The role of acquired host immunity in periodontal diseases.

The aim of this narrative review is to relate the contribution of European researchers to the complex topic of the host immune system in periodontal disease, focusing on acquired immunity. Other chapters in this volume will address the genetics and autoantibody responses and other forms of immunity to periodontal disease. While the contribution of European authors is the focus, global literature is included in this descriptive narrative for contextual clarity, albeit many with European co-authors. The topic is relatively intense and is thus broken down into sections outlined below, tackled as descriptive narratives to enhance understanding. Any attempt at a systematic or scoping review was quickly abandoned given the descriptive nature and marked variation of approach in almost all publications. Even the most uniform area of this acquired periodontal immunology literature, antibody responses to putative pathogens in periodontal diseases, falls short of common structures and common primary outcome variables one would need and expect in clinical studies, where randomized controlled clinical trials (RCTs) abound. Addressing 'the host's role' in immunity immediately requires a discussion of host susceptibility, which necessitates consideration of genetic studies (covered elsewhere in the volume and superficially covered here).

Randomized open-label controlled study of cancer vaccine OSE2101 versus chemotherapy in HLA-A2-positive patients with advanced non-small-cell lung cancer with resistance to immunotherapy: ATALANTE-1.

BACKGROUND: Patients with advanced non-small-cell lung cancer (NSCLC) treated with immune checkpoint blockers (ICBs) ultimately progress either rapidly (primary resistance) or after durable benefit (secondary resistance). The cancer vaccine OSE2101 may invigorate antitumor-specific immune responses after ICB failure. The objective of ATALANTE-1 was to evaluate its efficacy and safety in these patients. PATIENTS AND METHODS: ATALANTE-1 was a two-step open-label study to evaluate the efficacy and safety of OSE2101 compared to standard-of-care (SoC) chemotherapy (CT). Patients with human leukocyte antigen (HLA)-A2-positive advanced NSCLC without actionable alterations, failing sequential or concurrent CT and ICB were randomized (2 : 1) to OSE2101 or SoC (docetaxel or pemetrexed). Primary endpoint was overall survival (OS). Interim OS futility analysis was planned as per Fleming design. In April 2020 at the time of interim analysis, a decision was taken to prematurely stop the accrual due to coronavirus disease 2019 (COVID-19). Final analysis was carried out in all patients and in the subgroup of patients with ICB secondary resistance defined as failure after ICB monotherapy second line ≥12 weeks. RESULTS: Two hundred and nineteen patients were randomized (139 OSE2101, 80 SoC); 118 had secondary resistance to sequential ICB. Overall, median OS non-significantly favored OSE2101 over SoC {hazard ratio (HR) [95% confidence interval (CI)] 0.86 [0.62-1.19], P = 0.36}. In the secondary resistance subgroup, OSE2101 significantly improved median OS versus SoC [11.1 versus 7.5 months; HR (95% CI) 0.59 (0.38-0.91), P = 0.017], and significantly improved post-progression survival (HR 0.46, P = 0.004), time to Eastern Cooperative Oncology Group (ECOG) performance status deterioration (HR 0.43, P = 0.006) and Quality of Life Questionnaire Core 30 (QLQ-C30) global health status compared to SoC (P = 0.045). Six-month disease control rates and progression-free survival were similar between groups. Grade ≥3 adverse effects occurred in 11.4% of patients with OSE2101 and 35.1% in SoC (P = 0.002). CONCLUSIONS: In HLA-A2-positive patients with advanced NSCLC and secondary resistance to immunotherapy, OSE2101 increased survival with better safety compared to CT. Further evaluation in this population is warranted.

Periods of environmental sensitivity couple larval behavior and development.

The typical life cycle in most animal phyla includes a larval period that bridges embryogenesis and adulthood1. Despite the great diversity of larval forms, all larvae grow, acquire adult morphology and function, while navigating their habitats to obtain resources necessary for development. How larval development is coordinated with behavior remains substantially unclear. Here, we describe features of the iterative organization of larval stages that serve to assess the environment and procure resources prior to costly developmental commitments. We found that male-excreted pheromones accelerate2-4 the onset of adulthood in C. elegans hermaphrodites by coordinately advancing multiple developmental events and growth during the last larval stage. The larvae are sensitive to the accelerating male pheromones only at the end of the penultimate larval stage, just before the acceleration begins. Other larval stages also contain windows of sensitivity to environmental inputs. Importantly, behaviors associated with search and consumption of food are distinct between early and late portions of larval stages. We infer that each larval stage in C. elegans is subdivided into two epochs: A) global assessment of the environment to identify the most suitable patch and B) consumption of sufficient food and acquisition of salient information for developmental events in the next stage. We predict that in larvae of other species behavior is also divided into distinct epochs optimized either for assessing the habitat or obtaining the resources. Thus, a major role of larval behavior is to coordinate the orderly progression of development in variable environments.

