Development of a density-based topology optimization of homogenized lattice structures for individualized hip endoprostheses and validation using micro-FE.

Prosthetic implants, particularly hip endoprostheses, often lead to stress shielding because of a mismatch in compliance between the bone and the implant material, adversely affecting the implant's longevity and effectiveness. Therefore, this work aimed to demonstrate a computationally efficient method for density-based topology optimization of homogenized lattice structures in a patient-specific hip endoprosthesis. Thus, the root mean square error (RMSE) of the stress deviations between the physiological femur model and the optimized total hip arthroplasty (THA) model compared to an unoptimized-THA model could be reduced by 81 % and 66 % in Gruen zone (GZ) 6 and 7. However, the method relies on homogenized finite element (FE) models that only use a simplified representation of the microstructural geometry of the bone and implant. The topology-optimized hip endoprosthesis with graded lattice structures was synthesized using algorithmic design and analyzed in a virtual implanted state using micro-finite element (micro-FE) analysis to validate the optimization method. Homogenized FE and micro-FE models were compared based on averaged von Mises stresses in multiple regions of interest. A strong correlation (CCC > 0.97) was observed, indicating that optimizing homogenized lattice structures yields reliable outcomes. The graded implant was additively manufactured to ensure the topology-optimized result's feasibility.

Efficacy of Adjuvants in Ophthalmic Regional Anesthesia: A Systematic Review and Network Meta-analysis.

PURPOSE: This network meta-analysis aims to determine the differences between adjuvants that are used in combination with local anesthetics for ophthalmic regional anesthesia. DESIGN: Systematic review and network meta-analysis. METHODS: A systematic literature search for randomized controlled trials, comparing the impact of adjuvants in ophthalmic regional anesthesia, in Embase, CENTRAL, MEDLINE and Web of Science was performed. Risk of bias was evaluated using the Cochrane risk of bias tool. Frequentist network meta-analysis was performed using a random effects model with saline as the comparator. Primary endpoints were the onset and the duration of sensory block and globe akinesia, as well as the duration of analgesia. Summary measure was the ratio of means (ROM). Secondary endpoints were the rates of side effects and adverse events. RESULTS: A total of 39 trials were identified as eligible for network meta-analysis, including 3046 patients. In all, 17 adjuvants were compared in the most extensive network (onset of globe akinesia). The addition of fentanyl (F), clonidine (C), or dexmedetomidine (D) showed the best overall results. Onset of sensory block was as follows: F 0.58 (CI = 0.47-0.72), C 0.75 (0.63-0.88), D 0.71 (0.61-0.84); onset of globe akinesia: F 0.71 (0.61-0.82), C 0.70 (0.61-0.82), D 0.81 (0.71-0.92); duration of sensory block: F 1.20 (1.14-1.26), C 1.22 (1.18-1.27), D 1.44 (1.34-1.55); duration of globe akinesia: F 1.38 (1.22-1.57), C 1.45 (1.26-1.67), D 1.41 (1.24-1.59); and duration of analgesia: F 1.46 (1.33-1.60), C 1.78 (1.63-1.96), D 1.41 (1.28-1.56). CONCLUSIONS: The addition of fentanyl, clonidine, or dexmedetomidine showed beneficial effects regarding onset and duration of sensory block and globe akinesia.

Calculating the individual probability of successful ocriplasmin treatment in eyes with vitreomacular traction-Validation and refinement of a multivariable prediction model.

PURPOSE: To evaluate a multivariable model predicting the individual probability of successful intravitreal ocriplasmin (IVO) treatment in eyes with vitreomacular traction (VMT). METHODS: Data from three prospective, multicenter IVO studies (OASIS, ORBIT, and INJECT) were pooled. Patients were included if they were treated for a symptomatic VMT without a full-thickness macular hole. A prediction model for VMT resolution using the factors 'age' and 'horizontal VMT diameter' was validated by receiver operating characteristic analysis and according to grouped prediction after calibration. Multivariable regression analysis was performed to check robustness and explore further improvements. RESULTS: Data from 591 eyes was included. In the univariate analysis all key factors (age, gender, VMT diameter, lens status, ERM) significantly correlated to treatment success. The prediction model was robust and clinically applicable to estimate the success rate of IVO treatment (AUC of ROC: 0.70). A refinement of the model was achieved through a calibration process. CONCLUSION: The developed multivariable model using 'horizontal VMT diameter' and 'age' is a valid tool for prediction of VMT resolution upon IVO treatment.

