Outracing champion Gran Turismo drivers with deep reinforcement learning.

Many potential applications of artificial intelligence involve making real-time decisions in physical systems while interacting with humans. Automobile racing represents an extreme example of these conditions; drivers must execute complex tactical manoeuvres to pass or block opponents while operating their vehicles at their traction limits1. Racing simulations, such as the PlayStation game Gran Turismo, faithfully reproduce the non-linear control challenges of real race cars while also encapsulating the complex multi-agent interactions. Here we describe how we trained agents for Gran Turismo that can compete with the world's best e-sports drivers. We combine state-of-the-art, model-free, deep reinforcement learning algorithms with mixed-scenario training to learn an integrated control policy that combines exceptional speed with impressive tactics. In addition, we construct a reward function that enables the agent to be competitive while adhering to racing's important, but under-specified, sportsmanship rules. We demonstrate the capabilities of our agent, Gran Turismo Sophy, by winning a head-to-head competition against four of the world's best Gran Turismo drivers. By describing how we trained championship-level racers, we demonstrate the possibilities and challenges of using these techniques to control complex dynamical systems in domains where agents must respect imprecisely defined human norms.

Portable polygraphic device (Somnocheck micro CARDIO®) provides accurate diagnostic information in psychiatric patients at risk for obstructive sleep apnoea: an observational cohort study.

BACKGROUND: Symptoms of obstructive sleep apnoea (OSA) overlap significantly with those of psychiatric disorders, making accurate diagnosis of OSA challenging within psychiatric settings. Diagnosing OSA in psychiatric patients is crucial because untreated OSA can exacerbate psychiatric symptoms, reduce treatment efficacy, and impair overall quality of life. This study aimed to determine the diagnostic accuracy of a readily accessible procedure for psychiatric patients in a real-world clinical setting by comparing the Somnocheck micro CARDIO® (SCm) portable cardiorespiratory polygraphy device with the gold standard polysomnography (PSG). METHODS: This observational cohort study included consecutive psychiatric patients at intermediate to high risk for OSA based on screening with the STOP-Bang questionnaire, admitted to a single tertiary care centre between June 1, 2016 and December 31, 2022. The Apnoea-Hypopnoea-Index (AHI), Apnoea-Index (AI), Oxygen-Desaturation-Index (ODI), and minimum oxygen saturation were measured sequentially by SCm and PSG. RESULTS: A total of 57 patients were analysed (median age 62.0 [Interquartile Range (IQR), 51.5-72.5] years; 34 [59.6%] men). Regarding AHI, no significant differences (AHI measured by PSG, median, 16.6 [IQR, 6.2-26.7] vs. AHI measured by SCm, median, 14.9 [IQR, 10.0-22.8]; p = 0.812; r = 0.71) were found between SCm and PSG. AI, ODI and minimum oxygen saturation differed significantly between SCm and PSG. Using optimised cut-off values (any OSA: AHISCm ≥ 9.25), SCm showed high sensitivity (0.894) and high specificity (0.800) for the diagnosis of OSA, with an area under the receiver operating characteristic curve of 0.877. CONCLUSIONS: This study found that the SCm portable device was accurate in identifying psychiatric patients with OSA. AHI measurement by SCm provided reliable diagnostic performance in comparison with the gold standard polysomnography. These findings support the integration of polygraphic measurements into the routine sleep assessment of psychiatric patients. Early and accurate diagnosis of OSA in this population can significantly improve the management of both sleep disorders and psychiatric conditions, potentially enhancing overall treatment outcomes and quality of life for these patients.

Laccase-Treated Polystyrene Surfaces with Caffeic Acid, Dopamine, and L-3,4-Dihydroxyphenylalanine Substrates Facilitate the Proliferation of Melanocytes and Embryonal Carcinoma Cells NTERA-2.

