis of more than 1500 samples from the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial of adults with type 2 diabetes. Methods: Using LC-MS with data-independent acquisition we evaluated four variables: plasma protein depletion, EDTA or citrated anti-coagulant blood collection tubes, plasma lipid depletion strategies and plasma freeze-thaw cycles. Optimised methods were applied in a pilot study of FIELD participants. Results: LC-MS of undepleted plasma conducted over a 45 min gradient yielded 172 proteins after excluding immunoglobulin isoforms. Cibachrome-blue-based depletion yielded additional proteins but with cost and time expenses, while immunodepleting albumin and IgG provided few additional identifications. Only minor variations were associated with blood collection tube type, delipidation methods and freeze-thaw cycles. From 65 batches involving over 1500 injections, the median intra-batch quantitative differences in the top 100 proteins of the plasma external standard was less than 2%. Fenofibrate altered seven plasma proteins. Conclusions and Clinical Relevance: A robust plasma handling and LC-MS proteomics workflow for abundant plasma proteins has been developed for large-scale biomarker studies that balances proteomic depth with time and resource costs. Publisher PDF

Purpose To develop a genotype assay to assess associations with common and rare age-related macular degeneration (AMD) risk variants, to calculate an overall genetic risk score (GRS), and to identify potential misdiagnoses with inherited macular dystrophies that mimic AMD. Design Case-control study. Participants Individuals (n = 4740) from 5 European cohorts. Methods We designed single-molecule molecular inversion probes for target selection and used next generation sequencing to sequence 87 single nucleotide polymorphisms (SNPs), coding and splice-site regions of 10 AMD-(related) genes (ARMS2, C3, C9, CD46, CFB, CFH, CFI, HTRA1, TIMP3, and SLC16A8), and 3 genes that cause inherited macular dystrophies (ABCA4, CTNNA1, and PRPH2). Genetic risk scores for common AMD risk variants were calculated based on effect size and genotype of 52 AMD-associated variants. Frequency of rare variants was compared between late AMD patients and control individuals with logistic regression analysis. Main Outcome Measures Genetic risk score, association of genetic variants with AMD, and genotype–phenotype correlations. Results We observed high concordance rates between our platform and other genotyping platforms for the 69 successfully genotyped SNPs (>96%) and for the rare variants (>99%). We observed a higher GRS for patients with late AMD compared with patients with early/intermediate AMD (P Conclusions This study reports a genotype assay for common and rare AMD genetic variants, which can identify individuals at intermediate to high genetic risk of late AMD and enables differential diagnosis of AMD-mimicking dystrophies. Our study supports sequencing of CFH, CFI, and C3 genes because they harbor rare high-risk variants. Carriers of these variants could be amendable for new treatments for AMD that currently are under development.

ImportanceSeveral ocular biomarkers have been proposed for the early detection of Alzheimer disease (AD) and mild cognitive impairment (MCI), particularly fundus photography, optical coherence tomography (OCT), and OCT angiography (OCTA).ObjectiveTo perform an umbrella review of systematic reviews to assess the diagnostic accuracy of ocular biomarkers for early diagnosis of Alzheimer disease.Data SourcesMEDLINE, Embase, and PsycINFO were searched from January 2000 to November 2021. The references of included reviews were also searched.Study SelectionSystematic reviews investigating the diagnostic accuracy of ocular biomarkers to detect AD and MCI, in secondary care or memory clinics, against established clinical criteria or clinical judgment.Data Extraction and SynthesisThe Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline checklist was followed and the Risk Of Bias in Systematic reviews tool was used to assess review quality.Main Outcomes and MeasuresThe prespecified outcome was the accuracy of ocular biomarkers for diagnosing AD and MCI. The area under the curve (AUC) was derived from standardized mean difference.ResultsFrom the 591 titles, 14 systematic reviews were included (median [range] number of studies in each review, 14 [5-126]). Only 4 reviews were at low risk of bias on all Risk of Bias in Systematic Reviews domains. The imaging-derived parameters with the most evidence for detecting AD compared with healthy controls were OCT peripapillary retinal nerve fiber layer thickness (38 studies including 1883 patients with AD and 2510 controls; AUC = 0.70; 95% CI, 0.53-0.79); OCTA foveal avascular zone (5 studies including 177 patients with AD and 371 controls; AUC = 0.73; 95% CI, 0.50-0.89); and saccadic eye movements prosaccade latency (30 studies including 651 patients with AD/MCI and 771 controls; AUC = 0.64; 95% CI, 0.58-0.69). Antisaccade error was investigated in fewer studies (12 studies including 424 patients with AD/MCI and 382 controls) and yielded the best accuracy (AUC = 0.79; 95% CI, 0.70-0.88).Conclusions and RelevanceThis umbrella review has highlighted limitations in design and reporting of the existing research on ocular biomarkers for diagnosing AD. Parameters with the best evidence showed poor to moderate diagnostic accuracy in cross-sectional studies. Future longitudinal studies should investigate whether changes in OCT and OCTA measurements over time can yield accurate predictions of AD onset.