IRF4 deficiency vulnerates B-cell progeny for leukemogenesis via somatically acquired Jak3 mutations conferring IL-7 hypersensitivity.

The processes leading from disturbed B-cell development to adult B-cell progenitor acute lymphoblastic leukemia (BCP-ALL) remain poorly understood. Here, we describe Irf4-/- mice as prone to developing BCP-ALL with age. Irf4-/- preB-I cells exhibited impaired differentiation but enhanced proliferation in response to IL-7, along with reduced retention in the IL-7 providing bone marrow niche due to decreased CXCL12 responsiveness. Thus selected, preB-I cells acquired Jak3 mutations, probably following irregular AID activity, resulting in malignant transformation. We demonstrate heightened IL-7 sensitivity due to Jak3 mutants, devise a model to explain it, and describe structural and functional similarities to Jak2 mutations often occurring in human Ph-like ALL. Finally, targeting JAK signaling with Ruxolitinib in vivo prolonged survival of mice bearing established Irf4-/- leukemia. Intriguingly, organ infiltration including leukemic meningeosis was selectively reduced without affecting blood blast counts. In this work, we present spontaneous leukemogenesis following IRF4 deficiency with potential implications for high-risk BCP-ALL in adult humans.

Opticopathy Caused by Endoprosthesis-Related Cobalt Intoxication. / Optikopathie durch Hüft-TEP-bedingte Kobaltintoxikation.

Cobalt intoxication is a rare cause of toxic opticopathy, and may be caused by metal endoprostheses. Since its clinical appearance is unspecific and the incidence low, diagnosis is challenging. Due to the dramatic consequences of delayed treatment, cobalt intoxication should be considered as a rare differential diagnosis of bilateral loss of vision in patients with appropriate history.

Predicting the individual probability of macular hole closure following intravitreal ocriplasmin injections for vitreomacular traction release using baseline characteristics.

The primary objective was to create and establish a new formula that predicts the individual probability of macular hole closure for eyes with full thickness macular holes (FTMH) accompanied by vitreomacular traction (VMT) which received enzymatic vitreolysis using intravitreally administered ocriplasmin. The secondary objective was to evaluate the forecast reliability of a previously published formula for VMT resolution in VMT-only eyes (OddsIVO-Success = eIntercept × ORyears × ORln(µm); ProbabilityIVO-Success = OddsIVO-Success/(OddsIVO-Success + 1)) on VMT resolution using the current dataset of eyes with FTMH accompanied by VMT. Retrospective analysis of the OASIS, ORBIT, and INJECT-studies. Patients with FTMH and VMT with complete information (n = 213) were included. The effect of gender, age, FTMH diameter, lens status and the presence of epiretinal membranes (ERM) on FTMH closure was assessed using separate univariate logistic regression analyses. With regard to VMT release separate univariate regression analyses were carried out and results were compared with formerly published data of VMT resolution in eyes with VMT only. Overall, 126 eyes (63%) experienced VMT resolution within 28 days. Younger age (p < 0.0001) and VMT diameter (p = 0.041) had a significant impact on VMT release. Overall, 81 eyes (38%) treated with ocriplasmin showed FTMH closure within 28 days. Univariate analysis of the different predictors analyzed revealed that FTMH diameter < 250 µm had a significant impact on treatment success (p = 0.0495). It was not possible to calculate and establish a new multivariate formula that can predict the individual FTMH closure probability for eyes with FTMHs and VMT. However, the results of VMT release prediction in eyes with FTMHs accompanied by VMT matched the prediction of VMT release in eyes with VMT only when using the previously published formula. All in all, predictors for calculating the individual probability of VMT resolution on the one hand and FTMH closure on the other hand are different suggesting diverse pathophysiological mechanisms.

Patient-Reported Quality of Life and Satisfaction After Refractive Lens Extraction Using a Diffractive Trifocal IOL: A Multicenter Retrospective Cohort Study.