This study presents the effects of treating polystyrene (PS) cell culture plastic with oxidoreductase enzyme laccase and the catechol substrates caffeic acid (CA), L-DOPA, and dopamine on the culturing of normal human epidermal melanocytes (NHEMs) and human embryonal carcinoma cells (NTERA-2). The laccase-substrate treatment improved PS hydrophilicity and roughness, increasing NHEM and NTERA-2 adherence, proliferation, and NHEM melanogenesis to a level comparable with conventional plasma treatment. Cell adherence dynamics and proliferation were evaluated. The NHEM endpoint function was quantified by measuring melanin content. PS surfaces treated with laccase and its substrates demonstrated the forming of polymer-like structures. The surface texture roughness gradient and the peak curvature were higher on PS treated with a combination of laccase and substrates than laccase alone. The number of adherent NHEM and NTERA-2 was significantly higher than on the untreated surface. The proliferation of NHEM and NTERA-2 correspondingly increased on treated surfaces. NHEM melanin content was enhanced 6-10-fold on treated surfaces. In summary, laccase- and laccase-substrate-modified PS possess improved PS surface chemistry/hydrophilicity and altered roughness compared to untreated and plasma-treated surfaces, facilitating cellular adherence, subsequent proliferation, and exertion of the melanotic phenotype. The presented technology is easy to apply and creates a promising custom-made, substrate-based, cell-type-specific platform for both 2D and 3D cell culture.

BET bromodomain inhibitors regulate keratinocyte plasticity.

Although most acute skin wounds heal rapidly, non-healing skin ulcers represent an increasing and substantial unmet medical need that urgently requires effective therapeutics. Keratinocytes resurface wounds to re-establish the epidermal barrier by transitioning to an activated, migratory state, but this ability is lost in dysfunctional chronic wounds. Small-molecule regulators of keratinocyte plasticity with the potential to reverse keratinocyte malfunction in situ could offer a novel therapeutic approach in skin wound healing. Utilizing high-throughput phenotypic screening of primary keratinocytes, we identify such small molecules, including bromodomain and extra-terminal domain (BET) protein family inhibitors (BETi). BETi induce a sustained activated, migratory state in keratinocytes in vitro, increase activation markers in human epidermis ex vivo and enhance skin wound healing in vivo. Our findings suggest potential clinical utility of BETi in promoting keratinocyte re-epithelialization of skin wounds. Importantly, this novel property of BETi is exclusively observed after transient low-dose exposure, revealing new potential for this compound class.

Role of Surgical Pathologist for the Detection of Immuno-oncologic Predictive Factors in Non-small Cell Lung Cancers.

Until very recently, surgery, chemotherapy, and radiation therapy have been the mainstay of treatment in non-small cell carcinomas (NSCLCs). However, recent advances in molecular immunology have unveiled some of the complexity of the mechanisms regulating cellular immune responses and led to the successful targeting of immune checkpoints in attempts to enhance antitumor T-cell responses. Immune checkpoint molecules such as cytotoxic T-lymphocyte associated protein-4, programmed cell death protein-1, and programmed death ligand (PD-L) 1 have been shown to play central roles in evading cancer immunity. Thus, these molecules have been targeted by inhibitors for the management of cancers forming the basis of immunotherapy. Advanced NSCLC has been the paradigm for the benefits of immunotherapy in any cancer. Treatment decisions are made based on the expression of PD-L1 on the tumor cells and the presence or absence of driver mutations. Patients with high PD-L1 expression (≥50%) and no driver mutations are treated with single-agent immunotherapy whereas, for all other patients with a lower level of PD-L1 expression, a combination of chemotherapy and immunotherapy is preferred. Thus, PD-L1 blockers are the only immunotherapeutic agents approved in advanced NSCLC without any oncogenic driver mutations. PD-L1 immunohistochemistry, however, may not be the best biomarker in view of its dynamic nature in time and space, and the benefits may be seen regardless of PD -L1 expression. Each immunotherapy molecule is prescribed based on the levels of PD-L1 expression as assessed by a Food and Drug Administration-approved companion diagnostic assay. Other biomarkers that have been studied include tumor mutational burden, the T-effector signature, tumor-infiltrating lymphocytes, radiomic assays, inflammation index, presence or absence of immune-related adverse events and specific driver mutations, and gut as well as local microbiome. At the current time, none of these biomarkers are routinely used in the clinical decision-making process for immunotherapy in NSCLC. However, in individual cases, they can be useful adjuncts to conventional therapy. This review describes our current understanding of the role of biomarkers as predictors of response to immune checkpoint molecules. To begin with a brief on cancer immunology in general and in NSCLC, in particular, is discussed. In the end, recent advancements in laboratory techniques for refining biomarker assays are described.