Red cell extracellular vesicles and coagulation activation pathways.

PURPOSE OF REVIEW: Packed red blood cells (PRBCs) are the most commonly transfused blood products. Preparation of PRBCs requires blood collection from donors, processing, and storage prior to transfusion to recipients. Stored red blood cells (RBCs) undergo structural and metabolic changes collectively known as the storage lesion. RBC extracellular vesicles (sREVs) are released in PRBC units during storage, and are transfused along with intact RBCs into recipients. For several decades, extracellular vesicles have been the focus of intense research, leading to the discovery of a wide variety of endogenous biological properties that may impact numerous physiologic and/or pathologic pathways. RECENT FINDINGS: This study reviews the characteristics of extracellular vesicles present in PRBC units and the impact of prestorage and pretransfusion processing, as well as storage conditions, on their generation. Importantly, we discuss recently described interactions of sREVs with coagulation pathways and related interplay with inflammatory pathways in vitro and in vivo using animal models. SUMMARY: Extracellular vesicles present in stored PRBC units are capable of activating coagulation pathways. However, it remains unclear whether this affects clinical outcomes in recipients of PRBC units. Further understanding of these pathways and their relationship to any adverse outcomes may yield novel strategies to mitigate complications of blood transfusion.

Serum Metabolites Associated with Muscle Hypertrophy after 8 Weeks of High- and Low-Load Resistance Training.

The mechanisms responsible for the similar muscle growth attained with high- and low-load resistance training (RT) have not yet been fully elucidated. One mechanism is related to the mechanical stimulus and the level of motor unit recruitment; another mechanism is related to the metabolic response. We investigated the electromyographic signal amplitude (sEMG) and the general metabolic response to high-load RT (HL) and low-load resistance training (LL). We measured muscle thickness by ultrasound, sEMG amplitude by electromyography, and analysis of metabolites expressed through metabolomics. No differences were observed between the HL and LL groups for metabolic response and muscle thickness. A greater amplitude of sEMG was observed in the HL group. In addition, a correlation was observed between changes in muscle thickness of the vastus lateralis muscle in the HL group and levels of the metabolites carnitine, creatine, 3-hydroxyisovalerate, phenylalanine, asparagine, creatine phosphate, and methionine. In the LL group, a correlation was observed between changes in muscle thickness of the vastus lateralis muscle and levels of the metabolites acetoacetate, creatine phosphate, and oxypurinol. These correlations seem to be related to the characteristics of activated muscle fibers, the metabolic demand of the training protocols used, and the process of protein synthesis.

Automated Adaptive Wideband Acoustic Stapedius Reflex Thresholds in Adults With Normal Hearing and Sensorineural Hearing Loss.

