Comparability of input parameters in the German Retina.net ROP registry and the EU-ROP registry - An exemplary comparison between 2011 and 2021.

PURPOSE: The German Retina.net ROP registry and its Europe-wide successor, the EU-ROP registry, collect data from patients treated for ROP. This analysis compares input parameters of these two registries to establish a procedure for joint analyses of different registry data using exemplary datasets from the two registries. METHODS: Exemplary datasets from the two databases over a 1-year period each (German Retina.net ROP Registry, 2011, 22 infants; EU-ROP Registry, 2021, 44 infants) were compared. The parameters documented in the two databases were aligned and analysed regarding demographic parameters, treatment modalities, complications within first 24 h and retreatments. RESULTS: The current analysis showed that data can be aligned for joint analyses with some adjustments within the data structure. The registry with more detailed data collection (EU-ROP) needs to be reduced regarding granularity in order to align the different registries, as the registry with lower granularity determines the level of analyses that can be performed in a comparative approach. In the exemplary datasets, we observed that the overall most common ROP severity in both registries was zone II, 3+ (2011: 70.5%; 2021: 65%), with decreasing numbers of clock hours showing preretinal neovascularisations (2011: 10-12 clock hours in 29% of cases, 2021: 4-6 clock hours in 38%). The most prevalent treatment method was laser coagulation in 2011 (75%) and anti-VEGF therapy in 2021 (86.1%). Within the anti-VEGF group, all patients were treated with bevacizumab in 2011 and with ranibizumab in 2021. Retreatment rates were comparable in 2011 and 2021. CONCLUSION: Data from two different ROP registries can be aligned and jointly analysed. The analysis reveals a paradigm shift in treatment modalities, from predominantly laser to anti-VEGF, and within the anti-VEGF group from bevacizumab to ranibizumab in Germany. In addition, there was a trend towards earlier treatment in 2021.

[Technical aspects of quality assurance for intravitreal injections (IVI)]. / Technische Umsetzung der Qualitätssicherung bei der intravitrealen operativen Medikamenteneingabe (IVOM).

BACKGROUND: Successful quality assurance in intravitreal injection (IVI) of medications requires a complex information technology infrastructure. The main challenges are data availability independent of location, standardization of clinical data, integration of extensive and currently non-standardized image documentation from coherence tomography and compliance with data protection regulations. OBJECTIVE: In this article the technical implementation and data protection principles are reviewed. MATERIAL AND METHODS: Essential aspects in the implementation of quality assurance in the field of IVI are discussed in a systematic approach. RESULTS: In the field of network architectures web-based applications supplemented by local virtual private networks (VPN) and/or other software instances have recently replaced the previously commonly used physical data medium exchange. The standardization of the data, e.g. by converting the visual acuity into logMAR, plays an important role in the collection of treatment data. Multiple non-standardized data formats in optical coherence tomography complicate the general quality assurance structure and comparability of data. CONCLUSION: International standards will probably facilitate this in the near future. Until then individual solutions have to be found on site.

Necrotizing enterocolitis after intravitreal bevacizumab in an infant with Incontinentia Pigmenti - a case report.

BACKGROUND: Incontinentia Pigmenti is a rare disease affecting multiple organs. Fifty of patients show affection of the eye with retinopathy and possible amaurosis being the worst outcome. Treatment has commonly been panretinal laser coagulation but intravitreal application of bevacizumab as VEGF-inhibitor has shown to effectively suppress retinal neovascularization. CASE PRESENTATION: A six-week-old female infant with Incontinentia Pigmenti developed a foudroyant necrotizing enterocolitis shortly after intravitreal injection of bevazicumab due to a retinopathy with impending tractional detachment of the left eye. Since the onset of abdominal symptoms occurred immediately after the intravitreal application, a link between the two events seemed likely. Sequential analyses of the VEGF serum concentrations showed a massive suppression of endogenous VEGF with only a very slow recovery over weeks. Such a severe systemic adverse event has not been reported after intravitreal treatment with bevacizumab in an infant. CONCLUSION: This case report shows a relevant systemic uptake of bevacizumab after intravitreal application as suppressed VEGF levels show. There seems to be a connection between suppressed VEGF levels and the onset of necrotizing enterocolitis. Therefore, treatment with bevacizumab should be carefully considered and further research is needed to assess this drug's safety profile.

