[Interdisciplinary Management of Orbital Diseases]. / Interdisziplinäre Therapie der Erkrankungen der Orbita.

Diagnosis and therapy of orbital diseases is an interdisciplinary challenge, in which i.e. otorhinolaryngologists, ophthalmologists, radiologists, radiation therapists, maxillo-facial surgeons, endocrinologists, and pediatricians are involved. This review article describes frequent diseases which both, otolaryngologists and ophthalmologists are concerned with in interdisciplinary settings. In particular the inflammatory diseases of the orbit including orbital complications, autoimmunological diseases of the orbit including Grave´s orbitopathy, and primary and secondary tumors of the orbit are discussed. Beside describing the clinical characteristics and diagnostic steps the article focusses on the interdisciplinary therapy. The review is completed by the presentation of most important surgical approaches to the orbit, their indications and possible complications. The authors tried to highlight the relevant facts despite the shortness of the text.

The 2021 European Group on Graves' orbitopathy (EUGOGO) clinical practice guidelines for the medical management of Graves' orbitopathy.

Graves' orbitopathy (GO) is the main extrathyroidal manifestation of Graves' disease (GD). Choice of treatment should be based on the assessment of clinical activity and severity of GO. Early referral to specialized centers is fundamental for most patients with GO. Risk factors include smoking, thyroid dysfunction, high serum level of thyrotropin receptor antibodies, radioactive iodine (RAI) treatment, and hypercholesterolemia. In mild and active GO, control of risk factors, local treatments, and selenium (selenium-deficient areas) are usually sufficient; if RAI treatment is selected to manage GD, low-dose oral prednisone prophylaxis is needed, especially if risk factors coexist. For both active moderate-to-severe and sight-threatening GO, antithyroid drugs are preferred when managing Graves' hyperthyroidism. In moderate-to-severe and active GO i.v. glucocorticoids are more effective and better tolerated than oral glucocorticoids. Based on current evidence and efficacy/safety profile, costs and reimbursement, drug availability, long-term effectiveness, and patient choice after extensive counseling, a combination of i.v. methylprednisolone and mycophenolate sodium is recommended as first-line treatment. A cumulative dose of 4.5 g of i.v. methylprednisolone in 12 weekly infusions is the optimal regimen. Alternatively, higher cumulative doses not exceeding 8 g can be used as monotherapy in most severe cases and constant/inconstant diplopia. Second-line treatments for moderate-to-severe and active GO include (a) the second course of i.v. methylprednisolone (7.5 g) subsequent to careful ophthalmic and biochemical evaluation, (b) oral prednisone/prednisolone combined with either cyclosporine or azathioprine; (c) orbital radiotherapy combined with oral or i.v. glucocorticoids, (d) teprotumumab; (e) rituximab and (f) tocilizumab. Sight-threatening GO is treated with several high single doses of i.v. methylprednisolone per week and, if unresponsive, with urgent orbital decompression. Rehabilitative surgery (orbital decompression, squint, and eyelid surgery) is indicated for inactive residual GO manifestations.

Asymmetry indicates more severe and active disease in Graves' orbitopathy: results from a prospective cross-sectional multicentre study.

PURPOSE: Patients with Graves' orbitopathy can present with asymmetric disease. The aim of this study was to identify clinical characteristics that distinguish asymmetric from unilateral and symmetric Graves' orbitopathy. METHODS: This was a multi-centre study of new referrals to 13 European Group on Graves' Orbitopathy (EUGOGO) tertiary centres. New patients presenting over a 4 month period with a diagnosis of Graves' orbitopathy were included. Patient demographics were collected and a clinical examination was performed based on a previously published protocol. Patients were categorized as having asymmetric, symmetric, and unilateral Graves' orbitopathy. The distribution of clinical characteristics among the three groups was documented. RESULTS: The asymmetric group (n = 83), was older than the symmetric (n = 157) group [mean age 50.9 years (SD 13.9) vs 45.8 (SD 13.5), p = 0.019], had a lower female to male ratio than the symmetric and unilateral (n = 29) groups (1.6 vs 5.0 vs 8.7, p < 0.001), had more active disease than the symmetric and unilateral groups [mean linical Activity Score 3.0 (SD 1.6) vs 1.7 (SD 1.7), p < 0.001 vs 1.3 (SD 1.4), p < 0.001] and significantly more severe disease than the symmetric and unilateral groups, as measured by the Total Eye Score [mean 8.8 (SD 6.6) vs 5.3 (SD 4.4), p < 0.001, vs 2.7 (SD 2.1), p < 0.001]. CONCLUSION: Older age, lower female to male ratio, more severe, and more active disease cluster around asymmetric Graves' orbitopathy. Asymmetry appears to be a marker of more severe and more active disease than other presentations. This simple clinical parameter present at first presentation to tertiary centres may be valuable to clinicians who manage such patients.