Influence of aging of PEEK attachment inserts on the pull-off force of implant-retained overdentures - A laboratory study.

OBJECTIVES: The aim of the current study is to investigate the influence of mechanical stress as well as cleaning agents on the performance of various polyether ether ketone (PEEK) inserts for implant-retained overdentures (IOD). MATERIALS AND METHODS: Three different standard PEEK inserts were subjected to rapid artificial aging through storage in chemical denture cleaning agents (acetic acid, sodium hypochlorite, or sparkling denture cleaner) as well as demineralized water. The pre-aged PEEK inserts were then placed in unilateral IOD and subjected to 200,000 chewing loads (5 kg ~ 50 N), with 5000 thermal cycles (5/55°C), and 1100 removal/insertion cycles (vertical movement 2 mm). RESULTS: For all the PEEK inserts, the retention forces decreased significantly with an increasing number of mechanical load cycles and after exposure to all the cleaning agents. PEEK inserts aged by exposure to chemical cleaning agents showed a significantly higher decline in retention force than the inserts stored in water. Confocal laser scanning microscopy indicated that the decline in retention force might be caused by wear on the internal insert surface in contact with the patrix. CONCLUSIONS: Within the limitations of this study, it can be concluded that the application of chemical cleaning agents accelerates the decline in the retention forces of PEEK retentive inserts in IODs.

5-Fluorouracil blocks quorum-sensing of biofilm-embedded methicillin-resistant Staphylococcus aureus in mice.

Antibiotic-resistant pathogens often escape antimicrobial treatment by forming protective biofilms in response to quorum-sensing communication via diffusible autoinducers. Biofilm formation by the nosocomial pathogen methicillin-resistant Staphylococcus aureus (MRSA) is triggered by the quorum-sensor autoinducer-2 (AI-2), whose biosynthesis is mediated by methylthioadenosine/S-adenosylhomocysteine nucleosidase (MTAN) and S-ribosylhomocysteine lyase (LuxS). Here, we present a high-throughput screening platform for small-molecular inhibitors of either enzyme. This platform employs a cell-based assay to report non-toxic, bioavailable and cell-penetrating inhibitors of AI-2 production, utilizing engineered human cells programmed to constitutively secrete AI-2 by tapping into the endogenous methylation cycle via ectopic expression of codon-optimized MTAN and LuxS. Screening of a library of over 5000 commercial compounds yielded 66 hits, including the FDA-licensed cytostatic anti-cancer drug 5-fluorouracil (5-FU). Secondary screening and validation studies showed that 5-FU is a potent quorum-quencher, inhibiting AI-2 production and release by MRSA, Staphylococcus epidermidis, Escherichia coli and Vibrio harveyi. 5-FU efficiently reduced adherence and blocked biofilm formation of MRSA in vitro at an order-of-magnitude-lower concentration than that clinically relevant for anti-cancer therapy. Furthermore, 5-FU reestablished antibiotic susceptibility and enabled daptomycin-mediated prevention and clearance of MRSA infection in a mouse model of human implant-associated infection.

The influence of different storage media on Vickers hardness and surface roughness of CAD/CAM resin composites.