Herein, we report the crystal structure of 2,7-dichlorofluorescein methyl ester (DCF-ME) and its fluorescence response to hydroxyapatite binding. The reported fluorophore is very selective for staining the bone matrix and provides turn-on fluorescence upon hydroxyapatite binding. The reported fluorophore can readily pass the cell membrane of the C2C12 cell line, and it is non-toxic for the cell line. The reported fluorophore DCF-ME may find applications in monitoring bone remodeling and microcalcification as an early diagnosis tool for breast cancer and age-related macular degeneration.

Zinc supplementation had been shown to be beneficial to slow the progression of age-related macular degeneration (AMD). However, the molecular mechanism underpinning this benefit is not well understood. In this study, we used single-cell RNA sequencing to identify transcriptomic changes induced by zinc supplementation in human primary retinal pigment epithelial (RPE) cells in culture. The RPE cells were allowed to mature for up to 19 weeks. After one or 18 weeks in culture, we supplemented the culture medium with 125 μM added zinc for one week. During maturation RPE cells developed high transepithelial electrical resistance, extensive, but variable, pigmentation and deposited sub-RPE material similar to the hallmark lesions of AMD. Unsupervised cluster analysis of the combined transcriptome of the cells isolated after two-, nine- and 19 weeks in culture, showed a significant degree of heterogeneity. Clustering based on 234 pre-selected RPE specific genes, identified from the literature, divided the cells into two distinct clusters we defined as more- and less-differentiated cells. The proportion of more differentiated cells increased with time in culture, but appreciable numbers of cells remained less differentiated even at 19 weeks. Pseudotemporal ordering identified 537 genes that could be implicated in the dynamics of RPE cell differentiation (FDR< 0.05). Zinc treatment resulted in the differential expression of 281 of these genes (FDR< 0.05). These genes were associated with several biological pathways including extracellular remodelling, retinoid metabolism and modulation of ID1/ID3 transcriptional regulation, to name a few. Overall, zinc had a multitude of effects on the RPE transcriptome including a number of genes that are involved in pigmentation, complement regulation, mineralisation and cholesterol metabolism processes associated with AMD.

A tanulmány az EU (Európai Unió) hat KKE-tagállama (kelet-közép-európai), Bulgária, Csehország, Lengyelország, Magyarország, Románia és Szlovákia NUTS 3-as (Nomenclature des Unités Territoriales Statistiques – Statisztikai célú területi egységek nómenklatúrája) szintű régióinak (megyéinek) gazdasági növekedését elemzi 2000 és 2018 között. A szerzők vizsgálata arra irányul, hogy a közel két évtized alatt elkülöníthetők-e a NUTS 3 régiók hasonló növekedési pályával leírható csoportjai, ún. konvergenciaklubjai, amelyeken belül a térségek ugyanazon klubspecifikus egyensúlyi állapothoz tartanak. A konvergenciaklubok elkülönítésére a Phillips és Sul [2007] által kifejlesztett regresszióalapú konvergenciatesztet, az ún. log t-tesztet használják. A klubokon belüli és klubok közötti egyenlőtlenségek alakulását pedig általánosított Theil-index segítségével mutatják be.

