De Rham compatible Deep Neural Network FEM.

On general regular simplicial partitions T of bounded polytopal domains Ω⊂Rd, d∈{2,3}, we construct exact neural network (NN) emulations of all lowest order finite element spaces in the discrete de Rham complex. These include the spaces of piecewise constant functions, continuous piecewise linear (CPwL) functions, the classical "Raviart-Thomas element", and the "Nédélec edge element". For all but the CPwL case, our network architectures employ both ReLU (rectified linear unit) and BiSU (binary step unit) activations to capture discontinuities. In the important case of CPwL functions, we prove that it suffices to work with pure ReLU nets. Our construction and DNN architecture generalizes previous results in that no geometric restrictions on the regular simplicial partitions T of Ω are required for DNN emulation. In addition, for CPwL functions our DNN construction is valid in any dimension d≥2. Our "FE-Nets" are required in the variationally correct, structure-preserving approximation of boundary value problems of electromagnetism in nonconvex polyhedra Ω⊂R3. They are thus an essential ingredient in the application of e.g., the methodology of "physics-informed NNs" or "deep Ritz methods" to electromagnetic field simulation via deep learning techniques. We indicate generalizations of our constructions to higher-order compatible spaces and other, non-compatible classes of discretizations, in particular the "Crouzeix-Raviart" elements and Hybridized, Higher Order (HHO) methods.

Crystal structure and Hirshfeld surface analysis of N-{[diphen-yl(vin-yl)sil-yl]meth-yl}-2-methyl-propan-2-ammonium chloride.

N-{[Diphen-yl(vin-yl)sil-yl]meth-yl}-2-methyl-propan-2-amine, C19H25NSi, is a newly synthesized secondary amino-methyl-silane that can be used, for example, to study carboli-thia-tion reactions of vinyl-silanes. Because the neutral compound did not crystallize well, the hydro-chloride salt, C19H26NSi+·Cl-, was formed, in which the two chloride ions in the asymmetric unit have crystallographic site symmetry. An unusually long Si-C bond of 1.9117 (10) Šis observed in the cation, which may be ascribed to electronic effects due to the ß N+ species. In the crystal, the cations and anions are linked by N-H⋯Cl hydrogen bonds to generate [001] chains. To further investigate the inter-molecular inter-actions, a Hirshfeld surface analysis was performed, which showed that H⋯H, C⋯H/H⋯C and H⋯Cl/Cl⋯H contacts contribute 70.4, 20.0 and 8.3%, respectively.

Comparing efficacy and side effects of two systemic chemotherapy regimens for eye-preserving therapy in children with retinoblastoma.

BACKGROUND: Eye-preserving therapy in retinoblastoma comprises systemic chemotherapy, but studies analyzing the efficacy of different chemotherapy regimens are scarce. METHODS: The efficacy and side effects of two different eye-preserving chemotherapy regimens containing either vincristine, etoposide, and carboplatin (VEC) or cyclophosphamide, vincristine, etoposide, and carboplatin (CyVEC) were compared in a prospective non-interventional observational study including children diagnosed with retinoblastoma between 2013 and 2019 in Germany and Austria. Event-free eye survival (EFES) and overall eye survival (OES) of all 164 eyes treated with both regimens and risk factors were investigated. RESULTS: The EFES after VEC (2-year EFES 72.3%) was higher than after CyVEC (2-year EFES 50.4%) (plogrank  < .001). The OES did not differ significantly between the two treatment groups (plogrank  = .77; 2-year OES VEC: 82.1% vs. CyVEC: 84.8%). Advanced International Classification of Retinoblastoma (ICRB) group was prognostic for a lower EFES (plogrank  < .0001; 2-year EFES ICRB A/B/C 71.3% vs. ICRB D/E 43.0%) and OES (plogrank  < .0001; 2-year OES ICRB A/B/C 93.1% vs. ICRB D/E 61.5%). The multivariate analysis showed that age at diagnosis older than 12 months and ICRB A/B/C were associated with better EFES. No second malignancies or ototoxicities were reported after a follow-up of median 3.1 years after diagnosis of retinoblastoma (range 0.1-6.9 years). CONCLUSIONS: Despite omitting cyclophosphamide, the EFES was higher after VEC chemotherapy that contains higher doses of carboplatin compared to CyVEC. The major risk factor for enucleation was advanced ICRB tumor grouping. Randomized clinical trials on efficacy and side effects of eye-preserving chemotherapy are required to tailor treatment protocols for retinoblastoma patients.