INTRODUCTION: This study examined Vickers hardness as well as surface characteristics of different computer-aided design/computer-aided manufacturing (CAD/CAM) resin composites prior to and after storage in various media. MATERIALS AND METHODS: CAD/CAM resin composite blocks (Grandio Blocs (GB), Lava Ultimate (LU), Brilliant Crios (BC), Cerasmart (GC), Shofu Block HC (SB), Tetric CAD (TC), Luxacam Composite (LC); incl. different translucency variants) were prepared, polished and surface free energy was determined. The specimens were divided into four groups: dry conditions for 24 h (25 °C), demineralized water (37 °C), Pepsi Cola (37 °C) and 75% ethanol (37 °C). After seven and 28 days of storage, Vickers hardness was determined. Surface roughness was measured after the entire storage period. RESULTS AND DISCUSSION: Vickers hardness was in the range of about 150 HV for GB, around 115 HV for LU, and 80-100 HV for BC, GC, SB, TC and LC. Only minor differences (total: 50.2 (6.4)-56.2 (3.2) mN/m) in surface free energy could be detected. No relationship was observed between surface free energy and filler content. However, a correlation between filler content and Vickers hardness was evident. Artificial aging caused a decrease of Vickers hardness (up to -40 HV or 35%) depending on storage media, duration and material. The changes in surface texture after immersion in different media were below a value of ΔSa = 0.015 µm. CONCLUSION: Artificial aging of CAD/CAM resin composites leads to a significant decrease of Vickers hardness for most materials, while only small changes in surface roughness were identified.

Lung cancer presenting with central nervous system metastasis: Clinicopathological and molecular analysis of 171 cases.

A subset of lung carcinoma presents initially with brain metastasis. Precise subtyping is mandatory for optimized treatment of these advanced aggressive carcinomas. We herein analyzed surgical biopsies from 171 Patients (99 males and 72 females aged 48-96; mean, 72), who presented with brain metastasis of lung cancer. In addition to conventional subtyping, we applied an extended immunohistochemistry (IHC) panel and performed several molecular tests looking for potential therapeutic targets other than EGFR mutations. Non-small cell carcinoma (NSCLC) comprised 157 (91.8 %) of cases: 109 (63.7 %) adenocarcinomas, 27 (15.8 %) squamous cell (SCC), 18 (10.5 %) large cell undifferentiated, 1 (0.6 %) adenosquamous and 2 (1.2 %) unclassified carcinomas. Of the adenocarcinomas, 81.7 % were TTF1+. Notably, 45 % of those TTF1-negative cases expressed HepPar1. SMARCA4 and SMARCA2 loss was observed in 13/171 (7.6 %) and 32/163 (19.6 %) cases, respectively; mainly TTF1- (40.0 %) and HepPar1+ (38.1 %) adenocarcinomas were affected by SMARCA2/4 loss. Loss of at least one mismatch repair (MMR) protein was observed in 3/156 (1.9 %) cases (2 adenocarcinomas and 1 large cell neuroendocrine carcinoma/LCNEC). Limited available data on mutation testing showed a frequency of EGFR mutations of 4.3% and of KRAS mutations of 57%. HER2 expression (2+/3+) was found in 45/166 (27.1 %) of cases with amplification verified by CISH in 18/38 (47.4 % of immunopositive cases and 10.5 % of the whole cohort); all but one were adenocarcinomas. Other genetic abnormalities detected included EML4::ALK rearrangements in 3 (1.8 %; 2 TTF1+ adenocarcinomas and 1 LCNEC) and RET rearrangements in one SCNEC. Variable subsets of tumors revealed amplifications of several potentially therapeutically targetable genes including MYC (30.0 %), MET (10.1 %), HER2 (10 %), FGFR1 (9.6 %), FGFR3 (4.6 %), and FGFR2 (3.4 %). This study highlights a highly heterogeneous molecular background in lung cancer presenting with CNS metastases. These findings highlight the need for individualized tumor testing strategies looking for potential therapeutic targets for this aggressive disease.