Electrostatic deflector studies using small-scale prototype electrodes.

The search for electric dipole moments of particles in storage rings requires the development of dedicated electrostatic deflector elements. The JEDI prototype-ring design consists of more than 50 electric deflectors of 1 m length with 60 mm spacing between the plates with electric fields of 10 MV m-1. This paper presents studies of scaled-down uncoated prototype electrodes with 10 mm radius made of stainless steel. The electric field at electrode gap distances from 1 mm to 0.05 mm increased from 15 to 90 MV m-1. In future investigations, we will study different materials and coatings at similar electrode spacings. Preparations are also underway to study large deflector elements.

[Treated cases of retinopathy of prematurity in Germany : 5-year data from the Retina.net ROP registry]. / Behandelte Frühgeborenenretinopathie in Deutschland : 5-Jahres-Daten des Retina.net ROP-Registers.

BACKGROUND: Retinopathy of prematurity (ROP) is one of the main reasons for childhood blindness. The number of infants requiring treatment, however, is low for individual centers. The Retina.net ROP registry has been founded to allow a joint analysis of treatment patterns and courses post treatment. OBJECTIVE: This paper reports treatment patterns over 5 years. MATERIAL AND METHODS: All infants born between January 2011 and December 2015 who were entered into the treatment registry by one of the 12 participating centers were analyzed. RESULTS: The data of 150 infants (292 eyes) were analyzed and ROP 3+ in zone II was the most prevalent treatment indication. Gestational age and birth weight remained stable over the years. The treatment patterns, however, changed with anti-VEGF treatment (bevacizumab or ranibizumab) accounting for only 10% of treated eyes in 2011 but for 56% and 30% in 2014 and 2015, respectively. Almost all eyes with AP-ROP or zone I disease received anti-VEGF treatment. Zone II disease was predominantly treated with laser photocoagulation. Recurrences were more common and appeared later in the anti-VEGF group compared to the laser group (23%/interval 60 days vs. 17%/interval 23 days). Perioperative complications were evenly distributed across treatment groups. CONCLUSION: The data in this analysis represent about 10-15% of treated infants in Germany. The results provide evidence for an increasing use of anti-VEGF agents for ROP. The data reflect a selection bias for anti-VEGF treatment in eyes with a more aggressive disease. This needs to be considered when interpreting data such as disease recurrence rates. The risk for late recurrences after anti-VEGF treatment is of particular clinical significance.

Secondary prevention and lifestyle indices after stroke in a long-term perspective.

OBJECTIVES: To describe the long-term perspective regarding prevalence of risk factors, secondary stroke prevention, and lifestyle indices after stroke. METHODS: From a population-based one-year cohort (n = 416), we performed an observational study of 145 survivors at 16 months and 10 years after stroke (age 27-97 years) regarding secondary prevention including reaching acceptable treatment goals; nutritional status with focus on underweight; and the lifestyle indices: living situation, level of dependence, and self-assessed health condition. RESULTS: Ten years after stroke, 50% of the subjects with hypertension diagnosis and 55% of those without hypertension diagnosis were within the blood pressure goal <140/90 compared with 32% (P = .008) and 37% (N.S.) at 16 months. Acceptable HbA1c levels among subjects with diabetes mellitus diagnosis increased from 35% to 45% (N.S.). Among those without diabetes diagnosis, satisfactory HbA1c levels decreased from 98% to 79% (P < .001). Underweight increased from 9% to 17% (P = .019). Among patients with cerebral infarction, the prevalence of atrial fibrillation increased from 22% to 29% (P = .004), and treatment with oral anticoagulants from 75% to 78% (N.S.). Acceptable LDL cholesterol levels increased from 59% to 80% (P = .033) among subjects on lipid lowering treatment, and from 18% to 40% among untreated (P = .010). At 10 years, 90% still lived in their own home. Health condition was reported as good/very good/excellent by 65%. Age, female sex, and living situation were associated with intensity of secondary prevention measures and underweight. CONCLUSIONS: The proportion of individuals within treatment goals improved over time, but secondary prevention still needed additional consideration 10 years after stroke.

