Dyslipidaemia after switch to tenofovir alafenamide (TAF)-based cART regimens in a cohort of HIV-positive patients: what clinical relevance?

OBJECTIVES: Switching from tenofovir (TDF) to tenofovir alafenamide (TAF) affects lipid profile. The aim of this study was to evaluate whether this results in an increased frequency of patients with low-density lipoprotein (LDL) above their cardiovascular-related target. METHODS: All HIV patients switching from TDF to TAF, with no changes of the anchor drug, and with plasma lipids available within 6 months before and after the switch, were included. Demographic, HIV-related parameters, cardiovascular (CV) risk factors and lipid profile on both TDF and TAF were collected. The CV risk score and the relative target of LDL for each patient were calculated according to 2016 European Society of Cardiology/European Atherosclerosis Society (ESC/EAS) guidelines for the management of dyslipidaemias. Modifications in lipid profiles and in the prevalence of patients with LDL above their CV-related target were evaluated after switch to TAF. RESULTS: Overall, 221 HIV patients were included, according to CV risk: 55% at low risk, 34% at moderate risk, and 11% at high/very high risk. By analysing lipid profiles according to CV risk, 38% of patients on TDF had LDL above their CV target; this prevalence increases to 60% after switching to TAF (P < 0.0001). The presence of cobicistat in the combination antiretroviral therapy (cART) regimen was associated with an increased risk of LDL above the CV-related target after switch to TAF [adjusted odds ratio (aOR) = 2.4, 95% confidence interval (CI): 1-5.1], P = 0.03) and with an increased prescription of lifestyle/therapeutic intervention (OR = 3.0, 95% CI: 1.7-5.3, P < 0.0001). DISCUSSION: Switching from TDF to TAF affects lipid parameters, and data from real life suggest a clinical relevance of this worsening that often leads clinicians to implement lifestyle/therapeutic interventions.

Marijuana smoke induces severe pulmonary hyperresponsiveness, inflammation, and emphysema in a predictive mouse model not via CB1 receptor activation.

Sporadic clinical reports suggested that marijuana smoking induces spontaneous pneumothorax, but no animal models were available to validate these observations and to study the underlying mechanisms. Therefore, we performed a systematic study in CD1 mice as a predictive animal model and assessed the pathophysiological alterations in response to 4-mo-long whole body marijuana smoke with integrative methodologies in comparison with tobacco smoke. Bronchial responsiveness was measured with unrestrained whole body plethysmography, cell profile in the bronchoalveolar lavage fluid with flow cytometry, myeloperoxidase activity with spectrophotometry, inflammatory cytokines with ELISA, and histopathological alterations with light microscopy. Daily marijuana inhalation evoked severe bronchial hyperreactivity after a week. Characteristic perivascular/peribronchial edema, atelectasis, apical emphysema, and neutrophil and macrophage infiltration developed after 1 mo of marijuana smoking; lymphocyte accumulation after 2 mo; macrophage-like giant cells, irregular or destroyed bronchial mucosa, goblet cell hyperplasia after 3 mo; and severe atelectasis, emphysema, obstructed or damaged bronchioles, and endothelial proliferation at 4 mo. Myeloperoxidase activity, inflammatory cell, and cytokine profile correlated with these changes. Airway hyperresponsiveness and inflammation were not altered in mice lacking the CB1 cannabinoid receptor. In comparison, tobacco smoke induced hyperresponsiveness after 2 mo and significantly later caused inflammatory cell infiltration/activation with only mild emphysema. We provide the first systematic and comparative experimental evidence that marijuana causes severe airway hyperresponsiveness, inflammation, tissue destruction, and emphysema, which are not mediated by the CB1 receptor.

Spectroscopic identification of the chemical interplay between defects and dopants in Al-doped ZnO.

The conduction and optoelectronic properties of transparent conductive oxides can be largely modified by intentional inclusion of dopants over a very large range of concentrations. However, the simultaneous presence of structural defects results in an unpredictable complexity that prevents a clear identification of chemical and structural properties of the final samples. By exploiting the unique chemical sensitivity of Hard X-ray Photoelectron Spectra and Near Edge X-ray Absorption Fine Structure in combination with Density Functional Theory, we determine the contribution to the spectroscopic response of defects in Al-doped ZnO films. Satellite peaks in O1s and modifications at the O K-edge allow the determination of the presence of H embedded in ZnO and the very low concentration of Zn vacancies and O interstitials in undoped ZnO. Contributions coming from substitutional and (above the solubility limit) interstitial Al atoms have been clearly identified and have been related to changes in the oxide stoichiometry and increased oxygen coordination, together with small lattice distortions. In this way defects and doping in oxide films can be controlled, in order to tune their properties and improve their performances.