OBJECTIVES: This study compared the measurement of the acoustic stapedius reflex threshold (ART) obtained using a traditional method with that obtained using an automated adaptive wideband (AAW) method. Participants included three groups of adults with normal hearing (NH), mild sensorineural hearing loss (SNHL), or moderate SNHL. The purpose of the study was to compare ARTs for the three groups and to determine which method had the best performance in detecting SNHL. DESIGN: Ipsilateral and contralateral ARTs were obtained using 0.5, 1, and 2 kHz tonal activators, and broadband noise (BBN) activators on a traditional admittance system (Clinical) at tympanometric peak pressures (TPP) and on an experimental wideband system using an AAW method at both ambient pressure and TPP. ART data previously reported for 39 NH adults with a mean age of 47.7 years were compared with data for 25 participants with mild SNHL with a mean age of 63.8 years, and 20 participants with moderate SNHL with a mean age of 65.7 years. Differences in ARTs between the normal-hearing and SNHL groups for the three methods were examined using a General Linear Model Repeated-Measures test. A receiver operating characteristic curve (ROC) analysis was also used to determine the ability of an ART test to detect SNHL. RESULTS: For the 0.5 kHz activator condition, there were no significant group mean differences in ART between NH and SNHL groups for either ipsilateral or contralateral activator presentation modes for the Clinical or AAW methods. There were significant group mean differences for the 1 and 2 kHz tonal activators and BBN activator for both ipsilateral and contralateral modes with greater differences in ART between groups for the AAW method than the Clinical method. In these conditions, the mean ART was lower for the AAW tests relative to the Clinical test. The greatest difference between groups was for the ipsilateral AAW tests for the comparison of NH with moderate SNHL for the BBN activator. This difference was approximately 20 dB for the AAW tests and 8 dB for the Clinical test. The ROC analysis showed that the area under the ROC curve (AUC) increased with the frequency of the activator stimulus and with the degree of hearing loss and was maximal for the BBN activator for both the AAW and Clinical methods for both ipsilateral and contralateral presentations. CONCLUSIONS: For ipsilateral and contralateral ART tests for activator frequencies above 0.5 kHz and BBN, listeners with SNHL generally had elevated ARTs compared with those with NH. The AAW method resulted in greater differences between SNHL groups and NH than the Clinical method. The AUC for detecting SNHL also increased with activator frequency and degree of hearing loss and was greatest for the BBN activator for the AAW method in both the ambient and TPP conditions. The results are encouraging for the use of an AAW ART method for the assessment of individuals with SNHL.

Passenger Lymphocyte Syndrome and Autoimmune Hypothyroidism Following Hematopoietic Stem Cell Transplantation.

We present the case of a 24-year-old male, who received a minor ABO-incompatible allogeneic hematopoietic stem cell transplant (HSCT, blood group O+ ⟶ A+) from an HLA-matched unrelated female donor, as consolidation therapy for relapsed precursor-B-cell acute lymphoblastic leukemia. The donor had a known history of Hashimoto's thyroiditis before HSCT. At day +10 posttransplant, the patient developed severe hemolysis, which required emergent red blood cell exchange. Additionally, about a year posttransplant, he had circulating antithyroglobulin antibodies, decreased free-T4 (fT4) and increased serum thyroid-stimulating hormone (TSH). The potential causes of the posttransplant hemolytic episode and hypothyroidism are discussed. While the hemolysis was worsened by the transfusion of A red blood cells (RBCs) in the context of passenger lymphocyte syndrome, the thyroid dysfunction might be explained by an autoimmune disease transferred from the donor. The case highlights the possibility of several non-relapse-related complications of HSCT occurring in the same patient. It is critical that such adverse outcomes are distinguished from classical graft-versus-host disease (GVHD) for adequate recipient counseling, posttransplant screening, and prompt treatment.

Risk assessment and implementation of risk reduction measures is not associated with increased transmission of SARS-CoV-2 compared with standard isolation at professional golf events.

Objectives: The purpose of this prospective study was to report incidence and transmission of SARS-CoV-2, among professional golfers and essential support staff undergoing risk assessment and enhanced risk reduction measures when considered a close contact as opposed to standard isolation while competing on the DP World Tour during the 2021 season. Methods: This prospective cohort study included all players and essential support staff participating in 26 DP World Tour events from 18 April 2021 to 21 November 2021. High-risk contacts were isolated for 10 days. Moderate-risk contacts received education regarding enhanced medical surveillance, had daily rapid antigen testing for 5 days, with reverse transcriptase-polymerase chain reaction (RT-PCR) tesing on day 5, mandated mask use and access to outside space for work purposes only. Low-risk contacts typically received rapid antigen testing every 48 hours and RT-PCR testing on day 5. Results: The total study cohort compromised 13 394 person-weeks of exposure. There were a total of 30 positive cases over the study period. Eleven contacts were stratified as 'high risk'. Two of these subsequently tested positive for SARS-CoV-2. There were 79 moderate-risk contact and 73 low-risk contacts. One moderate-risk contact subsequently tested positive for SARS-CoV-2 but did not transmit the virus. All other contacts, remained negative and asymptomatic to the end of the tournament week. Conclusions: A risk assessment and risk reduction-based approach to contact tracing was safe in this professional golf event setting when Alpha and Delta were the predominant variants. It enabled professional golfers and essential support staff to work.