[Screening for retinopathy of prematurity: Trends over the past 5 years in two German university hospitals]. / Frühgeborenenretinopathie-Screening: Trends über die vergangenen 5 Jahre an zwei deutschen Universitätskliniken.

BACKGROUND: The number of preterm births in Germany has been increasing continuously over the past decades. Retinopathy of prematurity (ROP) is a major complication of preterm birth and one of the leading causes of blindness in children. OBJECTIVES: This study analyzes the development of the incidence of ROP over the past 5 years at two German university hospitals, utilizing data from ROP screening examinations. MATERIAL AND METHODS: We assessed all children born in the years 2012-2016 who were included in the ROP screening program at two German university hospitals according to the criteria of the German ROP screening guidelines. Parameters such as gestational age, birth weight, ROP stage and zone, and need for therapeutic intervention were assessed. RESULTS: We analyzed the data of 863 children who had undergone a total of 4117 screening examinations. The number of children included in the screening program per study year increased continuously over the study period by a total of 43.1% (137 in 2012, 196 in 2016). Likewise, the number of screening examinations per year increased by 58.4% (608 in 2012, 963 in 2016). Overall, 27.5% of screened infants were diagnosed with ROP of any stage and 2.5% required treatment for ROP. The number of children diagnosed with ROP of any stage per year increased by 100.0% (32 in 2012, 64 in 2016). Mean gestational age (29.0 ± 3.0 weeks) and mean birth weight (1192 ± 513 g) remained stable over the study period. CONCLUSION: Screening data for ROP from two German university hospitals demonstrates a significant increase in both the number of screened infants and the number of infants affected by ROP over the past 5 years.

Effect of Partially Screened Nuclei on Fast-Electron Dynamics.

We analyze the dynamics of fast electrons in plasmas containing partially ionized impurity atoms, where the screening effect of bound electrons must be included. We derive analytical expressions for the deflection and slowing-down frequencies, and show that they are increased significantly compared to the results obtained with complete screening, already at subrelativistic electron energies. Furthermore, we show that the modifications to the deflection and slowing down frequencies are of equal importance in describing the runaway current evolution. Our results greatly affect fast-electron dynamics and have important implications, e.g., for the efficacy of mitigation strategies for runaway electrons in tokamak devices, and energy loss during relativistic breakdown in atmospheric discharges.

[Possibilities and Limitations of OCT-Angiography in Patients with Central Serous Chorioretinopathy]. / Möglichkeiten und Grenzen der OCT-Angiografie bei Patienten mit Chorioretinopathia centralis serosa.

Purpose Central serous chorioretinopathy (CSC) is a commonly acquired maculopathy characterized by the accumulation of subretinal fluid at the posterior pole. This study aims to analyze optical coherence tomography angiography (OCTA) findings in patients with acute and chronic CSC and to compare them to conventional imaging methods. Methods A series of 43 consecutive eyes of 29 patients diagnosed with CSC and 18 eyes of 9 healthy control subjects were included in this retrospective study. The OCTA images were assessed and compared to conventional fluorescence (FAG) and indocyanine green angiography (ICG). Results All CSC patients demonstrated abnormal areas of focal hypo- and hyperperfusion in the choriocapillaris. These were particularly evident in patients with chronic atrophic CSC. FAG and ICG imaging revealed leakage points in 10 of 43 eyes and choroidal neovascularization (CNV) in 3 of 43 eyes. OCTA imaging confirmed leakage points in 4 out of 10 cases and choroidal neovascularization in 2 out of 3 cases. In one case, OCTA demonstrated a CNV which was not detectable by FAG/ICG. Conclusion OCTA reveals areas of focal hypo- and hyperperfusion in the choriocapillaris in patients with CSC. Due to the inability to detect plasma flow, OCTA is not suitable to detect leakage points in CSC with confidence. However, OCTA reliably detects CNV in CSC even in the absence of exudative activity and may, therefore, represent an important supplement in the diagnosis of CSC.

Not a load of rubbish: simulated field trials in large-scale containers.

