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Abstract Malignancy grading of prostate cancer (PCa) is fundamental for risk stratification, patient counseling, and treatment decision-making. Deep learning has shown potential to improve the expert consensus for tumor grading, which relies on the Gleason score/grade grouping. However, the core problem of interobserver variability for the Gleason grading system remains unresolved. We developed a novel grading system for PCa and utilized artificial intelligence (AI) and multi-institutional international datasets from 2647 PCa patients treated with radical prostatectomy with a long follow-up of ≥10 years for biochemical recurrence and cancer-specific death. Through survival analyses, we evaluated the novel grading system and showed that AI could develop a tumor grading system with four risk groups independent from and superior to the current five grade groups. Moreover, AI could develop a scoring system that reflects the risk of castration resistant PCa in men who have experienced biochemical recurrence. Thus, AI has the potential to develop an effective grading system for PCa interpretable by human experts.

Abstract Invasive lobular carcinoma (ILC) is a special breast cancer type characterized by noncohesive growth and E‐cadherin loss. Focal activation of P‐cadherin expression in tumor cells that are deficient for E‐cadherin occurs in a subset of ILCs. Switching from an E‐cadherin deficient to P‐cadherin proficient status (EPS) partially restores cell–cell adhesion leading to the formation of cohesive tubular elements. It is unknown what conditions control EPS. Here, we report on EPS in ILC metastases in the large bowel. We reviewed endoscopic colon biopsies and colectomy specimens from a 52‐year‐old female (index patient) and of 18 additional patients (reference series) diagnosed with metastatic ILC in the colon. EPS was assessed by immunohistochemistry for E‐cadherin and P‐cadherin. CDH1/E‐cadherin mutations were determined by next‐generation sequencing. The index patient's colectomy showed transmural metastatic ILC harboring a CDH1/E‐cadherin p.Q610* mutation. ILC cells displayed different growth patterns in different anatomic layers of the colon wall. In the tunica muscularis propria and the tela submucosa, ILC cells featured noncohesive growth and were E‐cadherin‐negative and P‐cadherin‐negative. However, ILC cells invading the mucosa formed cohesive tubular elements in the intercryptal stroma of the lamina propria mucosae. Inter‐cryptal ILC cells switched to a P‐cadherin‐positive phenotype in this microenvironmental niche. In the reference series, colon mucosa infiltration was evident in 13 of 18 patients, one of which showed intercryptal EPS and conversion to cohesive growth as described in the index patient. The large bowel is a common metastatic site in ILC. In endoscopic colon biopsies, the typical noncohesive growth of ILC may be concealed by microenvironment‐induced EPS and conversion to cohesive growth.

The authors express their opinion on the endeavour of aligning psychology after the model of physics, especially to bring into play the relation of the latter with engineering, in order to propagate a separation of pure basic psychological science and applied disciplines. In the first instance the intention was to describe the real connexions between physics and engineering and hence there is no cause for the separation mentioned. For this very reason it is also possible to state some similarities between these disciplines and psychology. This is true if one considers general systemtheoretical or holistic perspectives from an epistemological view. But whenever the concrete subjects of research are under examination then it is becoming evident that there is no sense in comparisons between psychology and physics (including engineering).

Abstract Background The detection of causative pathogens plays a crucial role in the diagnosis and targeted treatment of periprosthetic joint infections (PJI). While there have been improvements in analytic methods in the past, pre-analytical procedures have not yet been sufficiently investigated. The objective of this study was to compare the culture yield of four different pre-analytical procedures. Methods Patients with perioperative diagnosis of PJI were included in a single center cross-sectional study (2021–2022). Tissue samples (n = 20) of each patient were randomly and equally distributed to each of the four study arms. Tissue samples were either send to the laboratory without culture medium (group A) or were transported in thioglycolate medium immediately after sampling at three different temperatures (room temperature, 4 °C, 37° for 24 h; group B-D). Culture media were investigated for growth on days 1, 3, 7, 12, 14. All organisms, the number of positive samples and the time to positivity were recorded and compared between the study arms. Single positive cultures were considered as contamination. Results In total, 71 patients were included. The proportions of culture negative samples (10–15%) and polymicrobial infections (51–54%) were comparable between the four arms. Seven patients (10%) were culture-negative in group A, but showed growth in thioglycolate media (group B-D). Furthermore, 13% of patients showed growth in all groups, but additional organisms were cultured in thioglycolate. There was growth beyond day 7 of culturing only in thioglycolate, but not in group A. A storage temperature of 4 °C showed a longer time to positivity compared to the other groups (p