Influence of dental prophylaxis procedures on the tooth veneer interface in resin-based composite and polymer-infiltrated ceramic veneer restorations: an in vitro study.

OBJECTIVES: The aim of this study was to investigate the influence of dental prophylaxis cleaning procedures and artificial aging on veneers in human teeth. The external marginal and internal tooth veneer as well as the restoration surfaces were examined. MATERIAL AND METHODS: Thirty-two extracted premolars were restored with resin-based composite (RBC) and polymer-infiltrated ceramic network (PICN) veneers. Artificial aging by alternating thermocycling and subsequent prophylaxis procedure (glycine-based powder air polishing or ultrasonic scaling) was conducted for five consecutive cycles. The external marginal interface was examined by height profile measurements and the internal interface was investigated using micro X-ray computed tomography. In addition, the surface texture of the veneer surface was analyzed using confocal laser scanning microscopy. RESULTS: The application of both prophylaxis procedures resulted in a deepening of the marginal interface (10 µm ± 8 µm) for materials. Furthermore, the internal interface of PICN restorations showed marginal gaps after both treatments and artificial aging (16 µm ± 3 µm). In contrast to the RBC specimens, a significant increase in surface roughness was identified for PICN veneers after ultrasonic scaling. CONCLUSIONS: The marginal and internal interface regions in veneers fabricated from PICN and RBC were affected by prophylaxis procedures. Furthermore, it may result in increased veneer surface roughness, especially in PICN and after ultrasonic scaling, which might affect bioadhesion and longevity. CLINICAL RELEVANCE: After dental prophylaxis procedures, examination of the marginal and the internal interface as well as the veneer surface provides a precise insight into damage mechanisms and offers an assessment of longevity.

Adhesive luting of orthodontic devices to silica-based ceramic crowns-comparison of shear bond strength and surface properties.

OBJECTIVES: The aim of this study was to analyse the impact of different clinical conditioning approaches and an ammonium polyfluoride- and trimethoxysilylpropyl methacrylate-based experimental primer for intraoral luting of buccal tubes on silica-based ceramic surfaces. MATERIALS AND METHODS: A total of 60 leucite-reinforced glass ceramic molar crowns were conditioned using different methods (n = 10): I-roughening, hydrofluoric acid, silane; II-roughening, silane; III-roughening, experimental coupling agent; IV-experimental coupling agent; V-roughening; VI-no treatment. A buccal tube was adhesively luted to the ceramic surface. Subsequently, water storage, thermocycling and chewing simulation were carried out. The shear bond strength (SBS) was determined, and changes in the surface were assessed. RESULTS: All tubes of the control group (group VI) debonded after incubation. The conditioning methods using coupling agents revealed mean values for SBS of 61.56 MPa (group I), 45.53 MPa (group III), 41.65 MPa (group II), and 23.14 MPa (group IV). In groups I-III, both composite residues and cracks/tear-outs were detected. CONCLUSIONS: The conditioning of silicate ceramic surfaces with a suitable coupling agent system appears to allow sufficient adhesive luting of buccal tubes. The intraoral luting of fixed appliance elements on silicate ceramic surfaces using an ammonium polyfluoride- and trimethoxysilylpropyl methacrylate-based ceramic primer can withstand orthodontic forces. CLINICAL RELEVANCE: Ammonium polyfluoride- and trimethoxysilylpropyl methacrylate-based ceramic primers revealed promising results for the intraoral adhesive luting of orthodontic devices to silica-based ceramic crowns.

Identifying the need for specialized palliative care in adult cancer patients - development and validation of a screening procedure based on proxy assessment by physicians and filter questions.