PURPOSE: To assess patient satisfaction and quality of life after refractive lens exchange with a trifocal intraocular lens (IOL). METHODS: Consecutive patients who underwent refractive lens exchange with the AT LISA tri or AT LISA tri toric IOL (Carl Zeiss Meditec AG) at one of five surgical centers were surveyed for their quality of life and satisfaction after surgery using a standardized questionnaire. Patient responses were compared to patient characteristics such as age, sex, axial lengths, and preoperative refraction. RESULTS: A total of 102 patients with 204 treated eyes were included in the analysis. The mean age was 54.6 ± 5.2 years. A total of 172 eyes were hypermetropic, 3 were emmetropic, and 25 were myopic, with a mean preoperative refractive error of 0.93 ± 2.17 diopters. Reported postoperative satisfaction was as follows: 81.4% stated that their expectations were completely met and 17.6% stated that they were partially met. Self-reported refractive error quality of life improved significantly in all queried areas of life. Most frequently reported postoperative limitations were driving at night and driving in bad weather conditions. Halos were reported by 91 (90.1%) patients. CONCLUSIONS: Patient satisfaction and self-reported quality of life after refractive lens exchange with the AT LISA tri or AT LISA tri toric IOL was high. Glare and halos remain the only significant drawback of the procedure, leading to 40% of patients experiencing difficulties in night driving. Preoperative communication of these drawbacks is obligatory to avoid postoperative disappointment. [J Refract Surg. 2021;37(11):768-774.].

[Treatment refractory multidrug-resistant bacterial keratitis]. / Therapierefraktäre 4-MRGN-Keratitis.

This article reports a case of severe, treatment refractory infectious keratitis. Multiple samples of the cornea and the anterior chamber were taken without detection of any pathogens. Ultimately a multidrug-resistant Pseudomonas aeruginosa was isolated and successfully treated with tobramycin and amikacin, according to its antibiotic sensitivity. If there is a clinical suspicion multiple samples should be taken and multidrug-resistant pathogens considered as a differential diagnosis.

Trabeculectomy offers better intraocular pressure reduction in intrapatient comparison to transscleral cyclophotocoagulation.

PURPOSE: Both trabeculotomy (TE) as well as transscleral endodiode laser cyclophotocoagulation (CPC) are common approaches in glaucoma surgery. The purpose of this study was to perform an intraindividual comparison of these procedures carried out by the same surgeon in the same patient on the same day. METHODS: An observational monocentric retrospective cohort study was conducted. Patients with a bilateral refractory open-angle glaucoma who underwent trabeculectomy in one eye and transscleral endodiode laser cyclophotocoagulation in the fellow eye simultaneously were included and followed up with over the course of 1 year. RESULTS: Eighty-two eyes of 41 patients were included. Seventeen patients (41.5%) were men and 24 (58.5%) women. The mean age was 68.7 ± 9.5 years. The diagnosis comprised 33 (80.5%) patients with a primary open-angle glaucoma, five (12.2%) patients with pseudoexfoliation glaucoma, and three (7.3%) patients with pigment dispersion glaucoma. A reduction in intraocular pressure (IOP) was seen in both after TE (from 26.2 ± 13.2 to 10.6 ± 4.1 mmHg, 52 weeks post-treatment) as well as CPC (from 24.2 ± 9.9 to 15.0 ± 5.4 mmHg, 52 weeks post-treatment). In comparison to each other, TE was significantly more effective in lowering the IOP (10.6 ± 4.1 vs. 13.4 ± 5.0; p = 0.0030, 52 weeks post-treatment) and needed antiglaucomatous medications (0.45 ± 0.80 vs. 1.24 ± 1.13; p = 0.0009, 52 weeks post-treatment). Consistently, the achievement rate of an IOP ≤ 16 mmHg without antiglaucomatous medications was significantly higher in TE-treated eyes (65.8% vs. 31.6%; p = 0.0019). Re-interventions, including 10 secondary TEs, were commonly required in those eyes undergoing CPC, especially in younger patients. CONCLUSIONS: Trabeculectomy was demonstrated to be more effective in reducing IOP in comparison to fellow eyes receiving CPC. In particular, in younger patients, an additional TE in the CPC-treated eyes was necessary. The outcome of those secondary TEs however was comparable to the primarily performed TEs. Our study thus supports the use of CPC as tool to control IOP, especially in the context of bilateral refractive glaucoma.