Structural and Optical Properties of Silicon Carbide Powders Synthesized from Organosilane Using High-Temperature High-Pressure Method.

The development of new strategies for the mass synthesis of SiC nanocrystals with high structure perfection and narrow particle size distribution remains in demand for high-tech applications. In this work, the size-controllable synthesis of the SiC 3C polytype, free of sp2 carbon, with high structure quality nanocrystals, was realized for the first time by the pyrolysis of organosilane C12H36Si6 at 8 GPa and temperatures up to 2000 °C. It is shown that the average particle size can be monotonically changed from ~2 nm to ~500 nm by increasing the synthesis temperature from 800 °C to 1400 °C. At higher temperatures, further enlargement of the crystals is impeded, which is consistent with the recrystallization mechanism driven by a decrease in the surface energy of the particles. The optical properties investigated by IR transmission spectroscopy, Raman scattering, and low-temperature photoluminescence provided information about the concentration and distribution of carriers in nanoparticles, as well as the dominant type of internal point defects. It is shown that changing the growth modes in combination with heat treatment enables control over not only the average crystal size, but also the LO phonon-plasmon coupled modes in the crystals, which is of interest for applications related to IR photonics.

Pilot evaluation of risk assessment and enhanced protocols regarding contacts at an international professional golf event.

OBJECTIVES: The aim of this study was to assess whether a risk assessment and managed risk approach to contact tracing was practical and feasible at the Gran Canaria Lopesan Open 2021 and could inform further pilot work regarding disease transmission during elite sporting events. METHODS: This prospective cohort study included all international attendees. All participants required a minimum of one negative reverse transcriptase PCR (RT-PCR) test prior to travelling to each tournament. High-risk contacts were isolated for 10 days. Moderate-risk contacts received education regarding enhanced medical surveillance, had daily rapid antigen testing for 5 days, with RT-PCR day 5, mandated mask use and access to outside space for work purposes only. Low-risk contacts received rapid antigen testing every 48 hours and PCR testing on day 5. RESULTS: A total of 550 persons were accredited and were required to undergo RT-PCR testing before the event. Two of these tests were positive (0.36%). Of these, case 1 had 1 high, 23 moderate and 48 low-risk contacts. Case 2 did not have any significant travel history within 2 days of positive test and had one high-risk contact. There were no further positive tests on site in the wider cohort of attendees, from a total of 872 RT-PCR and 198 rapid antigen tests. CONCLUSIONS: This pilot study showed it is practical, feasible and well accepted to provide enhanced (daily) virus testing and risk-mitigating measures at a professional golf event. Further study is required to assess the efficacy of these interventions; however, no transmission was found in this pilot study.

Elevated Plasma Fibrinogen Is Associated With Excessive Inflammation and Disease Severity in COVID-19 Patients.

Background: The coronavirus disease-19 (COVID-19) is characterized with intense inflammatory response, cardiac involvement, and coagulopathy. Fibrinogen, as a biomarker for inflammation, cardiovascular disease, and coagulation, has not been fully investigated yet. The aim of this study was to assess the clinical application of fibrinogen in COVID-19 patients. Methods: We retrospectively analyzed the demographic and laboratory characteristics of 119 COVID-19 patients in the University of Alabama of Birmingham Medical Center. Correlations of fibrinogen on admission with intensive care unit (ICU) admission, disease severity, and laboratory parameters were analyzed. Results: Among the 119 COVID-19 patients, 77.3% (92/119) had severe disease, and 59.5% (71/119) patients were admitted to the ICU. Elevated fibrinogen was detected in 67.2% (80/119) of the patients. Fibrinogen levels were significantly associated with inflammatory markers and disease severity, but not with cardiac injury biomarker high sensitivity troponin I. Patients with severe disease had increased fibrinogen levels upon admission compared to patients with non-severe disease (P = 0.001). Fibrinogen level at 528.0 mg/dl was the optimal cutoff to predict disease severity, with a sensitivity and specificity of 66.7% and 70.3% (area undty -60er the curve [AUC] 0.72, P = 0.0006). Conclusions: Fibrinogen is commonly elevated in COVID-19 patients, especially in those with severe disease. Elevated fibrinogen correlates with excessive inflammation, disease severity, and ICU admission in COVID-19 patients.

