Wednesday, December 7, 2022

No Reduction in the 226-Hz Probe Tone Acoustic Reflex Amplitude Following Severe Inner Hair Cell Loss in Chinchillas

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AbstractThe relationship between the middle ear acoustic reflex (AR) and inner hair cell (IHC) loss is currently unknown. Given that IHC are believed to convey nearly all acoustic information to the central auditory nervous system, it has been assumed that loss of IHC would significantly impact the AR. To evaluate this relationship, we assessed the presence and amplitude of the AR in chinchillas before and after treatment with carboplatin, an anticancer drug that reliably and selectively destroys IHC in this species. Baseline measures of hearing sensitivity, including auditory brainstem response (ABR) thresholds and distortion product otoacoustic emissions (DPOAE), were assessed and then re-evaluated following carboplatin treatment. Post-carboplatin ABR thresholds and DPOAE were found to b...
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Electrophysiological and Psychophysical Measures of Temporal Pitch Sensitivity in Normal-hearing Listeners

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AbstractTo obtain combined behavioural and electrophysiological measures of pitch perception, we presented harmonic complexes, bandpass filtered to contain only high-numbered harmonics, to normal-hearing listeners. These stimuli resemble bandlimited pulse trains and convey pitch using a purely temporal code. A core set of conditions consisted of six stimuli with baseline pulse rates of 94, 188 and 280 pps, filtered into a HIGH (3365 –4755 Hz) or VHIGH (7800–10,800 Hz) region, alternating with a 36% higher pulse rate. Brainstem and cortical processing were measured using the frequency following response (FFR) and auditory change complex (ACC), respectively. Behavioural rate change difference limens (DLs) were measured by r equiring participants to discriminate between a stimulus that ...
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Main Causal Agents of Occupational Asthma

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Abstract
Objectives
The definition of work-related Asthma (WRA) has changed in recent years and new etiologies and agents have been identified. The aim of this study is to describe the main causal agents of WRA in France in the period 2001–2018 in the main work sectors.
Methods
Data were collected from the French national network of occupational health surveillance and prevention [Réseau National de Vigilance et de Prévention des Pathologies Professionnelles (RNV3P)], Data between 2001 and 2018 with at least a probable or certain association with one occupational agent, were included.
Results
Work sectors with more cases OF WRA included personal service activities (10.6%), food industry (10.2%) and healthcare activities (7.6%). WRA cases were most frequently related to flour (10%), quaternary ammoniums compounds (5.3%), isocyanates (5.1%) and cleaning products (4.8%).
Conclusion
Occupational exposure to specific ag ents capable of causing WRA is still present, and four agents represent more than 25% of the cases. Actions to prevent respiratory exposure are still relevant.
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Efficacy and safety of ensitrelvir in patients with mild-to-moderate COVID-19: the phase 2b part of a randomized, placebo-controlled, phase 2/3 study

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Abstract
Background
This phase 2b part of a randomized phase 2/3 study assessed the efficacy and safety of ensitrelvir for mild-to-moderate coronavirus disease 2019 (COVID-19) during the Omicron epidemic.
Methods
Patients were randomized (1:1:1) to orally receive ensitrelvir fumaric acid 125 mg (375 mg on day 1) or 250 mg (750 mg on day 1) or placebo once daily for 5 days. The co-primary endpoints were the change from baseline in the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) titer on day 4 and time-weighted average change from baseline up to 120 hours in the total score of predefined 12 COVID-19 symptoms. Safety was assessed through adverse events.
Results
A total of 341 patients (ensitrelvir 125 mg group, 114; ensitrelvir 250 mg group, 116; and placebo group, 111; male, 53.5%–64.9%; mean age, 35.3–37.3 years) were included in the efficacy analyses. The change from baseline in the SARS-CoV-2 titer on da y 4 was significantly greater with both ensitrelvir doses than with placebo (differences from placebo: -0.41 log10 50% tissue-culture infectious dose/mL, P < 0.0001 for both). The total score of the 12 COVID-19 symptoms did not show a significant difference between the ensitrelvir groups and placebo group. The time-weighted average change from baseline up to 120 hours was significantly greater with ensitrelvir versus placebo in several subtotal scores, including acute symptoms and respiratory symptoms. Most adverse events were mild in severity.
Conclusions
Ensitrelvir treatment demonstrated a favorable antiviral efficacy and potential clinical benefit with an acceptable safety profile.
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Tuesday, December 6, 2022

Risk communication and community preparedness in the context of biotechnological hazards: A case of NBAF

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Abstract

Applying the Protection Motivation Theory, this study examines factors affecting community preparedness in the context of biotechnological hazards. In particular, residents living nearby the National Bio and Agro-Defence Facility (NBAF), a biosafety level-4 facility currently under construction, were surveyed. The survey assessed residents' perceptions of key risk communication elements, transparency, consistency, and source, as well as risk perception, knowledge, collective efficacy, involvement, civic engagement behaviours, and preparedness perceptions. Results indicate that sources such as local organisations and mass media, as opposed to social media and word-of-mouth, are more reliable and lead to increased knowledge. The structural model suggests that transparent and consistent risk communication leads to community preparedness through knowledge, involvement, risk perception, and collective efficacy. Theoretical implications for the Protection Motivation Theory and practical implications for risk communication regarding biotechnological hazards are discussed.