Purpose Geographic atrophy (GA) secondary to age-related macular degeneration is considered a single entity. This study aimed to determine whether GA subgroups exist that can be defined by their genotype and phenotype. Design Retrospective analysis of cross-sectional data. Participants Individuals (196 eyes of 196 patients) 50 years of age or older with GA from the EYE-RISK database. Methods Participants were graded for the presence of each of the following fundus features on color fundus photography: large soft drusen, reticular pseudodrusen (RPD), refractile drusen, hyperpigmentation, location of atrophy (foveal vs. extrafoveal), and multifocal lesions. Genotypes of 33 single nucleotide polymorphisms previously assigned to the complement, lipid metabolism, or extracellular matrix (ECM) pathways and ARMS2 also were included, and genetic risk scores (GRSs) for each of those 3 pathways were calculated. Hierarchical cluster analysis was used to determine subgroups of participants defined by these features. The discriminative ability of genotype, phenotype, or both for each subgroup was determined with 10-fold cross-validated areas under the receiver operating characteristic curve (cvAUCs), and the agreement between predicted and actual subgroup membership was assessed with calibration plots. Main Outcome Measures Identification and characterization of GA subgroups based on their phenotype and genotype. Results Cluster analyses identified 3 subgroups of GA. Subgroup 1 was characterized by high complement GRS, frequently associated with large soft drusen and foveal atrophy; subgroup 2 generally showed low GRS, foveal atrophy, and few drusen (any type); and subgroup 3 showed a high ARMS2 and ECM GRS, RPD, and extrafoveal atrophy. A high discriminative ability existed between subgroups for the genotype (cvAUC, ≥0.94), and a modest discriminative ability existed for the phenotype (cvAUC, Conclusions We identified 3 GA subgroups that differed mostly by their genotype. Atrophy location and drusen type were the most relevant phenotypic features.

Purpose: The current study aimed to identify metabolites associated with age-related macular degeneration (AMD) by performing the largest metabolome association analysis in AMD to date, as well as aiming to determine the effect of AMD-associated genetic variants on metabolite levels and investigate associations between the identified metabolites and activity of the complement system, one of the main AMD-associated disease pathways. Design: Case-control association analysis of metabolomics data. Participants: Five European cohorts consisting of 2267 AMD patients and 4266 control participants. Methods: Metabolomics was performed using a high-throughput proton nuclear magnetic resonance metabolomics platform, which allows quantification of 146 metabolite measurements and 79 derivative values. Metabolome–AMD associations were studied using univariate logistic regression analyses. The effect of 52 AMD-associated genetic variants on the identified metabolites was investigated using linear regression. In addition, associations between the identified metabolites and activity of the complement pathway (defined by the C3d-to-C3 ratio) were investigated using linear regression. Main Outcome Measures: Metabolites associated with AMD. Results: We identified 60 metabolites that were associated significantly with AMD, including increased levels of large and extra-large high-density lipoprotein (HDL) subclasses and decreased levels of very low-density lipoprotein (VLDL), amino acids, and citrate. Of 52 AMD-associated genetic variants, 7 variants were associated significantly with 34 of the identified metabolites. The strongest associations were identified for genetic variants located in or near genes involved in lipid metabolism (ABCA1, CETP, APOE, and LIPC) with metabolites belonging to the large and extra-large HDL subclasses. Also, 57 of 60 metabolites were associated significantly with complement activation levels, independent of AMD status. Increased large and extra-large HDL levels and decreased VLDL and amino acid levels were associated with increased complement activation. Conclusions: Lipoprotein levels were associated with AMD-associated genetic variants, whereas decreased essential amino acids may point to nutritional deficiencies in AMD. We observed strong associations between the vast majority of the AMD-associated metabolites and systemic complement activation levels, independent of AMD status. This may indicate biological interactions between the main AMD disease pathways and suggests that multiple pathways may need to be targeted simultaneously for successful treatment of AMD.

We have shown that all sub-retinal pigment epithelial (sub-RPE) deposits examined contain calcium phosphate minerals: hydroxyapatite (HAP), whitlockite (Wht), or both. These typically take the form of ca. 1 μm diameter spherules or >10 μm nodules and appear to be involved in the development and progression of age-related macular degeneration (AMD). Thus, these minerals may serve as useful biomarkers the for early detection and monitoring of sub-RPE changes in AMD. We demonstrated that HAP deposits could be imaged in vitro by fluorescence lifetime imaging microscopy (FLIM) in flat-mounted retinas using legacy tetracycline antibiotics as selective sensors for HAP. As the contrast on a FLIM image is based on the difference in fluorescence lifetime and not intensity of the tetracycline-stained HAP, distinguishing tissue autofluorescence from the background is significantly improved. The focus of the present pilot study was to assess whether vascular perfusion of the well tolerated and characterized chlortetracycline (widely used as an orally bioavailable antibiotic) can fluorescently label retinal HAP using human cadavers. We found that the tetracycline delivered through the peripheral circulation can indeed selectively label sub-RPE deposits opening the possibility for its use for ophthalmic monitoring of a range of diseases in which deposit formation is reported, such as AMD and Alzheimer disease (AD).

