[ANDROMEDA-an investigation of factors influencing the adherence of patients with neovascular age-related macular degeneration using the newly developed patient questionnaire LAF-IVT]. / ANDROMEDA ­ Eine Untersuchung von Einflussfaktoren auf die Adhärenz von Patienten mit neovaskulärer altersabhängiger Makuladegeneration mithilfe des neu konzipierten Patientenfragebogens LAF-IVT.

BACKGROUND: Lack of adherence to treatment is a widespread problem in the anti-VEGF (Vascular Endothelial Growth Factor) treatment of patients with neovascular age-related macular degeneration (nAMD). In contrast to the extent of the lack of treatment adherence, there is so far insufficient evidence for elucidating the causes of nonadherence. The ANDROMEDA study was initiated to investigate the influencing factors on the adherence of nAMD patients to treatment. The focus of the study was on patient reported endpoints, as the perceptions and experiences of the patients are of enormous importance for the investigation of the various aspects of adherence to treatment. OBJECTIVE: This publication presents the design of the ANDROMEDA study as well as the development of a new patient questionnaire for the assessment of barriers to treatment within the design of the study. MATERIAL AND METHODS: This prospective noninterventional observational study to assess the compliance of patients with nAMD and anti-VEGF treatment was started at the end of January 2019. It is planned to include 1000 patients in 120 study centers throughout Germany with an observational period of 24 months. Patient interviews on general and vision-related quality of life, treatment satisfaction and possible barriers to treatment will be conducted at the beginning and after 4, 12 and 24 months. All patient visits will be documented by the study centers as part of the clinical routine. To date, there has been no suitable instrument for recording patient-related circumstances and potential barriers to anti-VEGF treatment. Therefore, a specific patient questionnaire for longitudinal assessment of adherence factors to intravitreal (anti-VEGF) therapy (LAF-IVT) was developed as part of the study concept. The questionnaire, developed by an expert panel, was tested via qualitative interviews for its cognitive characteristics ahead of its use. RESULTS: The results of the study are expected in early 2023. The cognitive examination of the LAF-IVT confirmed the feasibility of the new questionnaire. The practicability and significance of the new instrument can be assessed after completion of the quantitative data collection. CONCLUSION: The symptoms, barriers, burdens and quality of life effects experienced by patients influence the adherence to treatment and thus the outcome. A better understanding of the patient's views and experiences is the basis for long-term optimization of care.

Current insights into animal models of Graves' disease and orbitopathy.

Graves' disease (GD) is a systemic autoimmune disease that is characterized by hyperthyroidism, orbitopathy and in rare cases dermopathy. Graves' orbitopathy (GO) is an inflammatory disease of eye and orbit which occurs in about 30-60% of patients. Hyperthyroidism occurs due to the presence of stimulating TSHR-autoantibodies (TRAbs) leading to increased serum levels of thyroid hormones. Attempts to induce Graves' disease in mice by immunization against the hTSHR or its variants have resulted in production of TRAbs that stimulate thyroid follicular cells to increase thyroid hormone secretion. Graves' like orbital changes, such as inflammation, adipogenesis and muscle fibrosis are more difficult to induce. In this review we summarize different methods used to induce murine Graves'-like disease and their impact on murine orbits.

Examination of orbital tissues in murine models of Graves' disease reveals expression of UCP-1 and the TSHR in retrobulbar adipose tissues.

Over the past decade a number of murine models of Graves' disease (GD) have been described. The full symptom complex, including typical orbital changes, however, could not yet be induced. In this report, we examined the influence of modified immunization protocols on orbital pathology. C57BL/6 and BALB/c mice were immunized against the human TSH receptor (TSHR), using either a TSHR encoding plasmid or a TSHR A-subunit adenovirus. Prior to immunization with the TSHR plasmid, regulatory T cells were depleted in one group of each strain. TSHR-stimulating antibodies (TSAbs) were evaluated and orbits were stained immunohistochemically for F4/80, uncoupling protein-1 (UCP-1) and the TSHR. We found that after depletion of regulatory T cells, incidence of TSAb was increased in TSHR plasmid immunized C57BL/6 mice. Examination of early immunized mice showed no antibody production. However, a TSHR epitope-specific cellular immune response could be detected by tetramer-analyses. Adenoviral immunization lead to TSAb production in all but one animal. Analysis of F4/80 positive cells in retrobulbar fat revealed no significant macrophage infiltration in the orbits of immunized mice. Immunohistochemical staining shows co-localization of F4/80 positive cells, UCP-1 and the TSHR in retrobulbar fat. Though targets for TSHR autoimmunity could clearly be shown, immunization methods were not efficient enough to cause clear signs of orbital inflammation.

The T393C polymorphism of the Galphas gene (GNAS1) is associated with the course of Graves' disease.