BACKGROUND: One challenge in caring for cancer patients with incurable disease is the adequate identification of those in need for specialized palliative care (SPC). The study's aim was to validate an easy to use phenomenological screening tool. METHODS: The German tool is based on the National Comprehensive Cancer Network (NCCN) Palliative Care guidelines and contains ten items in five domains that focus e.g. on diagnosis, functional status, complications, comorbidities, and palliative care relevant problems such as symptom management, distress, and support of family and team members. Sum score ranges from 0 to 14 (no need to great need). Assessment to identify SPC needs was done in university hospital wards between 1 and 08/2017 by health care professionals on admission of the patient if the disease was incurable and expected prognosis < 12 months. The Integrated Palliative Outcome Scale (IPOS, staff version), an outcome assessment instrument for palliative care that consists of ten items, served as external criterion; in sub samples inter-rater/test-retest were performed. RESULTS: Data from 208 patients with incurable disease and life expectancy < 12 months (54.8% female; average age 63.5 years, range 21-96) were assessed using the tool. The tool has good convergent validity; the correlation between the sum scores of IPOS and our tool showed a significant and substantial effect. The sum score was independent of the patient's age, gender and primary diagnosis. Patients who already were in contact with SPC had significantly higher screening scores than patients without. With a cut point of ≥ 5, 80.8% of the screened patients were in need for SPC. Cronbach's alpha was α = .600. Rater agreement (inter-rater, test-retest) varied between single items. Correlation coefficients showed significant substantial effects. CONCLUSIONS: This is the first validation of a screening procedure in German language identifying SPC needs of adult patients with advanced cancer and the first using filter questions as a pre-screening. Proxy assessment of SPC needs by physicians in cancer care settings is feasible and the suggested tool presents a valid instrument to trigger a PC consultation. TRIAL REGISTRATION: The study was not registered.

Identification of Bronchoalveolar Lavage Components Applying Confocal Laser Endomicroscopy.

BACKGROUND In many studies, confocal laser endomicroscopy (CLE) has proven to be a useful tool in pulmonology; nevertheless, the application in this field is still experimental. By contrast, CLE is almost a standard technique in gastroenterology. The aim of the present study was to demonstrate the identification of bronchoalveolar lavage (BAL) components applying CLE, using a dye. MATERIAL AND METHODS In 21 patients with various underlying diseases a bronchoscopy with BAL was performed. As in routine clinical practice common, BAL fluid (BALF) was analyzed in terms of cytologic, virologic, and microbiologic aspects. To one fraction of BALF, we added acriflavine. After centrifugation CLE was applied and the video sequences were analyzed by an experienced investigator. RESULTS Using CLE, BALF components (such as alveolar macrophages or leucocytes) could be easily identified. A further subdivision of leucocytes (neutrophilic, eosinophilic granulocytes, and lymphocytes) was not possible. Analogous to conventional cytology, a precise distinction of lymphocyte subpopulation (cd 4/cd 8 ratio) was not feasible. In terms of quantification, this is still the application field of flow cytometry and immunohistochemistry. CONCLUSIONS Using CLE, alveolar macrophages and leucocytes in stained BALF can be differentiated independent of smoking status. Further studies should be initiated in order to subclassify leucocytes in eosinophilic, neutrophilic granulocytes, and lymphocytes, which is important for routine clinical practice.

Confocal Laser Endomicroscopy for Diagnosing Malignant Pleural Effusions.

BACKGROUND Confocal laser endomicroscopy (CLE) enables "in vivo" microscopic tissue diagnosis based on tissue reflectance or tissue fluorescence upon application of fluorescence agents. The aim of the present study was to evaluate CLE as a new diagnostic approach for differentiation between malignant versus non-malignant pleural effusions. MATERIAL AND METHODS In 100 patients with pleural effusions, thoracentesis was performed. Cresyl violet and acriflavine were used as contrast agents for probe-based CLE of effusions. CLE video sequences were assessed by 4 independent investigators (2 experienced in this technique, 2 with only basic knowledge). In addition, all CLE samples were evaluated by an expert pathologist (p). Results were compared with conventional cytology of effusions and histology of cell blocks. RESULTS CLE reliably permitted identification of malignant cells in pleural effusions. Sensitivity for detection of malignant effusions was 87% (p: 87%) and 81% (p: 72%) for acriflavine and cresyl violet, respectively. With regard to specificity, acriflavine and cresyl violet yielded a mean value of 99% (p: 100%) and 92% (p: 100%). CONCLUSIONS In this pilot study, CLE permitted simple and rapid detection of malignant pleural effusions. Larger prospective studies are warranted to corroborate our findings.