PURPOSE: Retinal microvascular abnormalities measured on retinal images are a potential source of prognostic biomarkers of vascular changes in the neurodegenerating brain. We assessed the presence of these abnormalities in Alzheimer's dementia and mild cognitive impairment (MCI) using ultra-widefield (UWF) retinal imaging.METHODS: UWF images from 103 participants (28 with Alzheimer's dementia, 30 with MCI, and 45 with normal cognition) underwent analysis to quantify measures of retinal vascular branching complexity, width, and tortuosity.RESULTS: Participants with Alzheimer's dementia displayed increased vessel branching in the midperipheral retina and increased arteriolar thinning. Participants with MCI displayed increased rates of arteriolar and venular thinning and a trend for decreased vessel branching.CONCLUSIONS: Statistically significant differences in the retinal vasculature in peripheral regions of the retina were observed among the distinct cognitive stages. However, larger studies are required to establish the clinical importance of our findings. UWF imaging may be a promising modality to assess a larger view of the retinal vasculature to uncover retinal changes in Alzheimer's disease.TRANSLATIONAL RELEVANCE: This pilot work reports an investigation into which retinal vasculature measurements may be useful surrogate measures of cognitive decline, as well as technical developments (e.g., measurement standardization), that are first required to establish their recommended use and translational potential.

PURPOSE: To explore whether phenotypes in geographic atrophy (GA) secondary to age-related macular degeneration (AMD) can be separable into two or more partially distinct subtypes and if these have different genetic associations. This is important since the discovery of distinct GA subtypes associated with different genetic factors might require customized therapeutic approaches. DESIGN: Cluster analysis of participants within a controlled clinical trial, followed by assessment of phenotype-genotype associations. PARTICIPANTS: AREDS2 participants with incident GA during study follow-up: 598 eyes of 598 participants (median age 75.7y). METHODS: Phenotypic features from reading center grading of fundus photographs were subjected to cluster analysis, by both k-means and hierarchical methods, in cross-sectional analyses (using 15 phenotypic features assessed principally at GA emergence) and longitudinal analyses (using 14 phenotypic features). In pre-specified hypothesis tests, identified clusters were compared by four pathway-based genetic risk scores (complement, extracellular matrix, lipid, and ARMS2). The analyses were repeated in reverse, i.e., clustering by genotype and comparison by phenotype. MAIN OUTCOME MEASURES: Characteristics and quality of cluster solutions, assessed by Calinski-Harabasz scores, unexplained variance, and consistency; genotype-phenotype associations, assessed by t test. RESULTS: In cross-sectional phenotypic analyses, k-means identified two clusters (labeled A, B), while hierarchical clustering identified four (C-F); A-E membership differed principally by GA configuration but in relatively few other ways. In longitudinal phenotypic analyses, k-means identified two clusters (G, H), which differed principally by smoking status but in relatively few other ways. These three sets of cluster divisions were not similar to each other (r ≤ 0.20). Despite adequate power, pairwise cluster comparison by the four genetic risk scores demonstrated no significant differences (p>0.05 for all). In clustering by genotype, k-means identified two clusters (I/J). These differed principally at ARMS2, but no significant genotype-phenotype associations were observed (p>0.05 for all). CONCLUSIONS: Phenotypic clustering resulted in GA subtypes defined principally by GA configuration in cross-sectional analyses, but these were not replicated in longitudinal analyses. These negative findings, together with the absence of significant phenotype-genotype associations, indicate that GA phenotypes may vary continuously across a spectrum, rather than consisting of distinct subtypes that arise from separate genetic etiologies.

Age-related macular degeneration (AMD) is a common blinding disease in the western world that is linked to the loss of fenestration in the choriocapillaris that sustains the retinal pigment epithelium and photoreceptors in the back of the eye. Changes in ocular and systemic zinc concentrations have been associated with AMD, therefore, we hypothesized that these changes might be directly involved in fenestrae formation. To test this hypothesis, an endothelial cell (bEND.5) model for fenestrae formation was treated with different concentrations of zinc sulfate (ZnSO4) solution for up to 20 h. Fenestrae were visualized by staining for Plasmalemmal Vesicle Associated Protein-1 (PV-1), the protein that forms the diaphragms of the fenestrated endothelium. Size and distribution were monitored by transmission electron microscopy (TEM). We found that zinc induced the redistribution of PV-1 into areas called sieve plates containing ~70-nm uniform size and typical morphology fenestrae. As AMD is associated with reduced zinc concentrations in the serum and in ocular tissues, and dietary zinc supplementation is recommended to slow disease progression, we propose here that the elevation of zinc concentration may restore choriocapillaris fenestration resulting in improved nutrient flow and clearance of waste material in the retina.