DeepCME: A deep learning framework for computing solution statistics of the chemical master equation.

Stochastic models of biomolecular reaction networks are commonly employed in systems and synthetic biology to study the effects of stochastic fluctuations emanating from reactions involving species with low copy-numbers. For such models, the Kolmogorov's forward equation is called the chemical master equation (CME), and it is a fundamental system of linear ordinary differential equations (ODEs) that describes the evolution of the probability distribution of the random state-vector representing the copy-numbers of all the reacting species. The size of this system is given by the number of states that are accessible by the chemical system, and for most examples of interest this number is either very large or infinite. Moreover, approximations that reduce the size of the system by retaining only a finite number of important chemical states (e.g. those with non-negligible probability) result in high-dimensional ODE systems, even when the number of reacting species is small. Consequently, accurate numerical solution of the CME is very challenging, despite the linear nature of the underlying ODEs. One often resorts to estimating the solutions via computationally intensive stochastic simulations. The goal of the present paper is to develop a novel deep-learning approach for computing solution statistics of high-dimensional CMEs by reformulating the stochastic dynamics using Kolmogorov's backward equation. The proposed method leverages superior approximation properties of Deep Neural Networks (DNNs) to reliably estimate expectations under the CME solution for several user-defined functions of the state-vector. This method is algorithmically based on reinforcement learning and it only requires a moderate number of stochastic simulations (in comparison to typical simulation-based approaches) to train the "policy function". This allows not just the numerical approximation of various expectations for the CME solution but also of its sensitivities with respect to all the reaction network parameters (e.g. rate constants). We provide four examples to illustrate our methodology and provide several directions for future research.

Cotinine and cytokine levels in the vitreous body and blood serum of smokers and non-smokers - A pilot study.

Tobacco smoking is a risk factor for many ocular diseases. Of the multiple tobacco smoke compounds nicotine and its main metabolite cotinine are likely agents in disease modulation. The interaction of these compounds with exposed tissue is complex and ranges from proinflammatory to potentially neuroprotective properties. We aimed to determine cotinine and cytokines in the vitreous in smokers and non-smokers in this prospective, cross-sectional study at the Department of Ophthalmology, Medical University Graz, Austria. We included 10 smokers and 10 non-smokers. Vitreous and serum samples were analyzed for cotinine and cytokines. The cytokine analysis was performed with multiplex assay and cotinine was quantified with enzyme-linked immunosorbent assay. Cotinine was detectable in smokers only with a mean of 154.0 ng/ml ± 107.3 ng/ml in the vitreous and of 194.1 ng/ml ± 121.3 ng/ml in the serum. The difference between intraocular and systemic levels was statistically significant. There were no statistically significant differences between the cytokine levels of smokers and non-smokers. However, intravitreal VEGF-A was by trend elevated in smokers and correlated positively with intravitreal cotinine (r = 0.59, p = 0.073). In conclusion cotinine is detectable in the vitreous of smokers and is lower than the serum. There is a trend towards elevation of VEGF-A in the vitreous of smokers.

Long-term oncological and functional follow-up in low-dose-rate brachytherapy for prostate cancer: results from the prospective nationwide Swiss registry.