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Traditional versus conservative endodontic access impact on fracture resistance of chairside CAD‐CAM lithium disilicate anterior crowns: An in vitro study

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Abstract

Purpose

To evaluate the effect of traditional and conservative endodontic access hole preparation on fracture resistance of chairside computer-aided design and computer-aided manufacturing (CAD-CAM) lithium disilicate maxillary right central incisor crowns.

Materials and Methods

Fifty-seven milled lithium disilicate maxillary right central incisor crowns were designed and fabricated with a chairside CAD-CAM system (Planmeca Romexis, Planmeca). The abutment preparation had a 1.0 mm incisal reduction and 1.0 mm chamfer finish. The restorations were bonded with resin cement to printed resin dies (n = 19 per group) and were treated and divided into three groups, 1) no endodontic access, 2) traditional triangular endodontic access, and 3) conservative ovoidal endodontic access. The endodontic access of the crowns was sealed with flowable resin composite. Restorations were subjected to 10,000 cycles of thermal cycling between 5° and 55°C. Then, restorations were loaded and exposed to compressive loading force, and the crack initiation (CI) and complete fracture (CF) were recorded. SEM micrographs of broken specimens on the printed dies were captured. ANOVA test and Bonferroni's correction were used for statistical comparison.

Results

The fracture resistance among the three groups varied. Crowns with no endodontic access displayed significantly (p < 0.001) higher resistance [CI: 1025 (121) N; CF 1134 (127) N], followed by crowns with conservative ovoidal endodontic access [CI: 924 (60) N; CF: 1000 (72) N. Crowns with traditional triangular endodontic access showed the significantly (p < 0.001) lowest fracture resistance [CI: 635 (82) N; CF: 709 (75) N].

Conclusion

The fracture resistance of chairside CAD-CAM lithium disilicate maxillary anterior crowns is influenced by the type of endodontic access provided. Conservative ovoidal endodontic access provides crowns with higher fracture resistance than traditional triangular endodontic access. Crowns with no endodontic access provided the highest resistance than other types of endodontic access.

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Trotabresib, an oral potent bromodomain and extraterminal inhibitor, in patients with high-grade gliomas: a phase I, “windowofopportunity” study

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Abstract
Background
The bromodomain and extraterminal protein (BET) inhibitor trotabresib has demonstrated antitumor activity in patients with advanced solid tumors, including high-grade gliomas. CC-90010-GBM-001 (NCT04047303) is a phase I study investigating the pharmacokinetics, pharmacodynamics, and CNS penetration of trotabresib in patients with recurrent high-grade gliomas scheduled for salvage resection.
Methods
Patients received trotabresib 30 mg/day on days 1–4 before surgery, followed by maintenance trotabresib 45 mg/day 4 days on/24 days off after surgery. Primary endpoints were plasma pharmacokinetics and trotabresib concentrations in resected tissue. Secondary and exploratory endpoints included safety, pharmacodynamics, and antitumor activity.
Results
Twenty patients received preoperative trotabresib and underwent resection with no delays or cancellations of surgery; 16 patients received maintenance trot abresib after recovery from surgery. Trotabresib plasma pharmacokinetics were consistent with previous data. Mean trotabresib brain tumor tissue:plasma ratio was 0.84 (estimated unbound partition coefficient [KPUU] 0.37), and modulation of pharmacodynamic markers was observed in blood and brain tumor tissue. Trotabresib was well tolerated; the most frequent grade 3/4 treatment-related adverse event during maintenance treatment was thrombocytopenia (5/16 patients). Sixmonth progression-free survival was 12%. Two patients remain on treatment with stable disease at cycles 25 and 30.
Conclusions
Trotabresib penetrates the blood–brain-tumor barrier in patients with recurrent high-grade glioma and demonstrates target engagement in resected tumor tissue. Plasma pharmacokinetics, blood pharmacodynamics, and safety were comparable with previous results for trotabresib in patients with advanced solid tumors. Investigation of adjuvant trotabresib + temozolomide and concom itant trotabresib + temozolomide + radiotherapy in patients with newly diagnosed glioblastoma is ongoing (NCT04324840).
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Monday, December 5, 2022

Perceived legitimacy can moderate the effect of proscriptive vs. prescriptive injunctions on intentions to comply with UK government COVID‐19 guidelines and reactance