A fast BEM (boundary element method) based approach is developed to solve an EEG/MEG forward problem for a modern high-resolution head model. The method utilizes a charge-based BEM accelerated by the fast multipole method (BEM-FMM) with an adaptive mesh pre-refinement method (called b-refinement) close to the singular dipole source(s). No costly matrix-filling or direct solution steps typical for the standard BEM are required; the method generates on-skin voltages as well as MEG magnetic fields for high-resolution head models within 90 s after initial model assembly using a regular workstation. The forward method is validated by comparison against an analytical solution on a spherical shell model as well as comparison against a full h-refinement method on realistic 1M facet human head models, both of which yield agreement to within 5 % for the EEG skin potential and MEG magnetic fields. The method is further applied to an EEG source localization (inverse) problem for real human data, and a reasonable source dipole distribution is found.

Abstract Objective To investigate the clinical phenotype and treatment response in patients with rheumatoid arthritis (RA) with and without concomitant Sjögren’s disease (SjD). Methods In this observational cohort study, patients with RA from the Swiss Clinical Quality Management in Rheumatic Diseases registry were categorised according to the presence or absence of SjD. To assess treatment effectiveness, drug retention of tumor necrosis factor-α-inhibitors (TNFi) was compared to other mode of action (OMA) biologics and Janus kinase-inhibitors (JAKi) in RA patients with and without SjD. Adjusted hazard ratios (HR) for time to drug discontinuation were compared in crude and adjusted Cox proportional regression models for potential confounders. Results We identified 5974 patients without and 337 patients with concomitant SjD. Patients with SjD were more likely to be female, to have a positive rheumatoid factor, higher disease activity scores, and erosive bone damage. For treatment response, a total of 6781 treatment courses were analysed. After one year, patients with concomitant SjD were less likely to reach DAS28 remission with all three treatment modalities. Patients with concomitant SjD had a higher hazard for stopping TNFi treatment (adjusted HR 1.3 [95% CI 1.07–1.6]; OMA HR 1.12 [0.91–1.37]; JAKi HR 0.97 [0.62–1.53]). When compared to TNFi, patients with concomitant SjD had a significantly lower hazard for stopping treatment with OMA (adjusted HR 0.62 [95% CI 0.46–0.84]) and JAKi (HR 0.52 [0.28–0.96]). Conclusion RA patients with concomitant SjD reveal a severe RA phenotype, are less responsive to treatment, and more likely to fail TNFi.

Abstract Introduction We investigated the time to reimplantation (TTR) during two-stage revision using static spacers with regard to treatment success and function in patients with chronic periprosthetic joint infection (PJI) of the knee. Methods 163 patients (median age 72 years, 72 women) who underwent two-stage exchange for chronic knee PJI between 2012 and 2020 were retrospectively analyzed (based on the 2011 Musculoskeletal Infection Society criteria). A cutoff TTR for increased risk of reinfection was identified using the maximally selected log-rank statistic. Infection control, aseptic revisions and overall survival were analyzed using Kaplan–Meier survival estimates. Adjustment for confounding factors—the Charlson Comorbidity Index (CCI) and C-reactive protein (CRP)—was done with a Cox proportional hazards model. Results When TTR exceeded 94 days, the adjusted hazard of reinfection was increased 2.8-fold (95% CI 1.4–5.7; p = 0.0036). The reinfection-free rate was 67% (95% CI 52-79%) after 2 years and 33% (95% CI 11–57%) after 5 years for a longer TTR compared to 89% (95% CI 81–94%) and 80% (95% CI 69–87%) at 2 and 5 years, respectively, for a shorter TTR. Adjusted overall survival and number of aseptic revisions did not differ between the longer TTR and shorter TTR groups. Maximum knee flexion was 90° (IQR 84–100) for a longer TTR and 95° (IQR 90–100) for a shorter TTR (p = 0.0431), with no difference between the groups in Oxford Knee Score. Baseline characteristics were similar (body mass index, age, previous surgeries, microorganisms) for the two groups, except that there was a higher CCI (median 4 vs. 3) and higher CRP (median 3.7 vs 2.6 mg/dl) in the longer TTR group. Conclusion A long TTR is sometimes unavoidable in clinical practice, but surgeons should be aware of a potentially higher risk of reinfection. Level of evidence: III, retrospective comparative study.