OBJECTIVE: To evaluate the long-term oncological, functional and toxicity outcomes of low-dose-rate brachytherapy (LDR-BT) in relation to risk factors and radiation dose in a prospective multicentre cohort. PATIENTS AND METHODS: Data of patients from 12 Swiss centres undergoing LDR-BT from September 2004 to March 2018 were prospectively collected. Patients with a follow-up of ≥3 months were analysed. Functional and oncological outcomes were assessed at ~6 weeks, 6 and 12 months after implantation and annually thereafter. LDR-BT was performed with 125 I seeds. Dosimetry was done 6 weeks after implantation based on the European Society for Radiotherapy and Oncology recommendations. The Kaplan-Meier method was used for biochemical recurrence-free survival (BRFS). A prostate-specific antigen (PSA) rise above the PSA nadir + 2 was defined as biochemical failure. Functional outcomes were assessed by urodynamic measurement parameters and questionnaires. RESULTS: Of 1580 patients in the database, 1291 (81.7%) were evaluable for therapy outcome. The median (range) follow-up was 37.1 (3.0-141.6) months. Better BRFS was found for Gleason score ≤3+4 (P = 0.03, log-rank test) and initial PSA level of <10 ng/mL (P < 0.001). D'Amico Risk groups were significantly associated with BRFS (P < 0.001), with a hazard ratio of 2.38 for intermediate- and high-risk patients vs low-risk patients. The radiation dose covering 90% of the prostate volume (D90) after 6 weeks was significantly lower in patients with recurrence. Functional outcomes returned close to baseline levels after 2-3 years. A major limitation of these findings is a substantial loss to follow-up. CONCLUSION: Our results are in line with other studies showing that LDR-BT is associated with good oncological outcomes together with good functional results.

Vitreous albumin redox state in open-angle glaucoma patients and controls: a pilot study.

PURPOSE: Numerous studies suggest that reactive oxygen species play a crucial role in the development of glaucoma. Since glaucoma patients exhibit posterior vitreous detachment earlier than controls, it has been suggested that reactive oxygen species-increased in glaucoma-also affect the vitreous. In the present study we evaluated the influence of open-angle glaucoma oxidative stress on the redox state of vitreous albumin. METHODS: Albumin redox states of the vitreous and plasma were evaluated in 22 subjects-11 open-angle glaucoma patients and 11 controls-matched for age, gender, and vitreous state. According to the redox state of cysteine-34, albumin can be separated into: human mercaptalbumin (the thiol form), human nonmercaptalbumin1 (a reversible modification due to mild oxidation), and human nonmercaptalbumin2 (an irreversible modification due to severe oxidation). RESULTS: Albumin of both, the open-angle glaucoma group and the control group, was more oxidized in the vitreous compared to plasma. Furthermore, significantly higher human nonmercaptalbumin1 fractions were found in the vitreous of open-angle glaucoma patients compared to controls. No significant differences were found in the plasma albumin fractions between the groups. CONCLUSION: Our results support the hypothesis that oxidative stress plays a crucial role in open-angle glaucoma and that reactive oxygen species in glaucomatous eyes may also affect the vitreous.

Gender differences in albumin and ascorbic acid in the vitreous antioxidant system.

Ascorbic acid is present at high concentrations in the vitreous and plays a central role in vitreous redox chemistry. Albumin is the main protein in the vitreous with antioxidant properties and occurs in different oxidation states, which can be used as redox indicators, but have not been studied in the vitreous. This study, therefore, addressed the vitreous redox state of cysteine-34 of albumin in relation to the ascorbic acid content, which has been suggested to exert a main function in detoxifying reactive oxygen in the vitreous. A total of 58 vitreous samples obtained from patients undergoing vitrectomy were analyzed for (i) human mercaptalbumin (HMA), the reduced thiol form; (ii) human non-mercaptalbumin1 (HNA1), a reversible oxidative modification with a disulfide at cysteine-34; and (iii) human non-mercaptalbumin2 (HNA2), a non-reversibly (highly) oxidized form of albumin; as well as (iv) ascorbic acid concentrations, to study possible relations. In addition, blood samples were taken to compare albumin redox state between plasma and the vitreous. Vitreous albumin showed greater variability in the redox state of cysteine-34 and a shift to the oxidized fractions compared to plasma albumin (P < 0.001). A strong positive relation was observed between the vitreous ascorbic acid concentrations and the reversibly oxidized form, HNA1 (P < 0.001), and a negative relation with the reduced form, HMA. Positive relations between ascorbic acid and HNA1 in the vitreous were stronger in men than in women. In contrast to HMA and HNA1, there was a distinct gender difference noted for the irreversibly oxidized form, HNA2. While males showed a positive relation between the vitreous ascorbic acid concentrations and HNA2, there was no correlation found with HNA2 in females. Our results support the view that ascorbic acid, by decreasing either directly or indirectly the concentrations of molecular oxygen, generates hydrogen peroxide, and that thiols, including HMA, are acting as antioxidants. This study for the first time provides evidence that vitreous albumin can be used as a marker molecule for the appearance of reactive oxygen species in the vitreous of patients undergoing vitrectomy. Moreover, it can be shown that there are gender differences in vitreous ascorbic acid and albumin concentrations as well as in oxidation state of vitreous albumin.