Lessons from mouse models of Graves' disease.

Graves' disease (GD) is an autoimmune condition with the appearance of anti-TSH receptor (TSHR) autoantibodies in the serum. The consequence is the development of hyperthyroidism in most of the patients. In addition, in the most severe cases, patients can develop orbitopathy (GO), achropachy and dermopathy. The central role of the TSHR for the disease pathology has been well accepted. Therefore immunization against the TSHR is pivotal for the creation of in vivo models for the disease. However, TSHR is well preserved among the species and therefore the immune system is highly tolerant. Many differing attempts have been performed to break tolerance and to create a proper animal model in the last decades. The most successful have been achieved by introducing the human TSHR extracellular domain into the body, either by injection of plasmid or adenoviruses. Currently available models develop the whole spectrum of Graves' disease-autoimmune thyroid disease and orbitopathy and are suitable to study disease pathogenesis and to perform treatment studies. In recent publications new immunomodulatory therapies have been assessed and also diseaseprevention by inducing tolerance using small cyclic peptides from the antigenic region of the extracellular subunit of the TSHR.

Detector-Agnostic Phase-Space Distributions.

The representation of quantum states via phase-space functions constitutes an intuitive technique to characterize light. However, the reconstruction of such distributions is challenging as it demands specific types of detectors and detailed models thereof to account for their particular properties and imperfections. To overcome these obstacles, we derive and implement a measurement scheme that enables a reconstruction of phase-space distributions for arbitrary states whose functionality does not depend on the knowledge of the detectors, thus defining the notion of detector-agnostic phase-space distributions. Our theory presents a generalization of well-known phase-space quasiprobability distributions, such as the Wigner function. We implement our measurement protocol, using state-of-the-art transition-edge sensors without performing a detector characterization. Based on our approach, we reveal the characteristic features of heralded single- and two-photon states in phase space and certify their nonclassicality with high statistical significance.

Quantum-enhanced interferometry with large heralded photon-number states.

Quantum phenomena such as entanglement can improve fundamental limits on the sensitivity of a measurement probe. In optical interferometry, a probe consisting of N entangled photons provides up to a N enhancement in phase sensitivity compared to a classical probe of the same energy. Here, we employ high-gain parametric down-conversion sources and photon-number-resolving detectors to perform interferometry with heralded quantum probes of sizes up to N = 8 (i.e. measuring up to 16-photon coincidences). Our probes are created by injecting heralded photon-number states into an interferometer, and in principle provide quantum-enhanced phase sensitivity even in the presence of significant optical loss. Our work paves the way towards quantum-enhanced interferometry using large entangled photonic states.

Quantum interference enables constant-time quantum information processing.

It is an open question how fast information processing can be performed and whether quantum effects can speed up the best existing solutions. Signal extraction, analysis, and compression in diagnostics, astronomy, chemistry, and broadcasting build on the discrete Fourier transform. It is implemented with the fast Fourier transform (FFT) algorithm that assumes a periodic input of specific lengths, which rarely holds true. A lesser-known transform, the Kravchuk-Fourier (KT), allows one to operate on finite strings of arbitrary length. It is of high demand in digital image processing and computer vision but features a prohibitive runtime. Here, we report a one-step computation of a fractional quantum KT. The quantum d-nary (qudit) architecture we use comprises only one gate and offers processing time independent of the input size. The gate may use a multiphoton Hong-Ou-Mandel effect. Existing quantum technologies may scale it up toward diverse applications.

[Evaluation of the medical treatment situation of the visually impaired : Significant differences between young and old]. / Evaluation der Versorgungssituation von Sehbehinderten : Signifikante Unterschiede zwischen Jung und Alt.