Purpose: Micrometer-sized spherules formed of hydroxyapatite or whitlockite were identified within extracellular deposits that accumulate in the space between the basal lamina (BL) of retinal pigment epithelium (RPE) and the inner collagenous layer of Bruch’s membrane (sub-RPE–BL space). This investigation aimed to characterize the morphologic features, structure, and distribution of these spherules in aged human eyes with and without clinical indications of age-related macular degeneration (AMD)..Design: Experimental studyParticipants: Five human eyes with varying degrees of sub-RPE–BL deposits were obtained from the University College London Institute of Ophthalmology and Moorfield’s Eye Hospital Tissue Repository or the Advancing Sight Network. Two eyes were reported as having clinical indications of AMD (age, 76–87 years), whereas 3 were considered healthy (age, 69–91 years).Methods: Cadaveric eyes with sub-RPE–BL deposits were embedded in paraffin wax and sectioned to a thickness of 4-10 μm. Spherules were identified and characterized using high-resolution scanning electron microscopy (SEM), energy-dispersive x-ray spectroscopy, and time-of-flight secondary ion mass spectroscopy.Main Outcome Measures: High-resolution scanning electron micrographs of spherules, the size-frequency distribution of spherules including average diameter, and the distribution of particles across the central-peripheral axis. Elemental maps and time-of-flight secondary ion mass spectra also were obtainedResults: The precipitation of spherules is ubiquitous across the central, mid-peripheral, and far-peripheral axis in aged human eyes. No significant difference was found in the frequency of spherules along this axis. However, statistical analysis indicated that spherules exhibited significantly different sizes in these regions. In-depth analysis revealed that spherules in the sub-RPE–BL space of eyes with clinical signs of AMD were significantly larger (median diameter, 1.64 μm) than those in healthy aged eyes (median diameter, 1.16 μm). Finally, spherules showed great variation in surface topography and internal structure..Conclusions: The precipitation of spherules in the sub-RPE–BL space is ubiquitous across the central–peripheral axis in aged human eyes. However, a marked difference exists in the size and frequency of spherules in eyes with clinical signs of AMD compared to those without, suggesting that the size and frequency of spherules may be associated with AMD.

PURPOSE: Genetic and epidemiologic studies have shown that lipid genes and High Density Lipoproteins (HDL) are implicated in age-related macular degeneration (AMD). We studied circulating lipid levels in relation to AMD in a large European dataset, and investigated whether this relationship is driven by certain sub fractions. DESIGN: (Pooled) analysis of cross-sectional data. PARTICIPANTS: 30,953 individuals aged 50+ participating in the E3 consortium; and 1530 individuals from the Rotterdam Study with lipid sub fraction data. METHODS: In E3, AMD features were graded per eye on fundus photographs using the Rotterdam Classification. Routine blood lipid measurements were available from each participant. Data on genetics, medication and confounders such as body mass index, were obtained from a common database. In a subgroup of the Rotterdam Study, lipid sub fractions were identified by the Nightingale biomarker platform. Random-intercepts mixed-effects models incorporating confounders and study site as a random-effect were used to estimate the associations. MAIN OUTCOME MEASURES: early, late or any AMD, phenotypic features of early AMD, lipid measurements. RESULTS: HDL was associated with an increased risk of AMD, corrected for potential confounders (Odds Ratio (OR) 1.21 per 1mmol/L increase (95% confidence interval[CI] 1.14-1.29); while triglycerides were associated with a decreased risk (OR 0.94 per 1mmol/L increase [95%CI 0.91-0.97]). Both were associated with drusen size, higher HDL raises the odds of larger drusen while higher triglycerides decreases the odds. LDL-cholesterol only reached statistical significance in the association with early AMD (p=0.045). Regarding lipid sub fractions: the concentration of extra-large HDL particles showed the most prominent association with AMD (OR 1.24 [95%CI 1.10-1.40]). The CETP risk variant (rs17231506) for AMD was in line with increased-HDL levels (p=7.7x10-7); but LIPC risk variants (rs2043085, rs2070895) were associated in an opposite way (p=1.0x10-6 and 1.6x10-4). CONCLUSIONS: Our study suggests that HDL-cholesterol is associated with increased risk of AMD and triglycerides negatively associated. Both show the strongest association with early AMD and drusen. Extra-large HDL sub fractions seem to be drivers in the relation with AMD, variants in lipid genes play a more ambiguous role in this association. Whether systemic lipids directly influence AMD or represent lipid metabolism in the retina remains a question to be answered.