Assessing the risk of SARS-CoV-2 transmission in international professional golf.

OBJECTIVES: There is no published data on the incidence or risk of SARS-CoV-2 transmission when playing golf, a sport played outdoors where social distancing is possible. The purpose of this prospective study was to report incidence and transmission regarding SARS-CoV-2, of professional golfers competing on the PGA European Tour across 23 events in 11 countries. METHODS: Daily symptom and temperature checks and weekly reverse transcriptase PCR (RT-PCR) screening were performed to determine potential carriage of SARS-CoV-2. Onset and type of symptomology were analysed. Gene expression and cycle thresholds (Cts) were reviewed for all positive cases. Repeat PCR testing was performed on all positive players. RT-PCR analysis included human housekeeping genes and various RNA genes specific for SARS-CoV-2. RESULTS: During the study period, there were 2900 RT-PCR tests performed on 195 professional golfers competing on the European Tour. Four players tested positive on-site during the study period (0.14% of tests; positive results were declared with Ct <40). Two positive tests were returned as part of routine protocols, while two reported a history of close contact with an individual who had tested positive for SARS-CoV-2 and were isolated and target tested. All were asymptomatic at time of testing, with three developing symptoms subsequently. None required hospital admission. There was no transmission from player to player. CONCLUSION: Golf is an outdoor sport where social distancing is possible, meaning risks can be low if guidance is followed by participants. Risk of transmission of SARS-CoV-2 can be mitigated by highly accurate RT-PCR testing of participants and by setting up a safe bubble that includes testing players and support staff, as well as all persons coming into contact with them during the course of the tournament, for example, drivers and hotel staff. This report can also provide reassurance for participants and policy makers regarding community golf, which can be encouraged for the health benefits it provides, in a relatively low-risk environment, with minimal risk of transmission by observing sensible viral hygiene protocols.

Euglobulin clot lysis time reveals a high frequency of fibrinolytic activation in trauma.

Activation of the fibrinolytic system plays a central role in the host response to trauma. There is significant heterogeneity in the degree of fibrinolysis activation at baseline that is usually assessed by whole blood thromboelastography (TEG). Few studies have focused on plasma markers of fibrinolysis that could add novel insights into the frequency and mechanisms of fibrinolytic activation in trauma. Global fibrinolysis in plasma was assessed using a modified euglobulin clot lysis time (ECLT) assay in 171 major trauma patients and compared to commonly assessed analytes of fibrinolysis. The median ECLT in trauma patients was significantly shorter at 8.5 h (IQR, 1.3-19.5) compared to 19.9 h (9.8-22.6) in healthy controls (p < 0.0001). ECLT values ≤2.5th percentile of the reference range were present in 83 (48.5%) of trauma patients, suggesting increased fibrinolytic activation. Shortened ECLT values were associated with elevated plasmin-antiplasmin (PAP) complexes and free tissue plasminogen activator (tPA) levels in plasma. Sixteen (9.2%) individuals met the primary outcome for massive transfusion, here defined as the critical administration threshold (CAT) of 3 units of packed red cells in any 60-minute period within the first 24 h. In a univariate screen, plasma biomarkers associated with CAT included D-dimer (p < 0.001), PAP (p < 0.05), free tPA (p < 0.05) and ECLT (p < 0.05). We conclude that fibrinolytic activation, measured by ECLT, is present in a high proportion of trauma patients at presentation. The shortened ECLT is partially driven by high tPA levels and is associated with high levels of circulating PAP complexes. Further studies are needed to determine whether ECLT is an independent predictor of trauma outcomes.

Plasmin-mediated cleavage of high-molecular-weight kininogen contributes to acetaminophen-induced acute liver failure.