Shared Decision-Making for Patients with Advanced Urological Malignancies: Evaluation of a Joint Urological-Oncological Clinic Model.

BACKGROUND: To provide rapid evaluation of patients with advanced urological malignancies, a joint urological-oncological clinic was initiated at our institution in January 2015. We present the first 3-year evaluation of this joint urological-oncological clinic in Switzerland. METHOD: We performed a retrospective analysis of the characteristics and treatment of all patients reviewed at the joint clinic between January 2015 and December 2017. Statistical analysis was performed by survival analysis. A patient satisfaction questionnaire was handed out to new patients (from April to September 2017). RESULTS: A total of 135 new patients were counseled in the joint clinic and 563 consultations were performed in the period from January 2015 to December 2017. The majority were men with prostate cancer (85%), followed by bladder cancer (9%), and renal cell carcinoma (4%). Men with newly diagnosed metastatic prostate cancer (n = 69) received ADT alone (57%), ADT with docetaxel or abiraterone (33%), and metastasis-directed therapy (10%). High rates of patient satisfaction were reported based on the questionnaire. CONCLUSIONS: The joint clinic model has been successfully implemented at our institution and continues on a weekly basis. The clinic is increasingly used, not only for newly diagnosed metastatic prostate cancer, but also for other complex uro-oncological cases. The clinic allows optimized oncological treatment without delay and with a reduced effort for patients.

A Retrospective Study of 199 Xen45 Stent Implantations From 2014 to 2016.

PURPOSE: The aim of this study is to determine the postoperative course after Xen45 Gel Stent implantation at the Medical University of Graz from 2014-2016. METHODS: Single-center, retrospective study. All patients with Xen implantation between 2014 and 2016 were included. Clinical records and reports received from supervising ophthalmologists were used for evaluations. Investigated parameters were intraocular pressure (IOP), the number of medications, visual acuity, and the number of previous operations, IOP-follow-up, intraoperative and postoperative complications, the rate of interventions (needling), and additionally performed surgeries. RESULTS: Xen was implanted in 199 eyes of 160 patients. Mean preoperative IOP was 22.8±6.9 mm Hg on 2.9±1.0 IOP-lowering medication. After 12 months follow-up, mean IOP was 17.1±5.9 mm Hg (n=89, P<0.0001; mean reduction of 22.7%) on 1.8±1.4 (n=87; P<0.0001) IOP-lowering medications. There were no intraoperative complications and in two cases (1.0%) severe postoperative adverse events occurred (aqueous misdirection and late-onset endophthalmitis). Postoperative needling was indicated in 44 cases (22.1%), while in 28 cases (14.1%) an additional glaucoma surgery was performed. CONCLUSIONS: Our results indicate that Xen implantation is an effective surgical intervention leading to a significant reduction of IOP and number of medications with a low rate of complications. An attentive postoperative management seems to be mandatory.

Late seed migration after prostate brachytherapy with Iod-125 permanent implants.