Pleural thickening can be the result of inflammation or infection but can also have a neoplastic origin. Depending on the clinical context, a pleural lesion or mass is often initially suspected of malignancy. Benign pleural tumors are rare, and their appearance on ultrasound (US) is also described less frequently than pleural metastases or malignancies. There are few descriptions of contrast-enhanced Ultrasound (CEUS) in particular. This review introduces the basics of transthoracic ultrasound (TUS) of the pleura and CEUS of the pleura and lung. CEUS is recommended for pulmonary applications in the EFSUMB guidelines in non-hepatic applications. This article provides an overview of the characteristics of benign pleural thickening, tumor-like lesions, and benign pleural tumors on transthoracic B-mode US with color Doppler imaging (CDI) and CEUS. In detail, characteristics in TUS and CEUS are described for infectious/inflammatory pleural thickening (empyema, tuberculous pleuritis, hemothorax, fibrothorax), pleural thickening in various systemic diseases, in tumor-like conditions (plaques, splenosis, endometriosis, mesothelial cysts, lymphangiomatosis) and benign tumors (lipoma, benign SFT, schwannoma, solitary extramedullary/extraosseous plasmacytoma). The descriptions are illustrated by corresponding US and CEUS images.

[1] From early Miocene to the present-day the core parts of the western European Alps experienced brittle extensional deformations, mostly in a strike-parallel direction. Here we present new data constraining the brittle deformation of the Vanoise area (French Alps) and a synthesis of 312 paleostress tensors in the whole arc of the internal western Alps. The data show a continuous change in the direction of extension, from N065[degrees] (Simplon area), to N-S (Vanoise area) and to NNW-SSE (Briancon area). The abundance of orogen-perpendicular [[sigma].sub.3] axes increases from the north to the south. In the Briangonnais area, an extensional reactivation of the Basal Penninic Thrust seems to be the origin of the E-W to NE-SW oriented [[sigma].sub.3]. In light of these new data and the regional paleostress synthesis, we propose a predominant orogen-parallel extension in the internal zone as a whole. This orogen-parallel extension is related to the indentation/rotation of the Apulian microplate and to the opening of the Ligurian Sea during the lower-middle Miocene. The locally observed orogen-perpendicular extension is interpreted as an effect of the exhumation of the Internal Crystalline massifs, the uplift of the External Crystalline massifs and/or the present-day geodynamics (postorogenic gravitational collapse). Some transcurrent tectonics, older than the extension in the Valais area and younger than the extension farther south is observed in the entire inner western Alps; strike-slip movements are correlated with the Apulian rotation and local permutation of stress axes. Citation: Champagnac, J. D., C. Sue, B. Delacou, P. Tricart, C. Allanic, and M. Burkhard (2006), Miocene lateral extrusion in the inner western Alps revealed by dynamic fault analysis, Tectonics, 25, TC3014, doi:10.1029/2004TC001779.

ObjectiveTo validate the prognostic accuracy of anti-apolipoprotein A-1 (AAA1) IgG for incident major adverse cardiovascular (CV) events (MACE) in rheumatoid arthritis (RA) and study their associations with the lipid paradox at a multicentric scale.MethodBaseline AAA1 IgG, lipid profile, atherogenic indexes, and cardiac biomarkers were measured on the serum of 1,472 patients with RA included in the prospective Swiss Clinical Quality Management registry with a median follow-up duration of 4.4 years. MACE was the primary endpoint defined as CV death, incident fatal or non-fatal stroke, or myocardial infarction (MI), while elective coronary revascularization (ECR) was the secondary endpoint. Discriminant accuracy and incidence rate ratios (IRR) were respectively assessed using C-statistics and Poisson regression models.ResultsDuring follow-up, 2.4% (35/1,472) of patients had a MACE, consisting of 6 CV deaths, 11 MIs, and 18 strokes; ECR occurred in 2.1% (31/1,472) of patients. C-statistics indicated that AAA1 had a significant discriminant accuracy for incident MACE [C-statistics: 0.60, 95% confidence interval (95% CI): 0.57–0.98, p = 0.03], mostly driven by CV deaths (C-statistics: 0.77; 95% CI: 0.57–0.98, p = 0.01). IRR indicated that each unit of AAA1 IgG increase was associated with a fivefold incident CV death rate, independent of models’ adjustments. At the predefined and validated cut-off, AAA1 displayed negative predictive values above 97% for MACE. AAA1 inversely correlated with total and HDL cholesterol.ConclusionsAAA1 independently predicts CV deaths, and marginally MACE in RA. Further investigations are requested to ascertain whether AAA1 could enhance CV risk stratification by identifying patients with RA at low CV risk.