Genotypes of the T393C SNP of GNAS1, a gene that encodes for the Galphas subunit of G proteins have been significantly associated with the clinical course in a variety of cancers. Since this SNP may also influence the course of Graves' disease (GD) and, especially, Graves' ophthalmopathy (GO), we determined genotype and allele frequency in a series of 359 patients, which were referred to our clinic within 6 months of the onset of GO. Among them, 336 patients also suffered from associated hyperthyroidism. Data on relapse and remission rates 12 months after termination of a 1 year antithyroid drug therapy was available for 276 patients. As controls, 820 healthy individuals were recruited. Our data suggest that the T393C SNP does not represent a risk factor for the development of both GD and GO. It was, however, significantly associated with the course of hyperthyroidism (p=0.013) and a similar trend was evident for the course of GO (p=0.093). Homozygous TT carriers showed a significantly increased risk (p=0.03) for hyperthyroidism to relapse (OR 2.4; 95% CI 1.1-5.4). Also, the TT genotype was associated with significantly increased serum TRAb levels (CC+CT: 5.4 IU/l vs. TT: 9.3 IU/l). This is probably caused by increased G-Protein susceptibility to TSHR-mediated stimulation through TRAb. Genotyping of the T393C SNP of GNAS1 may become a useful additional tool to predict the clinical course of GD and GO. This may allow the clinician to identify patients at risk for more severe courses of disease and to come to more timely decisions for treatment.

Current insights into the pathogenesis of Graves' orbitopathy.

Graves' orbitopathy (GO) is part of an autoimmune disease constellation comprising hyperthyroidism, orbitopathy, pretibial myxedema, and acropachy. Signs and symptoms of GO occur due to inflammation of the orbital connective tissue, inflammation and fibrosis of the extraocular muscles, and adipogenesis. Stimulatory TSH receptor (TSHR) antibodies (TRAb) cause hyperthyroidism, but pathogenetic mechanisms in the orbit are less clear. The TSHR is one of the favoured candidate antigens; others such as the IGF1R might also play a role. Compared with other anatomical locations, orbital fibroblasts are extremely reactive to inflammatory stimuli, especially via CD40 activation. Orbital fibroblasts also differentiate into adipocytes, in response to the prevailing inflammatory cytokine milieu. Consequently TSHR gene expression increases together with expression of adipogenesis related genes. The same genes that confer susceptibility to Graves' disease (GD), both thyroid specific and immunoregulatory, also influence GO, although an increasing number of candidate genes with higher impact on orbitopathy are being identified. Smoking is the only environmental factor known to increase the likelihood and severity of GO developing in GD patients. A robust animal model of GO would facilitate the evaluation of new treatments. To date most models have centered on provoking autoimmune responses to the TSHR, but other antigens, alone or in combination with this receptor, hopefully will succeed in inducing the full spectrum of GD.

Evaluation of colitis: usefulness of CT enterography technique.

Computed tomographic enterography (CTE) is a useful technique for evaluating the small bowel and has the capability to include the colon for evaluation of patients with inflammatory bowel disease (IBD). The aims of this study are (1) to determine if CTE is a sensitive method for detecting Crohn colitis and ulcerative colitis and (2) to assess the accuracy of determining the extent and activity of colonic disease in patients with proven IBD. Seventy patients (35 patients with proven colitis at colonoscopy and 35 negative patients with a proven normal colon) having both a CTE examination and recent colonoscopy formed the retrospective study group. A radiologist evaluated the examinations in a blinded fashion for disease presence, activity, and extent. Sensitivity was 93% for the detection of moderate and severe disease in well-distended colons. Specificity was 91%. In good to excellent distended colons, mild, moderate, and severe disease was detected with a sensitivity of 67%, 90%, and 100%, respectively. Severe disease activity was commonly underestimated, and mild disease when detected was usually overestimated. The full extent of colonic disease at CTE was usually underestimated. CTE is a valid technique for detecting colitis in the colon in patients with IBD. Better methods for assessing disease activity and extent are needed.

Adenoviral p53 gene transfer inhibits human Tenon's capsule fibroblast proliferation.

BACKGROUND/AIM: Although antiproliferative drugs have been used successfully to prevent scarring after filtration surgery in patients with glaucoma, complications associated with their use (such as hypotony or endophthalmitis) energise the search for an alternative treatment. Single application of beta radiation leads to long term growth arrest and expression of p53 in human Tenon's capsule fibroblasts (hTf). The authors assume that the activation of p53 is one of the cellular triggers. Their aim was to analyse the effect of p53 overexpression on hTf and to determine which pathways are involved. METHODS: A recombinant adenoviral vector (rAd.p53) containing transgenes encoding for human p53 and green fluorescent protein (GFP) was used to induce overexpression of p53 in hTF and a control vector (rAd.GFP). Transgene expression was detected by western blot (p53 and p21WAF-1/Cip1). Cell proliferation and viability were investigated using cell counts, 5'-bromodeoxyuridine incorporation (BrdU assay) and tetrazolium reduction (MTT assay). RESULTS: Infection of hTf with rAd.p53 resulted in significant inhibition of cell proliferation, DNA synthesis, and metabolic activity in vitro. Western blot showed increased levels of p53 and p21WAF-1/Cip1 in rAd.p53 infected cells, but not in rAd.GFP and uninfected cells. Apoptosis was excluded with flow cytometry. CONCLUSIONS: Adenoviral p53 gene transfer leads to significant growth inhibition in hTf. P53 induces p21(WAF-1/Cip1) expression and does not cause apoptosis in hTf in vitro. p53 as an antiproliferative drug has the potential to replace mitomycin C and 5-fluorouracil in glaucoma surgery.