Acetaminophen (APAP)-induced liver injury is associated with activation of coagulation and fibrinolysis. In mice, both tissue factor-dependent thrombin generation and plasmin activity have been shown to promote liver injury after APAP overdose. However, the contribution of the contact and intrinsic coagulation pathways has not been investigated in this model. Mice deficient in individual factors of the contact (factor XII [FXII] and prekallikrein) or intrinsic coagulation (FXI) pathway were administered a hepatotoxic dose of 400 mg/kg of APAP. Neither FXII, FXI, nor prekallikrein deficiency mitigated coagulation activation or hepatocellular injury. Interestingly, despite the lack of significant changes to APAP-induced coagulation activation, markers of liver injury and inflammation were significantly reduced in APAP-challenged high-molecular-weight kininogen-deficient (HK-/-) mice. Protective effects of HK deficiency were not reproduced by inhibition of bradykinin-mediated signaling, whereas reconstitution of circulating levels of HK in HK-/- mice restored hepatotoxicity. Fibrinolysis activation was observed in mice after APAP administration. Western blotting, enzyme-linked immunosorbent assay, and mass spectrometry analysis showed that plasmin efficiently cleaves HK into multiple fragments in buffer or plasma. Importantly, plasminogen deficiency attenuated APAP-induced liver injury and prevented HK cleavage in the injured liver. Finally, enhanced plasmin generation and HK cleavage, in the absence of contact pathway activation, were observed in plasma of patients with acute liver failure due to APAP overdose. In summary, extrinsic but not intrinsic pathway activation drives the thromboinflammatory pathology associated with APAP-induced liver injury in mice. Furthermore, plasmin-mediated cleavage of HK contributes to hepatotoxicity in APAP-challenged mice independently of thrombin generation or bradykinin signaling.

Decitabine Inhibits Bone Resorption in Periodontitis by Upregulating Anti-Inflammatory Cytokines and Suppressing Osteoclastogenesis.

DNA methylation controls several inflammatory genes affecting bone homeostasis. Hitherto, inhibition of DNA methylation in vivo in the context of periodontitis and osteoclastogenesis has not been attempted. Ligature-induced periodontitis in C57BL/6J mice was induced by placing ligature for five days with Decitabine (5-aza-2'-deoxycytidine) (1 mg/kg/day) or vehicle treatment. We evaluated bone resorption, osteoclast differentiation by tartrate-resistant acid phosphatase (TRAP) and mRNA expression of anti-inflammatory molecules using cluster differentiation 14 positive (CD14+) monocytes from human peripheral blood. Our data showed that decitabine inhibited bone loss and osteoclast differentiation experimental periodontitis, and suppressed osteoclast CD14+ human monocytes; and conversely, that it increased bone mineralization in osteoblastic cell line MC3T3-E1 in a concentration-dependent manner. In addition to increasing IL10 (interleukin-10), TGFB (transforming growth factor beta-1) in CD14+ monocytes, decitabine upregulated KLF2 (Krüppel-like factor-2) expression. Overexpression of KLF2 protein enhanced the transcription of IL10 and TGFB. On the contrary, site-directed mutagenesis of KLF2 binding site in IL10 and TFGB abrogated luciferase activity in HEK293T cells. Decitabine reduces bone loss in a mouse model of periodontitis by inhibiting osteoclastogenesis through the upregulation of anti-inflammatory cytokines via KLF2 dependent mechanisms. DNA methyltransferase inhibitors merit further investigation as a possible novel therapy for periodontitis.

Inferring temporal organization of postembryonic development from high-content behavioral tracking.

Understanding temporal regulation of development remains an important challenge. Whereas average, species-typical timing of many developmental processes has been established, less is known about inter-individual variability and correlations in timing of specific events. We addressed these questions in the context of postembryonic development in Caenorhabditis elegans. Based on patterns of locomotor activity of freely moving animals, we inferred durations of four larval stages (L1-L4) in over 100 individuals. Analysis of these data supports several conclusions. Individuals have consistently faster or slower rates of development because durations of L1 through L3 stages are positively correlated. The last larval stage, the L4, is less variable than the earlier stages and its duration is largely independent of the rate of early larval development, implying existence of two distinct larval epochs. We describe characteristic patterns of variation and correlation, as well as the fact that stage durations tend to scale relative to total developmental time. This scaling relationship suggests that each larval stage is not limited by an absolute duration, but is instead terminated when a subset of events that must occur prior to adulthood have been completed. The approach described here offers a scalable platform that will facilitate the study of temporal regulation of postembryonic development.

Effects of Otosclerosis on Middle Ear Function Assessed With Wideband Absorbance and Absorbed Power.