BACKGROUND AND OBJECTIVE: Patients with irreversible visual impairment need individual visual rehabilitation to regain or improve reading ability and mobility. To analyze the prescription of low vision aids (LVA) and their relation to age, we performed a retrospective chart analysis of our specialized low vision outpatient clinic. METHODS: Patient charts of all patients who attended our low vision outpatient clinic from 2014-2016 were analyzed with respect to the diagnosis, visual acuity, magnification needs, age and prescribed or used LVA. RESULTS: The evaluation comprised data from 1548 patients (age 0-97 years). Most patients (72%) were underage (<18 years). Retinoblastoma (11%), congenital cataract (10%) and age-related macular degeneration (AMD, 6%) were the most frequent diagnoses. Mean magnification need of the 568 patients with LVAs was 9.9 ± 7. Desktop video magnifiers (22%), cut-off filter spectacles (15%) and electronic magnifiers (13%) were most commonly prescribed. Children and juveniles used smart phones and tablets (smart devices) as a LVA significantly more often (8% vs. 0.6%, p < 0.01) compared to older visually impaired patients (>60 years). Electronic magnifying devices were more often prescribed to these older patients (30% vs. 3%, p < 0.01). CONCLUSION: The visual rehabilitation showed significant differences between underage and older visually impaired patients. Children and juveniles needed electronic magnifiers less often because they used smart devices as a mobile LVA. This significant difference might be due to much lower social stigmatization of smart devices and the higher affinity to technology of this age group. Based on the positive experiences of younger visually impaired patients, such smart devices should also be introduced to older patients.

[Management of anticoagulants in ophthalmic surgery-a survey among ophthalmic surgeons in Germany]. / Umgang mit gerinnungshemmenden Substanzen in der Ophthalmochirurgie ­ eine Umfrage unter Ophthalmochirurgen in Deutschland.

INTRODUCTION: As our population ages and comorbidities rise, ophthalmic surgeons are increasingly faced with patients on anticoagulant therapy or with clotting disorders. The ophthalmic surgeon has to weigh the perioperative risk of haemorrhage when anticoagulation continues against the risk of thromboembolism caused by discontinuation or changing the patient's medication (bridging, switching, cessation). There are currently no guidelines or recommendations. METHODS: A survey was sent to the DOG (German Ophthalmologic Society) divisions and associated surgical organizations to determine the status quo. A questionnaire was sent out and filled out by the different groups of specialists. RESULTS: All four divisions of the DOG and four associated organizations returned completed questionnaires. Surgical interventions were listed that are carried out during anticoagulant therapy without exceptions, as well as interventions that were classified to require medical adjustment. Although the assessments varied, general consensus was achieved regarding interventions not requiring adjustments due to anticoagulants (i. e., intravitreal injection, cataract surgery, laser and corneal operations, simple muscle surgery), and those interventions requiring adjustments in medications (glaucoma operations, complex retina surgery, eye socket surgery, complex surgery of the lid). CONCLUSION: Main result of this survey was the specification of serious bleeding complications which are permanent vision loss and re-operation. They could serve as endpoint parameters for essential future investigations. Nevertheless, this survey makes clear that the decision about an adjustment of anticoagulant medication in ophthalmic surgery is currently made individually and not based on established standards.

Genetic immunization with mouse thyrotrophin hormone receptor plasmid breaks self-tolerance for a murine model of autoimmune thyroid disease and Graves' orbitopathy.

Experimental models of Graves' hyperthyroid disease accompanied by Graves' orbitopathy (GO) can be induced efficiently in susceptible inbred strains of mice by immunization by electroporation of heterologous human TSH receptor (TSHR) A-subunit plasmid. In this study, we report on the development of a bona fide murine model of autoimmune Graves' disease induced with homologous mouse TSHR A-subunit plasmid. Autoimmune thyroid disease in the self-antigen model was accompanied by GO and characterized by histopathology of hyperplastic glands with large thyroid follicular cells. Examination of orbital tissues showed significant inflammation in extra-ocular muscle with accumulation of T cells and macrophages together with substantial deposition of adipose tissue. Notably, increased levels of brown adipose tissue were present in the orbital tissue of animals undergoing experimental GO. Further analysis of inflammatory loci by 19 F-magnetic resonance imaging showed inflammation to be confined to orbital muscle and optic nerve, but orbital fat showed no difference in inflammatory signs in comparison to control ß-Gal-immunized animals. Pathogenic antibodies induced to mouse TSHR were specific for the self-antigen, with minimal cross-reactivity to human TSHR. Moreover, compared to other self-antigen models of murine Graves' disease induced in TSHR knock-out mice, the repertoire of autoantibodies to mouse TSHR generated following the breakdown of thymic self-tolerance is different to those that arise when tolerance is not breached immunologically, as in the knock-out models. Overall, we show that mouse TSHR A-subunit plasmid immunization by electroporation overcomes tolerance to self-antigen to provide a faithful model of Graves' disease and GO.

Carrier photogeneration, drift and recombination in a semiconducting carbon nanotube network.