BACKGROUND: Seed migration is a common finding after low dose rate brachytherapy of the prostate. It has often been assessed soon after implantation, but little is known about late seed migration. We evaluated the incidence, site, symptoms, and therapeutic consequences of late seed migration more than 3 years postoperatively. MATERIALS AND METHODS: We retrospectively examined the data of 63 unselected patients with transrectal ultrasound-guided, transperineal low dose rate brachytherapy of the prostate with stranded seeds between 2001 and 2010. A pelvic X-ray was taken the day after implantation and after 6 weeks in combination with a pelvic computed tomography/magnetic resonance imaging scan (image fusion) for dosimetry. Late radiological follow-up with a further pelvic and chest X-ray was conducted 3 or more years postoperatively. We differed between seed loss without anatomical detection and seed migration into another anatomical region. RESULTS: We found seed loss up to 3 years and more after brachytherapy in 36 of 63 patients (57%). Between one and nine seeds had been lost. Late seed migration after 3 or more years occurred in two of 36 patients (6%), with pelvic migration of one seed and extrapelvic migration of one seed to the lung and two seeds to the liver, respectively. All late seed migrations were asymptomatic and had no therapeutic consequences. CONCLUSION: Beside a frequent number of seed losses, seed migration 3 or more years after implantation was as well a frequent finding but seems to be asymptomatic. Long-term follow-up with complementary radiological controls could be helpful in detecting any rare complications.

Iris Freckles a Potential Biomarker for Chronic Sun Damage.

Purpose: To investigate the role of sunlight exposure in iris freckles formation. Methods: We prospectively examined volunteers attending a skin cancer screening program conducted by ophthalmologists and dermatologists. Frequency and topographical variability of iris freckles were noted and associated with behavioral and dermatologic characteristics indicating high sun exposure. Results: Six hundred thirty-two participants (n = 360; 57% female) were examined. Mean age of all participants was 38.4 ± 18.4 years (range, 4-84 years). Of all individuals, 76.1% (n = 481) exhibited at least one iris freckle. Most freckles were observed in the inferior temporal quadrant. The presence of iris freckles was associated with higher age (participants with iris freckles: 41.8 ± 16.8 years versus participants without iris freckles: 27.6 ± 19.2 years), a high number of sunburns during lifetime (>10: 31% vs. 19%), sunlight-damaged skin (26% vs. 11%), presence of actinic lentigines (72% vs. 45%), and a high total nevus body count (>10; 78% vs. 67%). Conclusions: The association of iris freckles, behavioral factors, and dermatologic findings, as well as the topographical distribution, indicate that sunlight exposure may trigger the formation of iris freckles. The evaluation of iris freckles offers an easily accessible potential biomarker, which might be helpful in indicating sun damage on the skin associated with cutaneous malignancies. Furthermore, the evaluation of iris freckles could also be helpful in understanding the role of sunlight in several ophthalmologic diseases.

Absorption of Irrigation Fluid During Thulium Laser Vaporization of the Prostate.

PURPOSE: To assess the prevalence and extent of irrigation fluid absorption during thulium laser vaporization of the prostate. MATERIAL AND METHODS: Fifty-four patients undergoing thulium laser vaporization of the prostate were prospectively included into the trial at a tertiary referral center. Isotonic saline containing 1% ethanol was used for intraoperative irrigation. Absorption of irrigation fluid was measured periodically during the operation using the expired breath ethanol technique. Among others, intra- and postoperative changes in biochemical and hematological laboratory findings were assessed. RESULTS: Absorption of irrigation fluid was detected in 7 out of 54 (13%) patients with a median absorption volume of 265 mL (227-615). No significant differences of intra- and postoperative blood parameters were observed between absorbers and nonabsorbers. No risk factor (i.e., age, prostate size, surgery duration, applied energy, and amount of irrigation fluid) for the occurrence of fluid absorption could be identified. CONCLUSION: Absorption of irrigation fluid also occurs during thulium laser vaporization of the prostate and should be kept in mind, especially in patients at a high cardiovascular risk. However, compared with previously assessed resection and vaporization techniques, thulium vaporization might have a favorable safety profile regarding fluid absorption.