ERK7 is a negative regulator of protein secretion in response to amino-acid starvation by modulating Sec16 membrane association.

RNAi screening for kinases regulating the functional organization of the early secretory pathway in Drosophila S2 cells has identified the atypical Mitotic-Associated Protein Kinase (MAPK) Extracellularly regulated kinase 7 (ERK7) as a new modulator. We found that ERK7 negatively regulates secretion in response to serum and amino-acid starvation, in both Drosophila and human cells. Under these conditions, ERK7 turnover through the proteasome is inhibited, and the resulting higher levels of this kinase lead to a modification in a site within the C-terminus of Sec16, a key ER exit site component. This post-translational modification elicits the cytoplasmic dispersion of Sec16 and the consequent disassembly of the ER exit sites, which in turn results in protein secretion inhibition. We found that ER exit site disassembly upon starvation is TOR complex 1 (TORC1) independent, showing that under nutrient stress conditions, cell growth is not only inhibited at the transcriptional and translational levels, but also independently at the level of secretion by inhibiting the membrane flow through the early secretory pathway. These results reveal the existence of new signalling circuits participating in the complex regulation of cell growth.

Tooth-composite bond failure with a universal and an etch-and-rinse adhesive depending on mode and frequency of application.

OBJECTIVES: To evaluate the effect of an additional layer of universal adhesive on the interfacial enamel/dentin-composite gap formation in relation to application mode and aging, via spectral domain optical coherence tomography (SD-OCT) and scanning electron microscopy (SEM). METHODS: In vitro class V cavities in 114 caries-free premolars were restored by applying one or two layers of a universal adhesive (Scotchbond Universal, SBU) in self-etch (se) and etch-and-rinse (er) mode or the reference adhesive OptiBond FL (OFL-er). The restorations were imaged by SD-OCT (six groups, n = 8) and SEM (n = 3) directly after filling (t1), water storage (t2, 24 h), embedding (t3), and thermo-mechanical loading (t4, TCML). The interfacial gaps were quantified using 26 parameters and analyzed using principal component analysis and linear mixed effect models. RESULTS: Gap formation at enamel and dentin was significantly influenced by the adhesive, the application mode and number of layers (p < 0.001). This was due to the influence of the SBU-er mode (p < 1e-05), which showed significantly more gap formation and a greater range of variation with double application when compared to SBU-se and OFL. The fewest interfacial gaps occurred with one or two applications of OFL-er and one layer of SBU-er. SIGNIFICANCE: Adhesive application mode and the number of adhesive layers are relevant factors in the tooth-composite bond failure. Double application worsened the adaptation of SBU to freshly prepared dentin conditioned with phosphoric acid.

Confocal laser endomicroscopy for diagnosing lung cancer in vivo.

Confocal laser endomicroscopy is a novel endoscopic technique that may allow imaging of living cells in lung tissue in vivo. We assessed the potential of this technique for the detection of histology during screening bronchoscopy for lung cancer. 32 patients with suspected malignancies underwent bronchoscopy with endomicroscopy using acriflavine hydrochloride. Standardised areas and localised lesions were analysed by in vivo confocal imaging during bronchoscopy and biopsies were taken. Confocal images were graded and correlated prospectively with conventional histology from biopsies. Acriflavine hydrochloride yielded high-quality confocal images and strongly labelled airway epithelial cells. No side-effects were noted. 75,522 confocal images from 56 different locations were compared prospectively with histological data from biopsy specimens. Endomicroscopy allowed subsurface imaging with detailed analysis of cellular and subcellular structures. Neoplastic changes could be predicted with high accuracy (sensitivity 96.0%, specificity 87.1%, accuracy 91.0%). Confocal laser endomicroscopy with acriflavine is a novel diagnostic tool for the analysis of living cells during bronchoscopy and permits virtual histology of neoplastic changes in the airways with high accuracy. This technique may enable the rapid diagnosis of neoplasia during ongoing endoscopy in patients with suspected lung cancer.