Assessment of yield performance under fluctuating environmental conditions is a major aim of crop breeders. Unfortunately, results from controlled-environment evaluations of complex agronomic traits rarely translate to field performance. A major cause is that crops grown over their complete lifecycle in a greenhouse or growth chamber are generally constricted in their root growth, which influences their response to important abiotic constraints like water or nutrient availability. To overcome this poor transferability, we established a plant growth system comprising large refuse containers (120 L 'wheelie bins') that allow detailed phenotyping of small field-crop populations under semi-controlled growth conditions. Diverse winter oilseed rape cultivars were grown at field densities throughout the crop lifecycle, in different experiments over 2 years, to compare seed yields from individual containers to plot yields from multi-environment field trials. We found that we were able to predict yields in the field with high accuracy from container-grown plants. The container system proved suitable for detailed studies of stress response physiology and performance in pre-breeding populations. Investment in automated large-container systems may help breeders improve field transferability of greenhouse experiments, enabling screening of pre-breeding materials for abiotic stress response traits with a positive influence on yield.

Fibroblast activation protein-α, a stromal cell surface protease, shapes key features of cancer associated fibroblasts through proteome and degradome alterations.

Cancer associated fibroblasts (CAFs) constitute an abundant stromal component of most solid tumors. Fibroblast activation protein (FAP) α is a cell surface protease that is expressed by CAFs. We corroborate this expression profile by immunohistochemical analysis of colorectal cancer specimens. To better understand the tumor-contextual role of FAPα, we investigate how FAPα shapes functional and proteomic features of CAFs using loss- and gain-of function cellular model systems. FAPα activity has a strong impact on the secreted CAF proteome ("secretome"), including reduced levels of anti-angiogenic factors, elevated levels of transforming growth factor (TGF) ß, and an impact on matrix processing enzymes. Functionally, FAPα mildly induces sprout formation by human umbilical vein endothelial cells. Moreover, loss of FAPα leads to a more epithelial cellular phenotype and this effect was rescued by exogenous application of TGFß. In collagen contraction assays, FAPα induced a more contractile cellular phenotype. To characterize the proteolytic profile of FAPα, we investigated its specificity with proteome-derived peptide libraries and corroborated its preference for cleavage carboxy-terminal to proline residues. By "terminal amine labeling of substrates" (TAILS) we explored FAPα-dependent cleavage events. Although FAPα acts predominantly as an amino-dipeptidase, putative FAPα cleavage sites in collagens are present throughout the entire protein length. In contrast, putative FAPα cleavage sites in non-collagenous proteins cluster at the amino-terminus. The degradomic study highlights cell-contextual proteolysis by FAPα with distinct positional profiles. Generally, our findings link FAPα to key aspects of CAF biology and attribute an important role in tumor-stroma interaction to FAPα.

Effective critical electric field for runaway-electron generation.

In this Letter we investigate factors that influence the effective critical electric field for runaway-electron generation in plasmas. We present numerical solutions of the kinetic equation and discuss the implications for the threshold electric field. We show that the effective electric field necessary for significant runaway-electron formation often is higher than previously calculated due to both (1) extremely strong dependence of primary generation on temperature and (2) synchrotron radiation losses. We also address the effective critical field in the context of a transition from runaway growth to decay. We find agreement with recent experiments, but show that the observation of an elevated effective critical field can mainly be attributed to changes in the momentum-space distribution of runaways, and only to a lesser extent to a de facto change in the critical field.

NF-κB-dependent DNA damage-signaling differentially regulates DNA double-strand break repair mechanisms in immature and mature human hematopoietic cells.

Hematopoietic stem and progenitor cells (HSPC), that is, the cell population giving rise not only to all mature hematopoietic lineages but also the presumed target for leukemic transformation, can transmit (adverse) genetic events, such as are acquired from chemotherapy or ionizing radiation. Data on the repair of DNA double-strand-breaks (DSB) and its accuracy in HSPC are scarce, in part contradictory, and mostly obtained in murine models. We explored the activity, quality and molecular components of DSB repair in human HSPC as compared with mature peripheral blood lymphocytes (PBL). To consider chemotherapy/radiation-induced compensatory proliferation, we established cycling HSPC cultures. Comparison of pathway-specific repair activities using reporter systems revealed that HSPC were severely compromised in non-homologous end joining and homologous recombination but not microhomology-mediated end joining. We observed a more pronounced radiation-induced accumulation of nuclear 53BP1 in HSPC relative to PBL, despite evidence for comparable DSB formation from cytogenetic analysis and γH2AX signal quantification, supporting differential pathway usage. Functional screening excluded a major influence of phosphatidylinositol-3-OH-kinase (ATM/ATR/DNA-PK)- and p53-signaling as well as chromatin remodeling. We identified diminished NF-κB signaling as the molecular component underlying the observed differences between HSPC and PBL, limiting the expression of DSB repair genes and bearing the risk of an inaccurate repair.