Nehany eve a fejlett orszagok gazdasagfejlesztesi elkepzelesei kozott előterbe kerult az ujraiparositas, reszben a 2008. evi valsagra, reszben a negyedik ipari forradalomhoz kapcsolodo technologiai atalakulasra, szerkezetvaltasra adott egyik gazdasagpolitikai valaszkent. Tanulmanyunkban azt vizsgaljuk, hogy megfigyelhető-e ujraiparosodas az Europai Unio tagallamaiban, es hasonlok-e a szerkezetvaltasi folyamatok az Europai Unio 15 regi es 10 uj, posztszocialista tagallamaban, kulonos tekintettel Magyarorszagra. Az ujraiparosodas elemzesehez a feldolgozoipar brutto hozzaadott ertekenek es a foglalkoztatottak szamanak valtozasat vesszuk alapul a 2000 es 2016 kozotti időszakban. Az adatok alapjan Nyugat-Europaban tovabbra is dezindusztrializacio zajlik, mig Kelet-Kozep-Europa nehany orszagaban felemas, a foglalkoztatas merseklődese melletti ujraiparosodas figyelhető meg. Magyarorszag feldolgozoiparanak atalakulasa jobban hasonlit az EU15 orszagokban tapasztalhatokra, mint a tobbi posztszocialista orszagera.* Journal of Economic Literature (JEL) kod: O14, L6, O11.

Recent developments in imaging technologies now allow the documentation, qualitative and quantitative evaluation of peripheral retinal lesions. As wide field retinal imaging, capturing both the central and peripheral retina up to 200° eccentricity, is becoming readily available the question is: what is it that we gain by imaging the periphery? Based on accumulating evidence it is clear that findings in the periphery do not always associate to those observed in the posterior pole. However, the newly acquired information may provide useful clues to previously unrecognised disease features and may facilitate more accurate disease prognostication. In this review, we explore the anatomy and physiology of the peripheral retina, focusing on how it differs from the posterior pole, recount the history of peripheral retinal imaging, describe various peripheral retinal lesions and evaluate the overall relevance of peripheral retinal findings to different diseases.

Introduction: People with Down syndrome (DS) are particularly susceptible to Alzheimer’s disease (AD) due to the triplication of the amyloid precursor protein (APP)gene. In this cross-sectional study, we hypothesized that choroidal thinning reported in sporadic AD (sAD) is mirrored in adults with DS.Methods: The posterior pole of the eye for 24 adults with DS and 16 age-matched controls (Ctrl) were imaged with optical coherence tomography. Choroidal thickness (ChT)was measured and analyzed in relation to cognitive status and cerebral amyloid beta(Aβ) load.Results: ChT was increased in people with DS (pwDS) compared to Ctrl. This increase was associated with gender differences and positively correlated with cerebral Aβ load in a small subset. There was no significant correlation detected between ChT and age or cognitive status.Discussion: In contrast to sAD this study found a significantly thicker choroid in pwDS. Whether these changes are related to Aβ pathology in DS needs further investigation.

Simultaneous determination of proteins with micrometric resolution is a significant challenge. In this study, laser ablation (LA) inductively coupled plasma - mass spectrometry (ICP-MS) was employed to quantify the distribution of proteins associated to the eye disease age-related macular degeneration (AMD) using antibodies labelled with three different metal nanoclusters (MNCs). PtNCs, AuNCs and AgNCs contain hundreds of metal atoms and were used to detect metallothionein 1/2 (MT1/2), complement factor H (CFH) and amyloid precursor protein (APP) in retina, ciliary body, retinal pigment epithelium (RPE), choroid and sclera from human cadaveric eye sections. First, the labelling of MNCs bioconjugated primary antibodies (Ab) was optimised following an immunolabelling protocol to avoid the non-specific interaction of MNCs with the tissue. Then, the LA and ICP-MS conditions were studied to obtain high-resolution images for the simultaneous detection of the three labels at the same tissue section. A significant signal amplification was found when using AuNCs, AgNCs and PtNCs labelled Ab of 310, 723 and 1194 respectively. After the characterisation of MNCs labelled immunoprobes, the Ab labelling was used for determination of MT1/2, CFH and APP in the RPE-choroid-sclera, where accumulation of extracellular deposits related to AMD was observed. Experimental results suggest that this method is fully suitable for the simultaneous detection of at least three different proteins.