Controlled co-deposition of FePt nanoparticles embedded in MgO: a detailed investigation of structure and electronic and magnetic properties.

Films of FePt nanoparticles (NPs) embedded in MgO were obtained by controlled co-deposition of FePt NPs pre-formed by a gas aggregation source and of Mg evaporated in an oxygen atmosphere. Assemblies of core-shell FePt@MgO NPs and films of FePt NPs embedded in MgO matrix could be obtained by varying FePt and Mg deposition rates. Transmission electron microscopy (TEM) and high resolution-TEM revealed the core-shell structure of the NPs, with an FePt core (of average diameter (d) = 4.75 nm) presenting a multitwinned icosahedral structure, and MgO partially in crystalline form. The functional effect of the MgO shell in shielding the FePt core from external oxidation was shown with XPS. Upon controlled annealing, a transition from A1 to L10 ordering could be obtained, with structural and morphological re-arrangement. The magnetic hysteresis loops obtained from alternating gradient field magnetometry at room temperature show a 'wasp-waist' shape, with small values of coercive field (Hc = 300-1400 Oe), decreasing at increasing amounts of co-deposited MgO.

Characterization of effector memory CD8+ T cells in the synovial fluid of rheumatoid arthritis.

Little is known about the cellular characteristics of CD8(+) T cells in rheumatoid arthritis (RA). We addressed this by investigating whether the frequency of the CD8(+) T cell subsets and their phenotypic characteristics are altered in the peripheral blood and synovial fluid (SF) from patients with RA. In this study, CD8(+) T cells, mainly CD45RA(-) effector memory (EM) CD8(+) T cells, were increased significantly in the SF, but not in the peripheral blood from RA patients, compared with healthy controls. The synovial EM CD8(+) T cells were activated phenotypes with high levels of CD80, CD86, and PD-1, and had a proliferating signature in vivo upon Ki-67 staining, whereas the Fas-positive cells were prone to apoptosis. In addition, EM CD8(+) T cells in the SF were less cytotoxic, as they expressed less perforin and granzyme B. In particular, the proportions of synovial fluid mononuclear cells that were CCR4(+)CD8(+) T cells and IL-4-producing CD8(+) T cells (i.e., Tc2 cells) were significantly higher than those in peripheral blood mononuclear cells of patients with RA and healthy controls. In addition, the number of IL-10-producing CD8(+) suppressor T (Ts) cells increased significantly in the SF of RA patients. Especially, CD8(+) T cells were inversely correlated with disease activity. These findings strongly suggest that EM CD8(+) T cells in the SF are increased, likely because of inflammation, and they may be involved in modulating inflammation, thereby affecting the development and progression of RA.

IL-7Rαlow memory CD8+ T cells are significantly elevated in patients with systemic lupus erythematosus.

OBJECTIVE: Human effector memory (EM) CD8(+) T cells include IL-7Rα(high) and IL-7Rα(low) cells with distinct cellular characteristics, including the expression of cytotoxic molecules. Both NK cells and the NK cell-associated molecule 2B4 that is expressed on CD8(+) T cells promote cytotoxicity. Here we analysed the expression of 2B4 on IL-7Rα(high) and IL-7Rα(low) EM CD8(+) T cells and its contribution to cytotoxicity. We also analysed the frequency of IL-7Rα(high) and IL-7Rα(low) EM CD8(+) T cells in patients with SLE or lupus and in healthy individuals given the potential role of cytotoxic CD8(+) T cells in the pathogenesis of lupus. METHODS: We used flow cytometry to measure the expression of 2B4 on IL-7Rα(high) and IL-7Rα(low) EM CD8(+) T cells as well as the frequency of these cell populations in the peripheral blood of healthy individuals and patients with SLE. Also, 2B4-mediated cytotoxicity was quantitated in IL-7Rα(high) and IL-7Rα(low) EM CD8(+) T cells using target cells with CD48 antigen. RESULTS: We found that IL-7Rα(high) EM CD8(+) T cells had higher levels of 2B4 expression compared with IL-7Rα(low) EM CD8(+) T cells. Triggering 2B4 enhanced the cytotoxic function of IL-7Rα(low) EM CD8(+) T cells against target cells. We also noticed that patients with SLE had an increased frequency of IL-7Rα(low) EM CD8(+) T cells that correlated with disease manifestation. CONCLUSION: Our findings show that SLE patients have increased IL-7Rα(low) EM CD8(+) T cells, possibly contributing to tissue damage through 2B4-mediated cytotoxicity.