Comparison of the horizontal diameter to a modeled area of traction in eyes with vitreomacular traction: is the diameter close enough to the truth?

PURPOSE: In daily practice, vitreomacular traction (VMT) is described by the horizontal diameter of its attachment site implying a regular round shape of VMT. We investigated the deviation from this circular area of vitreous traction in patients with VMT. METHODS: A retrospective analysis of optical coherence tomography (OCT) scans was performed. The area of vitreomacular attachment was determined using six radial OCT scans (Ameasured). The assumed circular area of traction was calculated based on measuring the maximal horizontal diameter for comparison (Acircular). RESULTS: Thirty-seven eyes of 37 patients with pure VMT were included. Patients' mean age was 72.8 ± 8.2 years. Mean horizontal VMT diameter was 400.8 ± 230.5 µm (median 361 µm; range 44-991 µm). While there was no difference between mean areas of traction for Acircular and Ameasured (P = 0.93), the individual difference (|Acircular - Ameasured|) was 0.042 (± 0.044) mm2 in mean or relative 73.0% (± 135.8%). A difference of ≥ 30% of Ameasured to Acircular was found in 16 eyes (43.2%) and ≥ 100% in 7 eyes (18.9%), respectively. CONCLUSION: Vitreous attachment sites possess an irregular non-circular shape in a significant number of eyes with VMT. Consequently, the area of traction appears inaccurately described by its horizontal VMT diameter alone. As the area of traction is important for therapeutic recommendation, our results emphasize the need for a more precise description of the area of traction in eyes with VMT.

Calculating the individual probability of successful ocriplasmin treatment in eyes with VMT syndrome: a multivariable prediction model from the EXPORT study.

BACKGROUND/AIMS: To evaluate predictive factors for the treatment success of ocriplasmin and to use these factors to generate a multivariate model to calculate the individual probability of successful treatment. METHODS: Data were collected in a retrospective, multicentre cohort study. Patients with vitreomacular traction (VMT) syndrome without a full-thickness macular hole were included if they received an intravitreal injection (IVI) of ocriplasmin. Five factors (age, gender, lens status, presence of epiretinal membrane (ERM) formation and horizontal diameter of VMT) were assessed on their association with VMT resolution. A multivariable logistic regression model was employed to further analyse these factors and calculate the individual probability of successful treatment. RESULTS: 167 eyes of 167 patients were included. Univariate analysis revealed a significant correlation to VMT resolution for all analysed factors: age (years) (OR 0.9208; 95% CI 0.8845 to 0.9586; p<0.0001), gender (male) (OR 0.480; 95% CI 0.241 to 0.957; p=0.0371), lens status (phakic) (OR 2.042; 95% CI 1.054 to 3.958; p=0.0344), ERM formation (present) (OR 0.384; 95% CI 0.179 to 0.821; p=0.0136) and horizontal VMT diameter (µm) (OR 0.99812; 95% CI 0.99684 to 0.99941, p=0.0042). A significant multivariable logistic regression model was established with age and VMT diameter. CONCLUSION: Known predictive factors for VMT resolution after ocriplasmin IVI were confirmed in our study. We were able to combine them into a formula, ultimately allowing the calculation of an individual probability of treatment success with ocriplasmin in patients with VMT syndrome without FTHM.

IMPACT OF VITREORETINAL INTERFACE ARCHITECTURE ON SUCCESSFUL VITREOMACULAR TRACTION RESOLUTION IN EYES SCHEDULED FOR INTRAVITREAL OCRIPLASMIN THERAPY.