In this study, we analyse economic growth and structural change between 2000 and 2016 in the NUTS3 regions of the four countries forming the Visegrad Group (V4) and joining the European Union in 2004, Czechia, Poland, Hungary, and Slovakia. Our examination considers whether convergence can be observed in the case of the regions in the V4 countries over about one and a half decades, i.e., whether less developed regions catch up with more developed ones. Whether the economic growth of the regions took place at a relatively steady pace similar to that of the countries, or if there is a divide between the groups of regions (convergence clubs), which converge to different steady states. If there are convergence clubs, are the economic structure and workforce base of the clubs similar or different. Our study has two steps; first, we divide the 115 NUTS3 regions into convergence clubs with Phillips and Sul’s 2007 logt-test method, presenting the characteristics of their economic growth. We then conducted entropy calculations to test the robustness of the clubs, which provided information on the disparities inside and between the clubs, as well as inside and between the countries. Next, we present the economic structure and urbanrural types of clubs, covering the main characteristics of their labour force base and what factors the transition from one club to another depends on. The main conclusion of our study is that the five convergence clubs are completely separate and their economic structure and labour force base are also different.

Contains fulltext : 245098.pdf (Publisher’s version ) (Closed access) PURPOSE: Current prediction models for advanced age-related macular degeneration (AMD) are based on a restrictive set of risk factors. The objective of this study was to develop a comprehensive prediction model applying a machine learning algorithm allowing selection of the most predictive risk factors automatically. DESIGN: Two population-based cohort studies. PARTICIPANTS: The Rotterdam Study I (RS-I; training set) included 3838 participants 55 years of age or older, with a median follow-up period of 10.8 years, and 108 incident cases of advanced AMD. The Antioxydants, Lipids Essentiels, Nutrition et Maladies Oculaires (ALIENOR) study (test set) included 362 participants 73 years of age or older, with a median follow-up period of 6.5 years, and 33 incident cases of advanced AMD. METHODS: The prediction model used the bootstrap least absolute shrinkage and selection operator (LASSO) method for survival analysis to select the best predictors of incident advanced AMD in the training set. Predictive performance of the model was assessed using the area under the receiver operating characteristic curve (AUC). MAIN OUTCOME MEASURES: Incident advanced AMD (atrophic, neovascular, or both), based on standardized interpretation of retinal photographs. RESULTS: The prediction model retained (1) age, (2) a combination of phenotypic predictors (based on the presence of intermediate drusen, hyperpigmentation in one or both eyes, and Age-Related Eye Disease Study simplified score), (3) a summary genetic risk score based on 49 single nucleotide polymorphisms, (4) smoking, (5) diet quality, (6) education, and (7) pulse pressure. The cross-validated AUC estimation in RS-I was 0.92 (95% confidence interval [CI], 0.88-0.97) at 5 years, 0.92 (95% CI, 0.90-0.95) at 10 years, and 0.91 (95% CI, 0.88-0.94) at 15 years. In ALIENOR, the AUC reached 0.92 at 5 years (95% CI, 0.87-0.98). In terms of calibration, the model tended to underestimate the cumulative incidence of advanced AMD for the high-risk groups, especially in ALIENOR. CONCLUSIONS: This prediction model reached high discrimination abilities, paving the way toward making precision medicine for AMD patients a reality in the near future.

SIGNIFICANCE: Recent evidence suggests that hydroxyapatite (HAP) in sub-retinal pigment epithelial (sub-RPE) deposits in aged human eyes may act to nucleate and contribute to their growth to clinically detectable size. Sub-RPE deposits such as drusen are clinical hallmarks of age-related macular degeneration (AMD), therefore enhanced and earlier detection is a clinical need. We found that tetracycline-family antibiotics, long known to stain HAP in teeth and bones, can also label the HAP in sub-RPE deposits. However, HAP-bound tetracycline fluorescence excitation and emission spectra overlap with the well-known autofluorescence of outer retinal tissues, making them difficult to resolve.AIM: In this initial study, we sought to determine if the HAP-bound tetracyclines also exhibit enhanced fluorescence lifetimes, providing a useful difference in lifetime compared with the short lifetimes observed in vivo in the human retina by the pioneering work of Schweitzer, Zinkernagel, Hammer, and their colleagues, and thus a large enough effect size to resolve the HAP from background by fluorescence lifetime imaging.APPROACH: We stained authentic HAP with tetracyclines and measured the lifetime(s) by phase fluorometry, and stained aged, fixed human cadaver retinas with drusen with selected tetracyclines and imaged them by fluorescence lifetime imaging microscopy (FLIM).RESULTS: We found that chlortetracycline and doxycycline exhibited substantial increase in fluorescence lifetime compared to the free antibiotics and the retinal background, and the drusen were easily resolvable from the retinal background in these specimens by FLIM.CONCLUSIONS: These findings suggest that FLIM imaging of tetracycline (and potentially other molecules) binding to HAP could become a diagnostic tool for the development and progression of AMD.