Charge carrier photogeneration, drift and recombination in thin film networks of polymer-wrapped (6,5)-single-wall carbon nanotubes (SWNTs) blended with phenyl-C61-butyric acid methyl ester (PCBM) have been investigated by using transient photocurrent and time-delayed collection field (TDCF) techniques. Three distinct transient photocurrent components on the nano- and microsecond timescales have been identified. We attribute the dominant (>50% of total extracted charge) ultrashort photocurrent component with a decay time below our experimental time-resolution of 2 ns to the intratube hole motion. The second component on the few microsecond timescale is attributed to the intertube hole transfer, while the slowest component is assigned to the electron drift within the PCBM phase. The hole drift distance appears to be limited by gaps in the nanotube percolation network rather than by hole trapping or recombination. Photocurrent saturation was observed when excitation densities reached more than one charge pair per nanotube; we attribute this to the local electric field screening.

Detector-Independent Verification of Quantum Light.

We introduce a method for the verification of nonclassical light which is independent of the complex interaction between the generated light and the material of the detectors. This is accomplished by means of a multiplexing arrangement. Its theoretical description yields that the coincidence statistics of this measurement layout is a mixture of multinomial distributions for any classical light field and any type of detector. This allows us to formulate bounds on the statistical properties of classical states. We apply our directly accessible method to heralded multiphoton states which are detected with a single multiplexing step only and two detectors, which are in our work superconducting transition-edge sensors. The nonclassicality of the generated light is verified and characterized through the violation of the classical bounds without the need for characterizing the used detectors.

Graves' orbitopathy as a rare disease in Europe: a European Group on Graves' Orbitopathy (EUGOGO) position statement.

BACKGROUND: Graves' orbitopathy (GO) is an autoimmune condition, which is associated with poor clinical outcomes including impaired quality of life and socio-economic status. Current evidence suggests that the incidence of GO in Europe may be declining, however data on the prevalence of this disease are sparse. Several clinical variants of GO exist, including euthyroid GO, recently listed as a rare disease in Europe (ORPHA466682). The objective was to estimate the prevalence of GO and its clinical variants in Europe, based on available literature, and to consider whether they may potentially qualify as rare. Recent published data on the incidence of GO and Graves' hyperthyroidism in Europe were used to estimate the prevalence of GO. The position statement was developed by a series of reviews of drafts and electronic discussions by members of the European Group on Graves' Orbitopathy. The prevalence of GO in Europe is about 10/10,000 persons. The prevalence of other clinical variants is also low: hypothyroid GO 0.02-1.10/10,000; GO associated with dermopathy 0.15/10,000; GO associated with acropachy 0.03/10,000; asymmetrical GO 1.00-5.00/10,000; unilateral GO 0.50-1.50/10,000. CONCLUSION: GO has a prevalence that is clearly above the threshold for rarity in Europe. However, each of its clinical variants have a low prevalence and could potentially qualify for being considered as a rare condition, providing that future research establishes that they have a distinct pathophysiology. EUGOGO considers this area of academic activity a priority.

Identification of nonclassical properties of light with multiplexing layouts.

In Sperling et al. [Phys. Rev. Lett. 118, 163602 (2017)], we introduced and applied a detector-independent method to uncover nonclassicality. Here, we extend those techniques and give more details on the performed analysis. We derive a general theory of the positive-operator-valued measure that describes multiplexing layouts with arbitrary detectors. From the resulting quantum version of a multinomial statistics, we infer nonclassicality probes based on a matrix of normally ordered moments. We discuss these criteria and apply the theory to our data which are measured with superconducting transition-edge sensors. Our experiment produces heralded multiphoton states from a parametric down-conversion light source. We show that the known notions of sub-Poisson and sub-binomial light can be deduced from our general approach, and we establish the concept of sub-multinomial light, which is shown to outperform the former two concepts of nonclassicality for our data.

Identification of an AR Mutation-Negative Class of Androgen Insensitivity by Determining Endogenous AR Activity.