Aging and Fracture Resistance of Implant-Supported Molar Crowns with a CAD/CAM Resin Composite Veneer Structure.

Chipping of implant-supported molar crowns (iSCs) is a frequently reported complication. This study aimed to investigate the in-vitro aging and fracture resistance of iSCs with a CAD/CAM resin composite veneer structure fabricated with the Rapid Layer Technology (RLT) approach. Eight iSCs per group were fabricated by using two different CAD/CAM resin composites (Shofu Block HC: SH; Grandio blocs: GB) for veneer structures, and zirconia (ZrO2), polyetheretherketone (PEEK), and cobalt-chromium (CoCr; control) as framework materials. The surfaces to be bonded were sandblasted, cleaned in an ultrasonic bath, and a coupling agent was applied. A self-adhesive resin luting composite was used to adhesively lute the veneer structures to the frameworks. The crowns were semi-permanently cemented to the abutments. After storage in deionized water, iSCs were loaded in a chewing simulator (TCML, 10,000 thermal cycles 5 °C to 55 °C for 20 s, 1.2 million, loading force 50 N). Four ZrO2 and one CoCr crown did not survive the TCML. The fracture force was determined after 24 h storage in deionized water and yielded values of ≥974 N. Lowest fracture forces were yielded in the PEEK-SH group in comparison to CoCr or ZrO2 groups (p ≤ 0.031). For identical framework materials, no significant influence of the veneering material was observed. All PEEK-GB frameworks fractured, and chipping occurred for ZrO2-SH and all CoCr frameworks. PEEK-SH and ZrO2-GB presented both chipping and framework fractures. Within the limitations of this in-vitro study, the RLT with a CAD/CAM resin composite veneer structure might be a promising approach to veneer iSCs. Yet, the choice of the CAD/CAM resin composite and of the framework material determine the fracture resistance.

Aging Processes and Their Influence on the Mechanical Properties of Printable Occlusal Splint Materials.

Three-dimensional (3D)-printed occlusal splints are becoming more prevalent in the treatment of tooth substance loss due to their fast and cost-effective production. The purpose of this in vitro study was to investigate whether the mechanical properties (tensile strength-TS, modulus of elasticity in tension-ME, and Vickers hardness-HV) vary between the materials (printed dimethacrylate-based resins: Keyprint KeySplint soft-KEY, Luxaprint Ortho Plus-LUX, V-Print splint-VPR, printed methacrylate-based resins Freeprint splint 2.0-FRE, and milled methacrylate-based material, CLEAR splint-CLE), and the influence of aging processes (extraoral storage conditions and nightly or daily use) was examined. The printed methacrylate-based resins (FRE, LUX, and VPR) had much higher TS (43.7-48.5 MPa compared to 12.3-13.3 MPa), higher ME (2.01-2.37 GPa compared to 0.43-0.72 GPa), and higher HV (11.8-15.0 HV compared to 3.3-3.5 HV) than both of the methacrylate-based resins (KEY and CLE) after the production process. Although the TS, ME, and HV of the printed dimethacrylate resins (FRE, LUX, and VPR) decreased significantly under humid conditions with possibly elevated temperatures (thermocycling as well as 37 °C), these mechanical properties were significantly higher than both methacrylate-based resins (KEY and CLE). Therefore, printed dimethacrylate resins should be used rather than methacrylate-based resins for high expected masticatory forces, low wall thicknesses, or very long wearing times (≥6 months).