Color Change of Resin-based Composites After In Vitro Bleaching Protocols: A Systematic Review and Meta-analysis.

OBJECTIVES: To systematically review the literature on color stability of resin-based composites (RBC) after in vitro bleaching protocols and to assess the influence of bleaching protocols by meta-regression analysis on RBC color stability, and the association with clinical and experimental characteristics. METHODS: The electronic search was conducted in MEDLINE/PubMed, Scopus, and Web of Science databases and included English language studies that evaluated and reported color differences (CIELAB values) of RBC after in vitro bleaching procedures using hydrogen peroxide and/or carbamide peroxide. RESULTS: Database search for color change of RBC after bleaching retrieved 1335 eligible papers after removing duplicates. After initial screening, 66 articles were assessed for full-text reading with final inclusion of 23 published papers. A meta-regression analysis showed that storage time (p≤0.01), color measuring device (p≤0.01), and background color (p≤0.01) had influenced on color changes of RBC. The bleaching protocol (bleaching agent and time of application) did not influence on color changes of RBC (p>0.01). CONCLUSIONS: There is evidence that RBC change color after bleaching, but the change is not clinically significant.

The dangers of reused personal protective equipment: healthcare workers and workstation contamination.

BACKGROUND: Personal protective equipment (PPE) is essential to protect healthcare workers (HCWs). The practice of reusing PPE poses high levels of risk for accidental contamination by HCWs. Scarce medical literature compares practical means or methods for safe reuse of PPE while actively caring for patients. METHODS: In this study, observations were made of 28 experienced clinical participants performing five donning and doffing encounters while performing simulated full evaluations of patients with coronavirus disease 2019. Participants' N95 respirators were coated with a fluorescent dye to evaluate any accidental fomite transfer that occurred during PPE donning and doffing. Participants were evaluated using blacklight after each doffing encounter to evaluate new contamination sites, and were assessed for the cumulative surface area that occurred due to PPE doffing. Additionally, participants' workstations were evaluated for contamination. RESULTS: All participants experienced some contamination on their upper extremities, neck and face. The highest cumulative area of fomite transfer risk was associated with the hook and paper bag storage methods, and the least contamination occurred with the tabletop storage method. Storing a reused N95 respirator on a tabletop was found to be a safer alternative than the current recommendation of the US Centers for Disease Control and Prevention to use a paper bag for storage. All participants donning and doffing PPE were contaminated. CONCLUSION: PPE reusage practices pose an unacceptably high level of risk of accidental cross-infection contamination to healthcare workers. The current design of PPE requires complete redesign with improved engineering and usability to protect healthcare workers.

Involvement of Ca²+ signaling in intracellular invasion of non-phagocytic host cells by Orientia tsutsugamushi.

Calcium signaling has been implicated in various steps in bacterial pathogenesis. Here, we investigated the role of Ca(2+) signaling in intracellular invasion of non-phagocytic host cells infected with Orientia tsutsugamushi, the causative agent of scrub typhus. The bacteria induced a transient Ca(2+) increase in HeLa cells immediately after infection and the source of the mobilized Ca(2+) appears to be intracellular stores, not the extracellular milieu, as determined using extracellular (EGTA) or intracellular (BAPTA-AM) Ca(2+) chelators. O. tsutsugamushi rapidly induced activation of PLC-γ1, as indicated by tyrosine phosphorylation. PLC-γ1 activity increased within 1 min of infection and returned to the basal level by 5 min. Pretreatment of host cells with inhibitors of PLC-γ1 (U73122) or IP3R channel activity (2-APB) significantly blocked bacterial entry without affecting bacterial attachment. In addition, these chemical inhibitors were effective in suppressing not only the activation of ERK MAP kinase but also the expression of the chemokine MCP-1. Taken together, Ca(2+) signaling induced by O. tsutsugamushi may play a crucial role in bacterial pathogenesis including inflammatory reactions as well as intracellular invasion into non-phagocytic host cells.