CT colonography: determination of optimal CT technique using a novel colon phantom.

The aim of this study was to determine the thickest slice at the lowest radiation dose for detection of colon polyps larger than 5mm in diameter at computed tomographic (CT) colonography. A colon phantom containing haustral folds, flexures, and straight segments was constructed of borosilicate. One hundred forty simulated polyps (5, 7, 10, and 12 mm) of various shapes (sessile, flat, and pedunculated) were attached at different colon locations (wall, base of fold, on the fold and fold tip). Polyps were positioned parallel, perpendicular, and oblique to the CT gantry. The air-filled phantom was scanned at different slice thicknesses (1.25-5 mm) and x-ray tube currents (5-308 mA). All polyps were identified in all data sets except one (1.25 mm slice thickness, 5 mA). In this acquisition, image noise reduced polyp visibility, and five of 140 (3%) polyps could not be identified. Unidentified polyps were 5 mm, flat or sessile in shape, located on the colon wall or base of the fold, and oblique or parallel to CT gantry. All tested CT techniques provided optimal polyp detection except settings at 1.25 mm and 5 mAs. Thin collimation (<5 mm) scans may not be necessary to detect clinically significant polyps.

Accuracy of models for indirect posterior restorations.

Effects of materials and techniques on the accuracy of models used to make indirect restorations was measured using a 4-unit posterior model containing a MOD and full crown preparation. Improved stone and fast setting epoxy dies backed with either improved stone or a thermoplastic hot melt stone were made from single-viscosity addition silicone impressions. Technique variations included heating or not heating the impression, cooling and pouring dies and placement of the hot melt stone on set or unset epoxy. The dimensions of the MOD (L, W, H) and of the crown (W, H) dies were measured at 1 and 24 h. No clinically significant changes occurred between 1 and 24 h. The stone control reproduced the dimensions of the master die best, and models made by pouring epoxy into the impression followed by immediate pouring of the hot melt stone gave the poorest reproduction. Other variations in technique using epoxy for the anatomical portion gave no practical differences in accuracy. Of the epoxy dies, those prepared from a previously heated impression with hot melt poured after the epoxy set had the best values; however, epoxy dies were smaller than stone dies. The fast set epoxy was noteworthy for rapid processing and sharp detail, however, negative changes for W and H of the crown and H and L of the MOD showed that a die spacer would be essential in the preparation of indirect restorations.

Population growth and rural-urban migration, with special reference to Ghana.

PIP: While the population of Ghana is expected to double in 25 years at the current rate of increase (approximately 2.5% per annum), the population of urban centers is increasing even faster. The 1970 census shows the urban population growing by 4.8% per annum. This is mainly the result of rural to urban migration and, to a smaller extent, the increase in the number of urban centers from 39 in 1948 to 98 in 1960 to 135 in 1970. In the 1970 census only 57.1% of the population were enumerated in their locality of birth and only 20.9% in a locality other than their place of birth but in the same region. 4.1% were born outside Ghana, mostly in another West African country. 1 striking difference between urban and rural areas is the differing sex ratio of the working population. In rural areas there are 91.0 males aged 15-64 years for every 100 females while in urban areas there are 107.1. Most migration in Africa is for employment and those most likely to migrate are working-age males. Because secondary schools are scarce in rural areas, urban dwellers generally have a higher education level. There are no significant differences between overall labor force participation rates for females. The nationwide participation rate was 38.9% for both males and females (males 43.8%, females 34.1%); in urban areas the total was 40.0% (males 46.3%, females 33.7%) and in rural areas 38.5% (males 42.7%, females 34.3%). Ghanaian women have traditionally occupied a prominent place in the labor force. The theory that urban migration is due to urban-rural income disparities is not confirmed by figures. Considering the high amount of unemployment in urban areas, a rural dweller can average as much as a city dweller. In fact, poorly educated migrants are the ones most affected by urban unemployment. A recent study by Kodwo Ewusi considered the impact of many variables on migration; he found depressed social conditions at the place of origin are more compelling motivations than economic factors but that once people decide to migrate, they base their choice of destination primarily on economic opportunities available at that end. Distance bears little relationship to choice of destination. To stem this tide efforts need to be made to increase rural income, provide employment opportunities for those displaced as agriculture becomes more efficient, and to provide for greater amenities in rural areas. Urban unemployment is an ever-increasing problem, accentuated by population growth and migration. Intensive rural development is needed to reverse this trend.^ieng