Objectives To investigate lectin pathway proteins (LPPs) as biomarkers for axial spondyloarthritis (axSpA) in a cross-sectional cohort with a suspicion of axSpA, comprising newly diagnosed axSpA and chronic low back pain (cLBP) individuals.Methods Serum samples from 515 participants within the OptiRef cohort, including 151 axSpA patients and 364 cLBP patients, were measured using immunoassays for LPPs (mannan-binding lectin (MBL), collectin liver-1 (CL-L1), M-ficolin, H-ficolin and L-ficolin, MBL-associated serine proteases (MASP)−1, –2 and –3, MBL-associated proteins (MAp19 and MAp44) and the complement activation product C3dg).Results Serum levels of L-ficolin, MASP-2 and C3dg were elevated in axSpA patients, whereas levels of MASP-3 and CL-L1 were decreased, and this remained significant for C3dg and MASP-3 after adjustment for C reactive protein (CRP). A univariate regression analysis showed serum levels of CL-L1, MASP-2, MASP-3 and C3dg to predict the diagnosis of axSpA, and MASP-3 and C3dg remained significant in a multivariate logistic regression analysis. Assessment of the diagnostic potential showed that a combination of human leukocyte antigen B27 (HLA-B27) and measurements of L-ficolin, MASP-3 and C3dg increased the diagnostic specificity for axSpA, however, with a concomitant loss of sensitivity.Conclusions Serum levels of complement activation, that is, C3dg, and MASP-3 differed significantly between axSpA and cLBP patients after adjustment for CRP. Although combining HLA-B27 with measurements of L-ficolin, MASP-3 and C3dg increased the diagnostic specificity for axSpA, this seems unjustified due to the concomitant loss of sensitivity. However, both C3dg and MASP-3 were associated with axSpA diagnosis in multivariate logistic regression, suggesting an involvement of complement in the inflammatory processes and possibly pathogenesis in axSpA.

Abstract The elements hydrogen, carbon, nitrogen and oxygen are assumed to comprise the bulk of the interiors of the ice giant planets Uranus, Neptune, and sub-Neptune exoplanets. The details of their interior structures have remained largely unknown because it is not understood how the compounds H2O, NH3 and CH4 behave and react once they have been accreted and exposed to high pressures and temperatures. Here we study thirteen H-C-N-O compounds with ab initio computer simulations and demonstrate that they assume a superionic state at elevated temperatures, in which the hydrogen ions diffuse through a stable sublattice that is provided by the larger nuclei. At yet higher temperatures, four of the thirteen compounds undergo a second transition to a novel doubly superionic state, in which the smallest of the heavy nuclei diffuse simultaneously with hydrogen ions through the remaining sublattice. Since this transition and the melting transition at yet higher temperatures are both of first order, this may introduce additional layers in the mantle of ice giant planets and alter their convective patterns.

Electroencephalographic (EEG) source localization is a fundamental tool for clinical diagnoses and brain-computer interfaces. We investigate the impact of model complexity on reconstruction accuracy by comparing the widely used three-layer boundary element method (BEM) as an inverse method against a five-layer BEM accelerated by the fast multipole method (BEM-FMM) and coupled with adaptive mesh refinement (AMR) as forward solver. Modern BEM-FMM with AMR can solve high-resolution multi-tissue models efficiently and accurately. We generated noiseless 256-channel EEG data from 15 subjects in the Connectome Young Adult dataset, using four anatomically relevant dipole positions, three conductivity sets, and two head segmentations; we mapped localization errors across the entire grey matter from 4000 dipole positions. The average location error among our four selected dipoles is ∼5mm (±2mm) with an orientation error of ∼12∘ (±7∘). The average source localization error across the entire grey matter is ∼9mm (±4mm), with a tendency for smaller errors on the occipital lobe. Our findings indicate that while three-layer models are robust under noiseless conditions, substantial localization errors (10–20mm) are common. Therefore, models of five or more layers may be needed for accurate source reconstruction in critical applications involving noisy EEG data.

