Pyroptosis Accelerates Spiral Ganglion Neuronal Degeneration Induced by Aminoglycosides in the Cochlea

Background In aminoglycoside-induced hearing loss, damage to spiral ganglion neurons (SGNs) accelerates gradually after the acute outer hair cell death, accompanied by macrophage infiltration and cytokine release. Pyroptosis plays a critical role in neurodegenerative diseases. Here, we explored the potential role of pyroptosis in SGN degeneration. Methods C57BL/6J mice were randomly divided into a kanamycin plus furosemide group and saline control group. Auditory functions were evaluated by auditory brainstem response tests conducted before treatment and at 1, 5, 15, and 30 days after treatment. HCs and SGNs were assessed for morphological alterations. SGNs were subjected to RNA sequencing and mRNA and protein analyses of NLRP3 inflammasome-related molecules. Macrophage activation was evaluated based on morphological and mRNA alterations. The effect of NLRP3 inhibition on SGN survival after kanamycin treatment was evaluated in organ explant cultures treated with Mcc950, a specific inhibitor of the NLRP3 inflammasome. Results Kanamycin and furosemide administration led to irreversible deterioration of the auditory brainstem response threshold, accompanied by acute loss of outer hair cells and gradually progressive loss of inner hair cells. SGNs showed a progressive decrease in quantity, as well as swelling and membrane rupture, at 15 and 30 days. RNA sequencing of SGNs showed that inflammation and immune-related responses were significantly upregulated, as was the expression of the inflammasome-related gene NLRP3. During 30 days of kanamycin exposure, the canonical pyroptosis pathway was constantly activated in SGNs. Activation and infiltration of microglia-like cells/macrophages, and increased production of cytokines, hallmarks of neuroinflammation, were also observed. Mcc950 significantly ameliorated SGN degeneration by inhibiting NLRP3 expression and promoting release of interleukins 1β and 18. Conclusions Pyroptosis causes cell death during aminoglycoside-induced SGN degeneration. Activation of the NLRP3 inflammasome leads to a cascade of inflammatory events in SGNs. Inhibition of the NLRP3 inflammasome significantly alleviates SGN damage, suggesting that it could serve as a new molecular target for the treatment of aminoglycoside-induced SGN degeneration.

Dissociable influences of reward and punishment on adaptive cognitive control

To invest effort into any cognitive task, people must be sufficiently motivated. Whereas prior research has focused primarily on how the cognitive control required to complete these tasks is motivated by the potential rewards for success, it is also known that control investment can be equally motivated by the potential negative consequence for failure. Previous theoretical and experimental work has yet to examine how positive and negative incentives differentially influence the manner and intensity with which people allocate control. Here, we develop and test a normative model of control allocation under conditions of varying positive and negative performance incentives. Our model predicts, and our empirical findings confirm, that rewards for success and punishment for failure should differentially influence adjustments to the evidence accumulation rate versus response threshold, respectively. This dissociation further enabled us to infer how motivated a given person was by the consequences of success versus failure.

Improvement in Health-Related Quality of Life Measures after Long-Term, Daily, Subcutaneous Concizumab Prophylaxis in Patients with Hemophilia A/B with and without Inhibitors: Results from the Main and Extension Parts of Phase 2 Clinical Trials