OBJECTIVE: Wideband absorbance and absorbed power were evaluated in a group of subjects with surgically confirmed otosclerosis (Oto group), mean age 51.6 years. This is the first use of absorbed power in the assessment of middle ear disorders. Results were compared with control data from two groups of adults, one with normal hearing (NH group) mean age of 31 years, and one that was age- and sex-matched with the Oto group and had sensorineural hearing loss (SNHL group). The goal was to assess group differences using absorbance and absorbed power, to determine test performance in detecting otosclerosis, and to evaluate preoperative and postoperative test results. DESIGN: Audiometric and wideband tests were performed over frequencies up to 8 kHz. The three groups were compared on wideband tests using analysis of variance to assess group mean differences. Receiver operating characteristic (ROC) curve analysis was also used to assess test accuracy at classifying ears as belonging to the Oto or control groups using the area under the ROC curve (AUC). A longitudinal design was used to compare preoperative and postoperative results at 3 and 6 months. RESULTS: There were significant mean differences in the wideband parameters between the Oto and control groups with generally lower absorbance and absorbed power for the Oto group at ambient and tympanometric peak pressure (TPP) depending on frequency. The SNHL group had more significant differences with the Oto group than did the NH group in the high frequencies for absorbed power at ambient pressure and tympanometric absorbed power at TPP, as well as for the tympanometric tails. The greatest accuracy for classifying ears as being in the Oto group or a control group was for absorbed power at ambient pressure at 0.71 kHz with an AUC of 0.81 comparing the Oto and NH groups. The greatest accuracy for an absorbance measure was for the comparison between the Oto and NH groups for the peak-to-negative tail condition with an AUC of 0.78. In contrast, the accuracy for classifying ears into the control or Oto groups for static acoustic admittance at 226 Hz was near chance performance, which is consistent with previous findings. There were significant mean differences between preoperative and postoperative tests for absorbance and absorbed power. CONCLUSIONS: Consistent with previous studies, wideband absorbance showed better sensitivity for detecting the effects of otosclerosis on middle ear function than static acoustic admittance at 226 Hz. This study showed that wideband absorbed power is similarly sensitive and may perform even better in some instances than absorbance at classifying ears as having otosclerosis. The use of a group that was age- and sex-matched to the Oto group generally resulted in greater differences between groups in the high frequencies for absorbed power, suggesting that age-related norms in adults may be useful for the wideband clinical applications. Absorbance and absorbed power appear useful for monitoring changes in middle ear function following surgery for otosclerosis.

[New concepts of medical consultation in oncology]. / Nouveaux concepts de consultations médicales en oncologie.

New concepts of medical consultations are currently disrupting the practice of medicine. The use of standardized questionnaires, or patient-reported outcome (PRO and ePRO) has already significantly changed the relationship between the physician and the patient. Telemedicine, or even automatic conversational agents, such as chatbots, are also providing more convenient access to care and medical information for many patients. These tools have a major impact in oncology, precisely because of the rising chronicity of the diseases the radiation oncologists treat. In this article, we provide a detailed analysis of these new concepts.

TLR3-Dependent Activation of TLR2 Endogenous Ligands via the MyD88 Signaling Pathway Augments the Innate Immune Response.

The role of the adaptor molecule MyD88 is thought to be independent of Toll-like receptor 3 (TLR3) signaling. In this report, we demonstrate a previously unknown role of MyD88 in TLR3 signaling in inducing endogenous ligands of TLR2 to elicit innate immune responses. Of the various TLR ligands examined, the TLR3-specific ligand polyinosinic:polycytidylic acid (poly I:C), significantly induced TNF production and the upregulation of other TLR transcripts, in particular, TLR2. Accordingly, TLR3 stimulation also led to a significant upregulation of endogenous TLR2 ligands mainly, HMGB1 and Hsp60. By contrast, the silencing of TLR3 significantly downregulated MyD88 and TLR2 gene expression and pro-inflammatory IL1ß, TNF, and IL8 secretion. The silencing of MyD88 similarly led to the downregulation of TLR2, IL1ß, TNF and IL8, thus suggesting MyD88 to somehow act downstream of TLR3. Corroborating in vitro data, Myd88-/- knockout mice downregulated TNF, CXCL1; and phospho-p65 and phospho-IRF3 nuclear localization, upon poly I:C treatment in a mouse model of skin infection. Taken together, we identified a previously unknown role for MyD88 in the TLR3 signaling pathway, underlying the importance of TLRs and adapter protein interplay in modulating endogenous TLR ligands culminating in pro-inflammatory cytokine regulation.