Orogastric intubation with dental fixation for enteral nutrition: a proof-of-concept study.

In this crossover trial, we evaluated a new technique for enteral nutrition using orogastric intubation. Twelve volunteers were randomly assigned to both orogastric (OGI) and conventional nasogastric intubation (NGI) with a 15-day interval. The tip of the orogastric tube was fixed intraorally into an upper molar. Participants were asked to remain intubated for 24 hours and rated efficacy and safety using a Likert scale (1: worst / 10: best). Tolerance in hours was longer during OGI (median 21 versus 12.5; p=0.022). OGI was superior in comfort (median 7 versus 3; p=0.002), aesthetic (median 10 versus 1; p=0.002), speech (median 5.5 versus 3; p=0.014) and swallowing (median 8 versus 2; p=0.004). Both procedures were tolerated with mild local complaints. Diet volume through the tube was greater during NGI (p = 0.014). In healthy participants, orogastric intubation with dental fixation showed greater efficacy and similar safety to nasogastric intubation. CLINICAL TRIALS NUMBER: NCT03670238.

Global gene expression profile of Orientia tsutsugamushi.

Orientia tsutsugamushi, an obligate intracellular bacterium, is the causative agent of Scrub typhus. The control mechanisms for bacterial gene expression are largely unknown. Here, the global gene expression of O. tsutsugamushi within eukaryotic cells was examined using a microarray and proteomic approaches for the first time. These approaches identified 643 genes, corresponding to approximately 30% of the genes encoded in the genome. The majority of expressed genes belonged to several functional categories including protein translation, protein processing/secretion, and replication/repair. We also searched the conserved sequence blocks (CSBs) in the O. tsutsugamushi genome which is unique in that up to 40% of its genome consists of dispersed repeated sequences. Although extensive shuffling of genomic sequences was observed between two different strains, 204 CSBs, covering 48% of the genome, were identified. When combining the data of CSBs and global gene expression, the CSBs correlates well with the location of expressed genes, suggesting the functional conservation between gene expression and genomic location. Finally, we compared the gene expression of the bacteria-infected fibroblasts and macrophages using microarray analysis. Some major changes were the downregulation of genes involved in translation, protein processing and secretion, which correlated with the reduction in bacterial translation rates and growth within macrophages.

Intracellular invasion by Orientia tsutsugamushi is mediated by integrin signaling and actin cytoskeleton rearrangements.

Orientia tsutsugamushi, the causative agent of scrub typhus, is an obligate intracellular pathogen. Previously, we reported that the 56-kDa type-specific antigen (TSA56), a major outer membrane protein of O. tsutsugamushi, binds to fibronectin and facilitates bacterial entry into the host cell, potentially via an interaction with integrins. Here, we demonstrated that O. tsutsugamushi colocalizes with integrin alpha 5 beta 1 and activates integrin signaling effectors, including focal adhesion kinase, Src kinase, and RhoA GTPase, and also recruits signaling adaptors, such as talin and paxillin, to the site of infection. Inhibition of protein tyrosine kinases or RhoA reduced intracellular invasion. We also observed substantial actin reorganization and membrane protrusions at the sites of infection of nonphagocytic host cells. Finally, we identified a region in the extracellular domain of TSA56 that binds to fibronectin. A peptide containing this region was able to significantly reduce bacterial invasion. Taken together, these results clearly indicate that O. tsutsugamushi exploits integrin-mediated signaling and the actin cytoskeleton for invasion of eukaryotic host cells.

Role of amphipathic helix of a herpesviral protein in membrane deformation and T cell receptor downregulation.

Lipid rafts are membrane microdomains that function as platforms for signal transduction and membrane trafficking. Tyrosine kinase interacting protein (Tip) of T lymphotropic Herpesvirus saimiri (HVS) is targeted to lipid rafts in T cells and downregulates TCR and CD4 surface expression. Here, we report that the membrane-proximal amphipathic helix preceding Tip's transmembrane (TM) domain mediates lipid raft localization and membrane deformation. In turn, this motif directs Tip's lysosomal trafficking and selective TCR downregulation. The amphipathic helix binds to the negatively charged lipids and induces liposome tubulation, the TM domain mediates oligomerization, and cooperation of the membrane-proximal helix with the TM domain is sufficient for localization to lipid rafts and lysosomal compartments, especially the mutivesicular bodies. These findings suggest that the membrane-proximal amphipathic helix and TM domain provide HVS Tip with the unique ability to deform the cellular membranes in lipid rafts and to downregulate TCRs potentially through MVB formation.