PURPOSE: To evaluate the impact of the vitreoretinal interface architecture, in specific the angle between the posterior vitreous cortex and the internal limiting membrane, on vitreomacular traction (VMT) resolution in eyes treated with intravitreally injected ocriplasmin (Jetrea). METHODS: Retrospective, multicenter cohort study and exploratory data analysis. Spectral domain optical coherence tomography assessments were performed before scheduled ocriplasmin injections. General (age and sex) as well as ocular variables (lens status, presence of epiretinal membrane formations, horizontal diameter of VMT, central retinal thickness, and in particular various prespecified angles between the posterior vitreous cortex and internal limiting membrane) were analyzed to evaluate their impact on successful VMT resolution. RESULTS: Fifty-nine eyes of 59 patients were included. Univariate analysis of age (odds ratio [OR]: 0.881; 95% CI: [0.812-0.955]; P = 0.0022) and lens status (OR: 11.03; 95% CI: [2.23-54.57]; P = 0.0033) had a significant impact on successful VMT resolution, whereas sex (OR: 0.668; 95% CI: [0.126-2.065]; P = 0.4906), epiretinal membrane formation (OR: 0.581; 95% CI: [0.168-2.006]; P = 0.3903), horizontal diameter of VMT (OR: 0.99930; 95% CI: [0.99825-1.00035]; P = 0.1886), and central retinal thickness (OR: 0.9985; 95% CI: [0.9934-1.00436]; P = 0.56) failed. The angle at 500 µm apart from the fovea centralis, irrespective if measured nasally (OR: 1.135; 95% CI: [1.013-1.272]; P = 0.0289) or temporally (OR: 1.099; 95% CI: [1.001-1.208]; P = 0.0485), showed a significant correlation with VMT resolution. CONCLUSION: The angle between the posterior vitreous cortex and the internal limiting membrane 500 µm apart from the fovea centralis correlates with VMT resolution and may be a clinically useful marker for selection of patients to be treated with ocriplasmin. This observation needs to be proven in a prospective confirmatory investigation.

Mast cells have no impact on cutaneous leishmaniasis severity and related Th2 differentiation in resistant and susceptible mice.

The genus leishmania comprises different protozoan parasites which are causative agents of muco-cutaneous and systemic, potentially lethal diseases. After infection with the species Leishmania major, resistant mice expand Th1 cells which stimulate macrophages for Leishmania destruction. In contrast, susceptible mice generate Th2 cells which deactivate macrophages, leading to systemic spread of the pathogens. Th-cell differentiation is determined within the first days, and Th2 cell differentiation requires IL-4, whereby the initial IL-4 source is often unknown. Mast cells are potential sources of IL-4, and hence their role in murine leishmaniasis has previously been studied in mast cell-deficient Kit mutant mice, although these mice display immunological phenotypes beyond mast cell deficiency. We therefore readdressed this question by infecting Kit-independent mast cell-deficient mice that are Th1 (C57BL/6 Cpa(Cre) ) or Th2 (BALB/c Cpa(Cre) ) prone with L. major. Using different parasite doses and intra- or subcutaneous infection routes, the results demonstrate no role of mast cells on lesion size development, parasite load, immune cell phenotypes expanding in draining lymph nodes, and cytokine production during murine cutaneous leishmaniasis. Thus, other cell types such as ILCs or T cells have to be considered as primary source of Th2-driving IL-4.

Transcription factor IRF4 determines germinal center formation through follicular T-helper cell differentiation.

Follicular T-helper (T(FH)) cells cooperate with GL7(+)CD95(+) germinal center (GC) B cells to induce antibody maturation. Herein, we identify the transcription factor IRF4 as a T-cell intrinsic precondition for T(FH) cell differentiation and GC formation. After immunization with protein or infection with the protozoon Leishmania major, draining lymph nodes (LNs) of IFN-regulatory factor-4 (Irf4(-/-)) mice lacked GCs and GC B cells despite developing normal initial hyperplasia. GCs were also absent in Peyer's patches of naive Irf4(-/-) mice. Accordingly, CD4(+) T cells within the LNs and Peyer's patches failed to express the T(FH) key transcription factor B-cell lymphoma-6 and other T(FH)-related molecules. During chronic leishmaniasis, the draining Irf4(-/-) LNs disappeared because of massive cell death. Adoptive transfer of WT CD4(+) T cells or few L. major primed WT T(FH) cells reconstituted GC formation, GC B-cell differentiation, and LN cell survival. In support of a T-cell intrinsic IRF4 activity, Irf4(-/-) T(FH) cell differentiation was not rescued by close neighborhood to transferred WT T(FH) cells. Together with its known B lineage-specific roles during plasma cell maturation and class switch, our study places IRF4 in the center of antibody production toward T-cell-dependent antigens.