[Trisomy 21 in visual art]. / La trisomie 21 dans les arts visuels.

In 1866, J. Langdon Down published a paper on "an ethnic classification of idiots" and noted their facial resemblance with individuals of the Mongolian people. In 1959, J. Lejeune, M. Gautier, and R. Turpin demonstrated that the children with Down syndrome had an extra copy of chromosome 21. There is now a debate within the medical literature on the age of trisomy 21 as a disease affecting mankind. Since it was not described before 1866, some authors questioned whether this disease is an old or new condition in humans. Three methods of investigation are useful for demonstrating that trisomy 21 has been present in humans for a long time: the figuration of this condition in historical paintings, figurines, and pottery; its presence in old skeletal remains; and the origin of human chromosome 21 during primate phylogeny. Figurines strongly suggestive of trisomy 21 have been found in the Greco-Roman world, in many Central and South American pre-Columbian cultures, and in Khmer temples. In Europe, during the Renaissance, Italian and Flemish artists represented trisomy 21 in paintings of religious inspiration. Studies on the origin and pathology of chromosome 21 have shown that the ancestral human chromosome 21 arose 30-50 million years ago and that trisomy 21 has existed since time immemorial.

[VEGF inhibitors in vitreoretinal interventions]. / VEGF-Inhibitoren im Rahmen vitreoretinaler Eingriffe.

Vascular endothelial growth factor (VEGF) inhibitors are being used for an increasing number of indications. Beyond the classical use in exudative macular degeneration and macular edema, they are being used, for example off-label as additive treatment together with panretinal laser photocoagulation or in preparation for vitrectomy for ischemic retinopathy. In preparation for vitreoretinal surgery VEGF inhibitors are usually given prior to surgery. When given as an adjunct to laser treatment, VEGF inhibitors can be given either consecutively or parallel to laser photocoagulation. In most cases, however, anti-VEGF treatment does not render laser coagulation dispensable. The greatest danger with anti-VEGF treatment in the context of ischemic retinopathies lies in the fact that proliferative membranes are misjudged or overlooked. In these cases, anti-VEGF treatment can induce contraction of these membranes with induction of consecutive tractional retinal detachment. This review summarizes the current knowledge on VEGF inhibition as an adjunct to vitreoretinal surgery and also points out the gaps in the current knowledge and the need for further research.

Cathepsin proteases promote angiogenic sprouting and laser-induced choroidal neovascularisation in mice.

Cysteine cathepsins are a family of proteases involved in intracellular protein turnover and extracellular matrix degradation. Cathepsin B (Ctsb) and cathepsin Z (Ctsz) promote tumorigenesis and Ctsb is a known modulator of tumor angiogenesis. We therefore investigated the angiomodulatory function of these cathepsins in vitro as well as in a mouse model of laser-induced choroidal neovascularization (laser-CNV). Ctsb(-/-), Ctsz(-/-), Ctsb/Ctsz double-knockout (Ctsb/z DKO), and wild type (WT) mice underwent argon laser treatment to induce choroidal neovascularization (CNV). The neovascularized area was quantified individually for each lesion at 14 days after laser coagulation. In vitro the effects of cathepsin inhibitors on angiogenesis were analysed by endothelial cell (EC) spheroid sprouting and EC invadosome assays. Retinas from cathepsin KO mice did not show gross morphological abnormalities. In the laser CNV model, however, Ctsb/z DKO mice displayed a significantly reduced neovascularized area compared to WT (0.027 mm(2) vs. 0.052 mm(2); p = 0.012), while single knockouts did not differ significantly from WT. In line, VEGF-induced EC spheroid sprouting and invadosome formation were not significantly altered by a specific cathepsin B inhibitor alone, but significantly suppressed when more than one cathepsin was inhibited. Our results demonstrate that laser-CNV formation is significantly reduced in Ctsb/z DKO mice. In line, EC sprouting and invadosome formation are blunted when more than one cathepsin is inhibited in vitro. These results reveal an angiomodulatory potential of cathepsins with partial functional redundancies between different cathepsin family members.