Influence of Bleaching and Aging Procedures on Color and Whiteness of Dental Composites.

Bleaching can cause perceptible color changes on resin-based composite (RBC) restorations that may not be stable with aging. The objective of this study was to evaluate color stability and whiteness variations of RBCs after bleaching and aging procedures. Discs (10 mm in diameter and 1 mm thick) of shades A2 and A3 were fabricated from two RBCs (Filtek Z250 and Filtek Z350 XT) and divided into three subgroups (for each composite and shade) (n=5) as follows: control (no bleaching), at-home bleaching, and in-office bleaching. All specimens underwent an accelerated artificial aging up to 450 KJ/m2 and 900 KJ/m2 in an aging chamber (Suntest XXL+). A spectroradiometer (SpectraScan PR-670) was used to obtain CIE L*a*b* coordinates. CIEDE2000 color difference (ΔE00) and whiteness index for dentistry (WID) were used to evaluate color stability. Color and whiteness differences data were analyzed considering the 50:50% visual color difference thresholds (perceptibility [PT] and acceptability [AT]) and 50:50% whiteness thresholds (whiteness perceptibility [WPT] and whiteness acceptability [WAT]). Analysis of variance and Tukey tests (α=0.05) were used to statistically analyze the data. After bleaching, all specimens showed ΔE00 and ΔWID values below their corresponding acceptability thresholds (AT and WAT, respectively). After aging, L* and WID values decreased while b* values increased (p≤0.05), resulting in ΔE00 and ΔWID values above AT and WAT, respectively. Color changes after bleaching RBCs were clinically acceptable, while aging provoked clinically perceptible color changes.

A double blind randomized clinical trial of at-home tooth bleaching using two carbamide peroxide concentrations: 6-month follow-up.

OBJECTIVES: This double blind randomized clinical trial evaluated the longevity of the whitening effect (6-month follow-up) of two carbamide peroxide concentrations used in at-home vital bleaching. METHODS: Ninety-two volunteers with shade mean C1 or darker for the six maxillary anterior teeth were randomized into two balanced groups (n=46) according to bleaching agent concentration: 10% (CP10) or 16% (CP16) carbamide peroxide. Patients were instructed to use the whitening agent in a tray for 2h/day during 3 weeks. Shade evaluations were done with a value-oriented shade guide, and a spectrophotometer at baseline, and at 1-week and 6-month post-bleaching. Volunteers for both treatment groups had to answer questions related to dietary and oral hygiene behavior. RESULTS: At 6-month recall, tooth shade remained significantly lighter than at baseline, in both treatment groups, considering the color parameters: DeltaL, Deltaa, Deltab, DeltaE (p<0.0001) or the tooth shade median values (p<0.001). Additionally, shade median relapse at 6-month follow-up was not statistically different between CP10 and CP16 groups using the spectrophotometer (p=0.1) or the visual matching (p=0.7) analyses. Overall, subjects from CP10 and CP16 reported high consumption of beverage and food stains, which was not different between groups (p=0.5). CONCLUSIONS: The whitening effect remained similar 6-month after the bleaching treatment for both carbamide peroxide concentrations tested. Additionally, the high consumption of staining beverages and foods reported by patients had no influence in the whitening effect longevity at 6-month.

Delineation of four cell types comprising the giant cell tumor of bone. Expression of Ia and monocyte-macrophage lineage antigens.