Relative to the general population, health-related quality of life (HRQoL) is impaired in patients with hemophilia, who report increased pain and reduced physical activity. It is therefore of interest to assess the change in HRQoL after long-term prophylactic treatment. Concizumab is an anti-tissue factor pathway inhibitor monoclonal antibody in clinical development for a subcutaneous, prophylactic treatment of patients with hemophilia. Here, we present results from exploratory analyses assessing changes in HRQoL after long-term concizumab treatment (≤126 treatment weeks), which includes data from the main and extension parts of explorer4 (NCT03196284) and explorer5 (NCT03196297) phase 2 trials. Both trials comprised a main part (≤24 weeks), and an extension part (explorer4: ≤94 weeks; explorer5: ≤102 weeks). In explorer4, patients with hemophilia A and B with inhibitors (HAwI/HBwI) were recruited and randomized 2:1 to concizumab prophylaxis (n=17) or recombinant activated factor VII on-demand treatment (n=9). Patients in the on-demand arm switched to concizumab prophylaxis in the extension part. Twenty-six patients were recruited for explorer4, 25 patients were exposed to concizumab in the extension part, and 22 patients completed the trial. In explorer5, 36 patients with severe hemophilia A (HA) were recruited, 32 patients entered the extension part, and 30 patients completed the trial. Patients were asked to complete the 36-item Short Form Health Survey (SF-36v2) at baseline (for this analysis, baseline was defined as the last assessment before first treatment with concizumab), and throughout the main and extension parts. Scoring was conducted according to the SF-36v2 scoring software (version 5.0). Only patients who completed the entire trial were included for analysis. T score points of SF-36v2 domains were used to determine clinically meaningful differences at group level from baseline to the end of the extension part, based on minimally important difference criteria (MID; SF-36v2 manual 3rd edition, 2013). At an individual level, a responder analysis was conducted to identify the proportion of patients who had improved scores in the physical component summary (PCS), physical function (PF) and bodily pain (BP) domains, based on the recommended individual-level response threshold of 3.4, 4.3 and 6.2, respectively (based on 2009 United States general population norms; SF-36v2 manual). The results presented here demonstrate the change in HRQoL before and after long-term concizumab use in the main and extension parts of explorer4 and explorer5. For explorer4, 22 patients (14 HAwI; 8 HBwI) were included in the current exploratory analysis, which showed that the difference in improvement from baseline to end of extension part exceeded the MID thresholds for PCS score (Table 1), at group level. Additionally, the MID thresholds were also met for PF, BP, role-physical, general health, vitality, social functioning, and mental health domains in explorer4 (Table 1). At an individual level, the responder analysis revealed that 63.6%, 54.5% and 50.0% of 22 patients had an improvement that met or exceeded the response threshold for PCS, PF and BP scores. In the 30 patients with severe HA included in the explorer5 analysis, PCS score met the MID threshold for difference in improvement from baseline to end of extension, although large standard deviations were observed (Table 1). At an individual level, the responder analysis revealed that 43.3%, 33.3% and 33.3% of 30 patients had an improvement that met or exceeded the response threshold for PCS, PF and BP scores. While these analyses are exploratory and should be interpreted with caution, they illustrated that patients with HAwI/HBwI reported improved HRQoL after long-term, subcutaneous concizumab prophylaxis, particularly in clinically relevant domains such as PF and BP, suggesting a potential positive effect of concizumab prophylaxis on physical functioning and reduced pain. Interestingly, PCS improvement was observed across all hemophilia subgroups, suggesting better functional health, albeit the large standard deviation reported. The potential beneficial effect of concizumab prophylaxis on HRQoL in hemophilia patients is being investigated further in the ongoing phase 3 trials. Figure 1 Figure 1. Disclosures Faller: Novo Nordisk Health Care AG: Current Employment. Marie Tønder: Novo Nordisk Health Care AG: Current Employment. Porstmann: Novo Nordisk Health Care AG: Current Employment.

The emergence of a collective sensory response threshold in ant colonies

The sensory response threshold is a fundamental biophysical property of biological systems that underlies many physiological and computational functions, and its systematic study has played a pivotal role in uncovering the principles of neural computation. Here, we show that ant colonies, which perform computational tasks at the group level, have emergent collective sensory response thresholds. Colonies respond collectively to step changes in temperature and evacuate the nest during severe perturbations. This response is characterized by a group-size dependent threshold, and the underlying dynamics are dominated by social feedback between the ants. Using a binary network model, we demonstrate that a balance between short-range excitatory and long-range inhibitory interactions can explain the emergence of the collective response threshold and its size dependency. Our findings illustrate how simple social dynamics allow insect colonies to integrate information about the external environment and their internal state to produce adaptive collective responses.

Determination of a Treatment Response Threshold for the Eosinophilic Esophagitis Endoscopic Reference Score

Background and study aims: While endoscopic features of eosinophilic esophagitis (EoE) are measured using the validated EoE Endoscopic Reference Score (EREFS), a threshold for treatment response has not been defined. We aimed to determine a cut-point for endoscopic response as measured by EREFS. Patients and Methods: We performed a secondary analysis of a randomized clinical trial comparing budesonide slurry to swallowed fluticasone multidose inhaler for initial treatment of EoE. In the parent trial, EREFS was determined before and after treatment (score range 0-9), as were histologic findings and dysphagia symptoms. We performed tabular, flexible trend, and dependent mixture analyses of measures of treatment response to select the best clinical EREFS threshold. Results: In the 111 included subjects (mean age 39 years; 67% male; 96% white), an EREFS threshold of ≤2 was 80% sensitive (95% confidence limits 69 - 88%) and 83% specific (95% confidence limits 67 - 94%) for histologic response (peak of <15 eosinophils per high-power field). Flexible trend analysis and dependent mixture modeling similarly suggested a threshold of ≤2 best captured the correlation of EREFS with histologic and symptomatic measures. Dependent mixture modeling found near total membership in the response class at EREFS of 0 or 1 and >75% at EREFS of 2 or 3. Conclusions: An EREFS of ≤2 was the best clinical threshold for endoscopic response to topical steroid treatment and was consistent with clinical and histologic response. Therefore, future studies can report a binary outcome of endoscopic response when EREFS is two or less.