A makrogazdasagi kerdesekkel kivalo tanulmanyok sora foglalkozik, mig a magyar gazdasagi novekedes terbeli elemzese hatterbe szorult. A tema fontossagat indokolja, hogy a volt szocialista EU-tagallamok kozott Magyarorszag gazdasaga novekedett a leglassabban 2004 es 2016 kozott. Tanulmanyunkban attekintjuk, hogy a novekedeshez melyik megye, megyecsoport milyen mertekben jarult hozza 2000-től/2004-től 2016-ig. Egyik alapvető megfigyelesunk, hogy amig 2007-ig a novekedest elsősorban Budapest es vonzaskorzete generalta, addig a fővaros 2010-től mar egyertelműen visszafogta novekedesi utemet, egyre inkabb lemaradva tobb volt szocialista EU-­tagallam fővarosatol. Az adatokbol egy terbeli paradoxon rajzolodik ki: annak ellenere, hogy a gazdasagi novekedes alapvető tenyezői – peldaul a kepzett munkaerő, a K  F – a fővaros tersegeben koncentralodnak, itt szinte stagnal a novekedes, es csokken a munkatermelekenyseg. Az a negy-ot megye elenkiti a gazdasagot, amelyben kulfoldi erdekeltsegű feldolgozoipar műkodik, mig a tobbi megye – azok is, ahol egyetemi kozpontok vannak – a jelentős EU-forrasok ellenere csak mersekelten jarul hozza a kibocsatas fokozasahoz. Ha a gazdasagpolitika nem veszi figyelembe a gazdasag terbeli műkodesenek sajatossagait es az ezekhez kapcsolodo regiospecifikus szakpolitikai intezkedesek szuksegesseget, akkor az orszag gazdasagi novekedese a lehetősegekhez kepest tovabbra is visszafogott es serulekeny marad. Journal of Economic Literature (JEL) kod: O18, O40, R11.

The four Visegrad countries, the Czech Republic, Poland, Hungary, and Slovakia acceded to the European Union in 2004. Their inhabitants had high hopes of the accession, and according to more eager expectations, their standard of living could have caught up with that of the developed Western members within a few years. “Catching up”, “rapprochement” and “convergence” are multi-layered concepts used in various interpretations, but in less developed countries and regions they have been desired aims for around the last one and a half centuries. It is also one of the key objectives of European Union regional policy to accelerate the development of less developed regions and bring them up to level with the rest of the member states. In our study we examine the success of the catching-up process of this four, historically and socio-economically similar, moderately developed post-socialist countries between 2000 and 2014. We take the NUTS3 level as the basis of examination. Our key question is whether there was an observable process of catching up and, if yes, was it similar or significantly different for the different counties. We analyze GDP per capita trends in Purchasing Power Standard, and we study catching up inequalities with the help of entropy based Theil indexes. We provide a detailed analysis of two influencing factors, namely national processes and the possible role of the counties’ largest cities as beneficiaries of potential agglomeration economies. Based on the data, catching up is evident in the case of all four countries, although along two different trajectories. While the Czech and Hungarian economies halted between 2006 and 2008, the Slovakian and Polish economies developed relatively steadily throughout. In terms of achieved level and catching up, we categorized four county types. The county development is determined by the country effect and the role of national economic policies and institutions, including regional policy and regional development. The dynamic and high-level development of capital regions, especially in the case of Warsaw and Bratislava, is outstanding, while Budapest and its region, and Prague to some extent have stagnated in the past years. The population of the counties, and of their largest city in particular, is closely linked to the pace of catching up and the achieved level. All of the metropolitan regions reached a high level, but they strongly varied in terms of extent. In case of counties having a town of fewer than about 100 thousand inhabitants, both the achieved level and the extent of catching up correlated with the size of their largest city, presumably exploiting localization agglomeration economies. The role of settlement network is evident in the success of catching up, like in the case of the Polish polycentric settlement system, while in Hungary the “second-tier” towns were too small to provide a seat for the global corporates.