Primary pulmonary sarcoma and mesothelioma are rare malignancies. The review article discusses the appearance of these tumors in B-mode ultrasound (US), color Doppler ultrasound and contrast-enhanced ultrasound (CEUS). In particular, the article is intended to inspire the examination of thoracic wall tumors and pleural masses with the possibilities of ultrasonography and to obtain histologically evaluable material using US or CEUS-guided sampling.

Background: In response to inflammation, the absorption of nutritional iron is restricted. Since the pathophysiological significance of the presence and uptake of iron in chronic inflammation is still unknown, we tested the effect of a low iron diet on the clinical course of arthritis in the mouse model of collagen-induced arthritis (CIA). Methods: Six- to eight-week-old male DBA/1 mice were fed either a normal (51 mg/kg) or a low iron diet (5 mg/kg) starting four weeks before the first immunization. From day 4 after the second collagen booster made on day 25, the development of arthritis was regularly monitored until the end of the experiment (day 34), using a standard clinical arthritis score. Concentrations of mouse anti-bovine and anti-mouse collagen type 2 IgG antibodies were measured by ELISA; blood cell counts were performed and mediators of inflammation, tissue matrix degradation, oxygenation and oxidative stress were measured in the mouse sera of both diet groups at the end of the experiment by bead-based multiplex assay. Fe2+, Fe3+, oxidized and reduced glutathione (GSH and GSSG) and malondialdehyde (MDA) were quantified in whole paw tissue by ELISA. Quantitative PCR was performed in the tissues for glutathione peroxidase 4 and other key regulator genes of iron metabolism and ferroptosis. We used nonparametric tests to compare cross-sectional data. Nonlinear regression models were used for longitudinal data of the arthritis scores. Results: Mice fed a low iron diet showed a significantly less severe course of arthritis compared to mice fed a normal iron diet (p < 0.001). The immune response against bovine and mouse type 2 collagen did not differ between the two diet groups. Mice fed a low iron diet exhibited significantly lower serum levels of tissue inhibitor of metalloproteinase-1 (TIMP-1), a central regulator of inflammation and tissue matrix degradation (p < 0.05). In addition, a low iron diet led to a significant reduction in red blood cell indices, indicating restricted iron uptake and latent iron deficiency, but had no effect on hemoglobin concentrations or red blood cell counts. There were no differences between the dietary groups in Fe2+ or Fe3+ content in the paws. Based on calculation of the GSH/GSSG ratio and high MDA levels, high oxidative stress and lipid peroxidation were likewise detected in the paws of both diet groups of mice. Consequently, no differences associated with gene expression of key regulators of iron metabolism and ferroptosis could be detected between the paws of both diet groups. Conclusions: Restricted dietary iron intake alleviates immune-mediated inflammation in CIA without causing anemia. This finding suggests a promising option for dietary treatment of arthritis in inflammation. The underlying mechanism causing reduced arthritis may be linked to the complex regulatory network of TIMP-1 and appears to be independent from the local iron levels, oxidative stress and ferroptosis in the synovial tissues.

Increasing antibiotic resistance has been reported as an issue in the treatment of periprosthetic joint infection (PJI). A repeat two-stage revision for recurrent PJI is at high risk of reinfection. However, it is unclear if the microorganism profile plays a role with potentially more resistant or polymicrobial infections. This is a retrospective, single-center analysis of two-stage revisions performed between 2011 and 2017. We identified 46 patients who underwent a repeat resection arthroplasty for recurrent PJI of the same joint after a previous two-stage revision of the same joint at the same department. All microbiological findings were analyzed focusing on microbiological spectrum and resistance testing as well as the potential impact on reinfection-free survival. The most common organism found at the time of recurrent PJI were coagulase-negative Staphylococci (39%) followed by Gram-negative organisms (28%). The risk of polymicrobial infections, difficult-to-treat resistant organisms, and Gram-negative infections increased significantly. Among staphylococcal infections, there was a high percentage of methicillin-resistant species and resistance to oral antibiotics. Patients with Gram-negative organisms had a reduced infection-free survivorship, while resistant organisms were not associated with decreased survival. Patients who undergo a repeat two-stage revision for recurrent PJI have more polymicrobial and resistant organisms, although the impact on survivorship is unclear.