Retinopathy of Prematurity and Hearing Impairment in Infants Born with Very-Low-Birth-Weight: Analysis of a Korean Neonatal Network Database

Background: To investigate hearing impairment and its association with retinopathy of prematurity (ROP) among children born with very low birth weight (VLBW, birth weight < 1500 g). Methods: This prospective registry study included 7940 VLBW infants who underwent both ophthalmic (ROP) and hearing screening at the 70 participating centers of the Korean Neonatal Network. Hearing screening was performed using auditory brainstem response and/or automated otoacoustic emission testing. Hearing impairment, defined as a unilateral or bilateral hearing threshold of ≥40 dB on the auditory brainstem response threshold (ABR-T) test, was evaluated and compared between children with and without ROP at the corrected ages of 18 months and 3 years. Results: The frequency of infants who did not undergo hearing screening at near-term ages was higher in the ROP group than in the no-ROP group (18.2% vs. 12.0%, p < 0.001), and the prevalence of hearing impairment at 18 months was higher in the ROP group than in the no-ROP group (3.5% vs. 2.2%, p = 0.043). The prevalence of deafness was higher in children with ROP than those without ROP (0.4% vs. 0.1%, p = 0.049). There were significant differences in hearing impairment among the stages of ROP (p < 0.001). However, multivariate analyses and propensity score matching showed no significant association between ROP and hearing impairment at 18 months and 3 years after adjusting for prematurity-related variables (all p > 0.05). Conclusions: Among infants born with VLBW, hearing impairment was more common in those with ROP than in those without ROP at 18 months of age. However, there was no significant independent association between hearing impairment and ROP.

Ketamine-xylazine anesthesia depth affects auditory neuronal responses in the lateral superior olive complex of the gerbil

Studies of in vivo neuronal responses to auditory inputs in the superior olive complex (SOC) are usually done under anesthesia. However, little attention has been paid to the effect of anesthesia itself on response properties. Here, we assessed the effect of anesthesia depth under ketamine-xylazine anesthetics on auditory evoked response properties of lateral SOC neurons. Anesthesia depth was tracked by monitoring EEG spectral peak frequencies. An increase in anesthesia depth led to a decrease in spontaneous discharge activities and an elevated response threshold. The temporal responses to suprathreshold tones were also affected, with adapted responses reduced but peak responses unaffected. Deepening the anesthesia depth also increased first spike latency. However, spike jitter was not affected. Auditory brainstem responses to clicks confirmed that ketamine-xylazine anesthesia depth affects auditory neuronal activities and the effect on spike rate and spike timing persists through the auditory pathway. We concluded from those observations that ketamine-xylazine affects lateral SOC response properties depending on the anesthesia depth.

Endodontics-orthodontics interrelationship: a review.

The endodontic-orthodontic interface is not well understood due to the limited scientific literature on the topic. This article aims to provide an overview of the orthodontic treatment and the risk of root resorption, the effects of orthodontic tooth movement on dental pulp and endodontically treated teeth, the role of orthodontics in endodontic-restorative treatment planning, and interdisciplinary patient management. Articles published in English from 1982 to 2021 were searched manually from google scholar using keywords ‘endodontic-orthodontic interface’ and ‘endodontic-orthodontic interrelationship’. Another search engine was MEDLINE/PubMed database using keywords ‘endodontics AND orthodontics’, ‘orthodontic tooth movement AND dental pulp’, 'orthodontic tooth movement AND endodontic treatment' and ‘orthodontics AND dental trauma’. Other relevant articles were obtained from the references of the selected papers. Alterations to the dental pulp following orthodontic tooth movement can be histologic and/or cell biological reactions as well as the increased response threshold to pulp sensibility tests. However, the occurrence of root resorption is complex and multifactorial, and can be linked to individual variation, genetic predisposition and orthodontic treatment-related factors. Endodontically treated teeth can move as readily and respond similarly to orthodontic forces as vital teeth, however with inadequate endodontic treatment, the risk of apical inflammation and bone destruction following orthodontic tooth movement is increased. Dental treatment that involves endodontic and orthodontic specialities should be carefully planned according to the individual case, taking into consideration the skills and experience of the clinicians while applying interdisciplinary patient management and available scientific data.