Prevalence of posterior vitreous detachment in glaucoma patients and controls.

PURPOSE: To evaluate the impact of oxidative stress - present in glaucoma - on the vitreous. We therefore compare the presence of early and late stages of posterior vitreous detachment (PVD) between patients with glaucoma and controls. METHODS: The vitreous state was evaluated by the combination of optical coherence tomography and ultrasound. The main outcome was the vitreous state classified into 'no PVD', 'initial PVD' and 'advanced PVD'. RESULTS: We evaluated the vitreous state in 48 patients with glaucoma (age: mean 66.5 ± 11.9 years; visual field deviation: mean 10.4 ± 6.8 dB) and compared the results with 101 previously investigated controls (age: mean 73.6 ± 9.3 years). After one-to-one matching on age and sex, ordinal logistic regression revealed that patients with glaucoma were significantly more likely to exhibit advanced PVD stages compared to non-glaucoma patients (OR 2.60, 95% confidence interval: 1.06-6.36, p = 0.037). CONCLUSION: Our results suggest that the presence or absence of PVD might be a valuable hint for diagnosing glaucoma - however, further research is needed to determine whether PVD can be used to supplement current glaucoma screening guidelines.

[How Does one Avoid Micturition? A Question That not Only Children ask]. / Wie vermeidet man die Miktion? Eine Frage, die sich nicht nur Kinder stellen.

We report the history of a 53-year-old kiosk woman who presented with acute urinary retention. The diagnosis of an underactive bladder could be established, which can emerge when the bladder is chronically overstretched, which, in her case, was due to long phases without micturition due to her obligation to care for the kiosk. Despite therapeutic approaches with myocholine and sacral neuromodulation the hypercapacity of the bladder remained. The therapy still consists of a suprapubic cystostomy.

A Unifying Concept of Uveal Pigment Cell Distribution and Dissemination Based on an Animal Model: Insights into Ocular Melanogenesis.

Pigmented cells are derived from neural crest cells, which migrate along the peripheral nerve sheets into their specific final region. During their migration, cells progressively acquire pigment-producing capabilities, maturation, and the shape of melanocytes. These insights, along with specific clinical characteristics of melanocytic nevi, have led to new concepts of cutaneous, periocular, and iris nevogenesis. To further elucidate the specific ocular embryogenic melanoblast distribution and dissemination - that could explain the distinct distribution of uveal melanocytic neoplasms - we investigated the ocular pigmentation of dogs affected by a specific mutation called Merle, which results in either pigment- (wild type) or non-pigment- (mutated type) producing cells. Based on our observations, we propose a unifying concept of uveal pigment cell distribution and dissemination, which postulates melanoblast migration and maturation following the trigeminal V1 branch and, later, their entrance into the eye along the ciliary nerves and their finest iris branches. Our concept provides an explanation not only for the specific distribution of ocular melanocytic lesions, including uveal and iris nevi, but also for the different locations depending on the metastatic potential of the ocular melanoma. Though speculative, the higher metastatic potential of posterior uveal melanomas compared to iris melanomas may be related to a less differentiated stage in the maturation of migrating melanocytes in the posterior segment compared to the anterior segment of the eye. However, there is a need of further studies focusing on cell differentiation markers of melanocytes at different locations in the eye.

Dermoscopy in the era of dermato-oncology: from bed to bench side and retour.

Today dermoscopy is standard-of-care in the diagnosis and management of patients with benign and malignant skin tumors because it increases the diagnostic accuracy of skin lesions compared to the naked-eye examination up to 25%. Despite its role in the routine dermato-oncology, it increasingly gained interest as a bridge connecting clinical with basic molecular research in dermato-oncology. Here, we correlate dermoscopy patterns of nevi and melanomas with high and low susceptibility genes and somatic mutations, provide an overview on the clinical and dermoscopic patterns of cutaneous melanoma subtypes, and highlight the role of dermoscopy in the diagnosis of skin eruptions during systemic treatments of advanced melanoma including targeted therapies and immunotherapies.