[Pathogenesis of retinopathy of prematurity]. / Pathogenese der Frühgeborenenretinopathie.

Retinopathy of prematurity (ROP) is a complex disease with a multifactorial pathogenetic cascade that is still only partially understood. Important pathogenetic factors are gestational age at birth and birth weight. Potent postnatal factors are exposure to supplemental oxygen, slow weight gain and expression of angiogenic growth factors. Some of these crucial aspects of ROP pathogenesis will be discussed in this article and put into clinical context. With the introduction of intravitreal anti-VEGF (vascular endothelial growth factor) treatment into ROP therapy, the pathomechanistic role of VEGF in ROP deserves a special focus. Apart from VEGF, other factors will be discussed that may precede VEGF upregulation and thus may represent targets for an earlier and potentially protective intervention. Among these insulin-like growth factor 1 (IGF-1) appears to be most prominent. Finally, factors such as postnatal weight gain will be discussed in light of their potential role as screening parameters and their ability to predict ROP severity.

[Retinopathy of prematurity - pathophysiologic mechanisms and new treatment options]. / Frühgeborenenretinopathie - Pathophysiologische Grundlagen und aktuelle Behandlungsoptionen.

Retinopathy of prematurity (ROP), like other angioproliferative retinal disorders, has witnessed the advent of anti-VEGF therapy in clinical practice. The first report from the BEAT-ROP study published in 2011 represents the first comparison of anti-VEGF therapy versus conventional laser treatment in a randomised controlled trial. This review article investigates these novel aspects of ROP therapy from a pathophysiological angle and delineates the stages of ROP in which anti-VEGF treatment appears as a reasonable option. Furthermore, the novel chances of anti-VEGF therapy are being weighed against some still unanswered questions and novel study concepts are being presented.

Role of fatty acid transport protein 4 in oleic acid-induced glucagon-like peptide-1 secretion from murine intestinal L cells.

The antidiabetic intestinal L cell hormone glucagon-like peptide-1 (GLP-1) enhances glucose-dependent insulin secretion and inhibits gastric emptying. GLP-1 secretion is stimulated by luminal oleic acid (OA), which crosses the cell membrane by an unknown mechanism. We hypothesized that L cell fatty acid transport proteins (FATPs) are essential for OA-induced GLP-1 release. Therefore, the murine GLUTag L cell model was used for immunoblotting, [(3)H]OA uptake assay, and GLP-1 secretion assay as determined by radioimmunoassay following treatment with OA ± phloretin, sulfo-N-succinimidyl oleate, or siRNA against FATP4. FATP4(-/-) and cluster-of-differentiation 36 (CD36)(-/-) mice received intraileal OA, and plasma GLP-1 was measured by sandwich immunoassay. GLUTag cells were found to express CD36, FATP1, FATP3, and FATP4. The cells demonstrated specific (3)H[OA] uptake that was dose-dependently inhibited by 500 and 1,000 µM unlabeled OA (P < 0.001). Cell viability was not altered by treatment with OA. Phloretin and sulfo-N-succinimidyl oleate, inhibitors of protein-mediated transport and CD36, respectively, also decreased [(3)H]OA uptake, as did knockdown of FATP4 by siRNA transfection (P < 0.05-0.001). OA dose-dependently increased GLP-1 secretion at 500 and 1,000 µM (P < 0.001), whereas phloretin, sulfo-N-succinimidyl oleate, and FATP4 knockdown decreased this response (P < 0.05-0.01). FATP4(-/-) mice displayed lower plasma GLP-1 at 60 min in response to intraileal OA (P < 0.05), whereas, unexpectedly, CD36(-/-) mice displayed higher basal GLP-1 levels (P < 0.01) but a normal response to intraileal OA. Together, these findings demonstrate a key role for FATP4 in OA-induced GLP-1 secretion from the murine L cell in vitro and in vivo, whereas the precise role of CD36 remains unclear.