Giant cell tumors of bone dissociated by collagenase digestion were found to be composed of four different cell types defined by morphology, growth in culture, and pattern of staining with monoclonal antibodies. Giant cells comprised an average of 0.8% of the cells recovered, with the remainder consisting of small stromal cells. Of the giant cells, 20-57% expressed Ia antigens, while all lacked IgG Fc receptors and five differentiation antigens associated with mature members of the monocyte-macrophage lineage (M phi S-1, M phi P-9, M phi P-15, M phi S-39, and 63d3). One antigen, M phi U-50, found on early monocytoid forms was expressed on Ia+ giant cells. 6-36% of the remaining stromal tumor cells formed a second subpopulation that assumed either a rounded or elongated shape in culture. These cells bore Ia antigens, IgG Fc receptors, and five antigens of the monocyte-macrophage lineage usually found on blood monocytes. However, these cells differed from monocytes or macrophages in that the antigen M phi R-17 generally found on tissue macrophages was absent, and the M phi U-50 antigen present on more primitive cells was well expressed. A very limited endocytic capacity was demonstrable. A third population of up to 24% of the tumor cells was defined by the presence of intense staining for Ia antigens but the absence of antigens of mature monocytes. A proportion of these cells expressed M phi U-50 and a minority had IgG Fc receptors. The two Ia(+) populations of stromal cells were not identifiable after 2 wk of culture, nor did tumor cells selected for the presence of Ia antigens proliferate in culture. A fourth population of cells lacked Ia and monocyte lineage antigens, but showed pronounced intracellular staining for acid phosphatase. These cells had a distinctive plump epitheloid to fibroblastoid morphology and were readily established in long-term culture where they gave rise to large multinuclear Ia(-) cells containing acid phosphatase. The possibility is discussed that the cell types of these tumors relate to various stages in the development of osteoclasts from precursors in the mononuclear phagocyte lineage.

High frequency of autoantibodies bearing cross-reactive idiotopes among hybridomas using VH7183 genes prepared from normal and autoimmune murine strains.

Hybridomas obtained by in vitro stimulation with lipopolysaccharides (LPS) of BALB/c, MRL/lpr, and NZB splenocytes were selected for expression of VH7183 by hybridization using slot blotting. Northern blot analysis showed that the majority of hybrids produce a full length message complementary to the VH7183 probe. The frequency of VH7183 hybridomas was significantly higher in NZB mice as compared with BALB/c mice. Using multiple binding assays, 60% of the total antibodies encoded by VH7183 were specific for self-epitopes. Finally, the vast majority express cross-reactive idiotypes borne by autoantibodies of various specificities.

Masking Colored Substrates Using Monolithic and Bilayer CAD-CAM Ceramic Structures.

OBJECTIVE: To evaluate the masking ability and translucency of monolithic and bilayer CAD-CAM ceramic structures. METHODS: Discs of high translucency (HT) and low translucency (LT) lithium disilicate-based ceramic (IPS e.max CAD) with different thicknesses (0.7, 1, 1.5, and 2 mm) were evaluated as a monolithic structure or combined (bilayer) with a 0.5-mm-thick zirconia framework (IPS e.max ZirCAD). The masking ability and translucency were calculated based on CIE L*a*b* color coordinates measured with a spectrophotometer (SP60, X-Rite). The translucency parameter (TP) was calculated using color coordinates measured over standard white-and-black backgrounds. The masking ability was calculated by CIEDE2000 color difference metric (ΔE00) for each specimen measured over a tooth-colored substrate (shade A2) compared to three darker backgrounds (shade C4 and two metal substrates). Confidence intervals (CI) for the means (95% CI) were calculated for TP and ΔE00. The Pearson correlation between ΔE00 and TP was investigated for monolithic and bilayer structures over all backgrounds. RESULTS: The thinner the lithium disilicate layer, the greater the translucency and the higher the ΔE00 values. The effect of ceramic thickness on both translucency and masking ability was more pronounced for the monolithic structures. In addition, monolayers always presented a greater color variation than their bilayer counterparts. The metallic background produced greater ΔE00 than the C4-shaded substrate. CONCLUSION: Monolithic veneers were able to mask C4-shaded background but did not mask metallic backgrounds. Bilayer structures showed greater shade masking ability than monolithic structures.

ADM guidance-ceramics: Fatigue principles and testing.

BACKGROUND: Clinical failure of dental ceramics is usually reported as partial fracture of the restoration (chipping) or as catastrophic fracture of the whole structure. In contrast to metals, ceramics are linear-elastic, brittle materials exhibiting extremely low damage tolerance to failure. Well documented clinical and lab reports have shown this fracture event often occurs at loads far below their fracture strength due to intrinsic fatigue degradation via slow crack growth or cyclic fatigue mechanisms. The presence and development of surface flaws have a dominant role in damage accumulation and lifetime reduction of ceramic structures. AIMS: This ADM guidance document aims to summarize the aspects related to fatigue degradation of dental ceramics, reviewing the concepts of fatigue testing and furthermore aims to provide practical guidance to young scientists entering into fatigue related research. The description of fatigue strength is always accompanied by a clear understanding of the underlying fracture mechanisms.