CONTEXT: Only approximately 85% of patients with a clinical diagnosis complete androgen insensitivity syndrome and less than 30% with partial androgen insensitivity syndrome can be explained by inactivating mutations in the androgen receptor (AR) gene. OBJECTIVE: The objective of the study was to clarify this discrepancy by in vitro determination of AR transcriptional activity in individuals with disorders of sex development (DSD) and male controls. DESIGN: Quantification of DHT-dependent transcriptional induction of the AR target gene apolipoprotein D (APOD) in cultured genital fibroblasts (GFs) (APOD assay) and next-generation sequencing of the complete coding and noncoding AR locus. SETTING: The study was conducted at a university hospital endocrine research laboratory. PATIENTS: GFs from 169 individuals were studied encompassing control males (n = 68), molecular defined DSD other than androgen insensitivity syndrome (AIS; n = 18), AR mutation-positive AIS (n = 37), and previously undiagnosed DSD including patients with a clinical suspicion of AIS (n = 46). INTERVENTION(S): There were no interventions. MAIN OUTCOME MEASURE(S): DHT-dependent APOD expression in cultured GF and AR mutation status in 169 individuals was measured. RESULTS: The APOD assay clearly separated control individuals (healthy males and molecular defined DSD patients other than AIS) from genetically proven AIS (cutoff < 2.3-fold APOD-induction; 100% sensitivity, 93.3% specificity, P < .0001). Of 46 DSD individuals with no AR mutation, 17 (37%) fell below the cutoff, indicating disrupted androgen signaling. CONCLUSIONS: AR mutation-positive AIS can be reliably identified by the APOD assay. Its combination with next-generation sequencing of the AR locus uncovered an AR mutation-negative, new class of androgen resistance, which we propose to name AIS type II. Our data support the existence of cellular components outside the AR affecting androgen signaling during sexual differentiation with high clinical relevance.

Free-space spectro-temporal and spatio-temporal conversion for pulsed light.

We present a new apparatus for converting between spectral and temporal representation of optical information, designed for operating with pulsed light sources. Every input pulse is converted into a pulse train in which the pulse intensities represent the spatial or temporal frequency spectrum of the original pulse. This method enables spectral measurements to be performed by following the temporal response of a single detector and, thus, is useful for real-time spectroscopy and imaging, and for spectral correlation measurements. The apparatus is based on multiple round-trips inside a 2f-cavity-like mirror arrangement in which the spectrum is spread on the back focal plane, and a small section of it is allowed to escape after each round-trip. Unlike existing methods, it relies neither on fibers nor on interference effects. It offers easy wavelength range tunability, and a prototype built achieves over 10% average efficiency in the near infrared (NIR). We demonstrate the application of the prototype for an efficient measurement of the joint spectrum of a non-degenerate bi-photon source in which one of the photons is in the NIR.

The Effect of Early Thyroidectomy on the Course of Active Graves' Orbitopathy (GO): A Retrospective Case Study.

The aim of the work was to investigate the effect of early thyroidectomy on the course of active Graves' orbitopathy (GO) in patients with low probability of remission [high TSH receptor antibody (TRAb) serum levels, severe GO] compared to that of continued therapy with antithyroid drugs. Two cohorts were evaluated retrospectively (total n=92 patients with active GO, CAS≥4). Forty-six patients underwent early thyroidectomy (Tx-group) 6±2 months after initiation of antithyroid drug (ATD) therapy, while ATD was continued for another 6±2 months in the ATD-group (n=46). These controls were consecutively chosen from a database and matched to the Tx-group. GO was evaluated (activity, severity, TRAb) at baseline and at 6 month follow-up. At baseline, both cohorts were virtually identical as to disease severity, activity and duration, as well as prior anti-inflammatory treatment, age, gender, and smoking behavior. At 6 month follow-up, NOSPECS severity score was significantly decreased within each group, but did not differ between both groups. However, significantly more patients of the Tx-group presented with inactive GO (89.1 vs. 67.4%, * p=0.02), and mean CAS score was significantly lower in Tx-group (2.1) than in ADT-group (2.8; * p=0.02) at the end of follow-up. TRAb levels declined in both groups (Tx-group: from 18.6 to 5.2 vs. ATD-group: 12.8-3.2 IU/l, p0=0.07, p6months=0.32). Residual GO activity was lower in Tx-group, associated with a higher rate of inactivation of GO. This allows an earlier initiation of ophthalmosurgical rehabilitation in patients with severe GO, which may positively influence quality of life of the patients.

[Graves' ophthalmopathy]. / Endokrine Orbitopathie.

Graves' orbitopathy (GO) is the main extrathyroidal manifestation of Graves' disease and the full clinical picture can impair the quality of life of the patients considerably. Active inflammation can often be effectively treated by intravenous steroids/immunosuppression, however does not lead to full remission, since inflammation rather quickly results in irreversible fibrosis and increase of orbital fat. Very important is the control of risk factors (smoking cessation, good control of thyroid function, selenium supplementation) to prevent progression to severe stages. Treatment should rely on a thorough assessment of activity and severity of GO. Rehabilitative surgery (orbital decompression, squint surgery, eyelid surgery) is needed in many patients to restore function and appearance. Anti-thyroid-stimulating hormone (TSH) receptor antibodies do specifically occur in these patients and correlate to the course of thyroid and eye disease. The levels of these antibodies can be used for treatment decisions at certain time points of the disease.