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Abstract

Proscriptive injunctions (i.e., telling people what they should not do) have been found in research to elicit greater perceptions of a threat to freedom, and greater reactance (anger, irritation and annoyance), than prescriptive injunctions (i.e., telling people what they should do), across several health and social behaviours. The current research investigated the effects of Injunction Type (proscriptive vs. prescriptive) and perceived legitimacy of the injunction, on intentions to comply with UK government behavioural guidelines during the COVID-19 pandemic, and on reactance. In two online experimental studies (Study 1: N = 142; Study 2: N = 307), UK participants were presented with information about UK government COVID-19 guidelines that included either a proscriptive injunction or prescriptive injunction and reported their perceptions of the legitimacy of the injunction, their intentions to comply with government guidelines, a nd their reactance. In both Study 1 and Study 2, the effect of Injunction Type on intentions to comply and reactance was moderated by perceived legitimacy. In both studies, when perceived legitimacy was low, participants exposed to the proscriptive injunction indicated lower intentions to comply with UK government COVID 19 guidelines than did participants exposed to the prescriptive injunction, The findings imply that using a prescriptive injunction frame can elicit greater intentions to comply than using a proscriptive injunction frame when people perceive the injunction to be unreasonable. The results are discussed in relation to the role of legitimacy in determining the effectiveness of different types of injunctions on compliance with rules and guidelines.

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International variations in carcinoma and melanoma incidence in children and adolescents

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In order to compare the subtype distribution of carcinoma and melanoma in children and adolescents between Japan and other countries, we extracted information on cancer incidence in children and adolescents from the third volume of the International Incidence of Childhood Cancer series (IICC-3) (1). The IICC-3 reports the number or incidence rates of cancers diagnosed in childhood and adolescence, from cancer registries (regional or national) worldwide. We analysed carcinoma and melanoma incidence in four countries in Asia (Japan, China, the Republic of Korea and Thailand), two countries in Africa (Egypt and Uganda), four countries in the Americas (North: The United States of America and Canada, Latin and Caribbean: Brazil and Colombia), three countries in Europe (the United Kingdom [UK], France and Germany) and two countries in Oceania (Australia and New Z ealand). Information from the Republic of Korea, USA, UK, Australia and New Zealand was obtained at the national level, and that from the other countries was extracted from one or multiple regional cancer registries. The years of incidence included in the analyses varied from country to country, ranging from 1990 to 2014, with the shortest being 12 years (Egypt: 1999–2010, UK: 2000–2011) and the longest being 24 years (Japan and China: both 1990–2013). In this study, we compared the incidence and proportional distribution of carcinoma and melanoma subtypes in children (0–14 years old) and adolescents (15–19 years old) between these countries.
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Sunday, December 4, 2022

25‐Hydroxycholesterol induces odontoclastic differentiation through RANK–RANKL upregulation and NF‐κB activation in odontoblast‐like MDPC‐23 cells: An in vitro study

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Abstract

Aim

The physiological effects and cellular mechanism of 25-hydroxycholesterol (25-HC), which is an oxysterol synthesized from cholesterol by cholesterol-25-hydroxylase (CH25H) expressed under inflammatory conditions, are still largely unknown during odontoclastogenesis. This study aimed to evaluate a 25-HC-induced odontoclastogenesis and its cellular mechanisms in odontoblast-like MDPC-23 cells.

Methodology

To investigate 25-HC-induced odontoclastogenesis of MDPC-23 cells and its cellular mechanism, haemotoxylin and eosin staining, tartrate-resistant acid phosphatase (TRAP) staining, dentine resorption assay, zymography, reactive oxygen species (ROS) detection, immunocytochemistry, and nuclear translocation were performed. The experimental values are presented as mean ± standard deviation and were compared using analysis of variance, followed by post-hoc multiple comparison (Tukey's test) using SPSS software version 22 (IBM Corp.). A P value <0.05 was considered statistically significant.

Results

Lipopolysaccharide or receptor activator of nuclear factor-κB ligand (RANKL) induced the synthesis of 25-HC via the expression of CH25H in MDPC-23 cells (p<0.01). Multinucleated giant cells with morphological characteristics and TRAP activity of the odontoclast were increased by 25-HC in MDPC-23 cells (p<0.01). Moreover, 25-HC increased dentine resorption through the expression and activity of matrix metalloproteinases in MDPC-23 cells. It not only increased the expression of odontoclastogenic biomarkers but also translocated cytosolic nuclear factor-κB (NF-κB) to the nucleus in MDPC-23 cells. Additionally, 25-HC not only increased the production of ROS (p<0.01), expression of inflammatory mediators (p<0.01), pro-inflammatory cytokines, receptor activator of NF-κB (RANK), and RANKL but also suppressed the expression of osteoprotegerin (OPG) in MDPC-23 cells. In contrast, CDDO-Me, a chemical NF-κB inhibitor, decreased TRAP activity (p<0.01) and downregulated the expression of the odontoclastogenic biomarkers, including RANK and RANKL, in MDPC-23 cells.

Conclusion

25-HC induced odontoclastogenesis by modulating the RANK–RANKL–OPG axis via NF-κB activation in MDPC-23 cells. Therefore, these findings provide that 25-HC derived from cholesterol metabolism may be involved in the pathophysiological etiological factors of internal tooth resorption.

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