Elevated Thresholds Research Articles

Prognostic mortality factors in advanced light chain cardiac amyloidosis: A prospective cohort study.

Predicting mortality in severe AL cardiac amyloidosis is challenging due to elevated biomarker levels and limited thresholds for stratifying severe cardiac damage. This prospective, observational, cohort study included de novo, confirmed cardiac AL amyloidosis patients at the Henri Mondor National Reference Centre. The goal was to identify predictors of mortality to enhance prognostic stratification and improve informed decision-making regarding therapy. Over the 12-year study period, among the 233 patients included, 133 were NYHA III-IV and 179 Mayo 2004 III. The independent predictors for mortality identified were hsTnT, NT-proBNP, cardiac output, and conjugated bilirubin. A novel prognostic, conditional stratification, Mondor amyloidosis cardiac staging (MACS) was developed with biomarker cut-off values for Stage 1: hsTnT≤107ng/L and NT-proBNP≤3867ng/L (n=77; 33%); for stage 2 NT-proBNP>3867ng/L (n=72; 30%). For stage 3, if troponin >107ng/L, regardless of NT-proBNP then CB 4μmol/L, was added (n=41; 17.5%) and stage 4: CB>4μmol/L (n=43; 18.5%). The median overall survival was 8months 95% CI [2-24]. At 1year, 102 (44%) patients died and the Kaplan-Meier median survival with MACS Stage 1 was not reached, while stage 2 was 15.2months (95% CI [11-18]) and stage 3, 6.6months (95% CI [1-13]). Notably, among European stage II patients, 17.1%, n=8 were MACS stage 3 and European stage IIIb 21.4% (n=23) were MACS stage 4. Importantly, among European stage IIIb patients 42.2% (n=29) were classified MACS stage 4 and 12.5% n=9 were only MACS stage 2. The Mondor prognostic staging system, including conjugate bilirubin may significantly improve prognostic stratification for patients with severe cardiac amyloidosis.

Leadless pacemakers at 5-year follow-up: the Micra transcatheter pacing system post-approval registry.

Prior reports have demonstrated a favourable safety and efficacy profile of the Micra leadless pacemaker over mid-term follow-up; however, long-term outcomes in real-world clinical practice remain unknown. Updated performance of the Micra VR leadless pacemaker through five years from the worldwide post-approval registry (PAR) was assessed. All Micra PAR patients undergoing implant attempts were included. Endpoints included system- or procedure-related major complications and system revision rate for any cause through 60 months post-implant. Rates were compared through 36 months post-implant to a reference dataset of 2667 transvenous pacemaker patients using Fine-Gray competing risk models. 1809 patients were enrolled between July 2015 and March 2018 and underwent implant attempts from 179 centres in 23 countries with a median follow-up period of 51.1 months (IQR: 21.6-64.2). The major complication rate at 60 months was 4.5% [95% confidence interval (CI): 3.6%-5.5%] and was 4.1% at 36 months, which was significantly lower than the 8.5% rate observed for transvenous systems (HR: .47, 95% CI: .36-.61; P < .001). The all-cause system revision rate at 60 months was 4.9% (95% CI: 3.9%-6.1%). System revisions among Micra patients were mostly for device upgrades (41.2%) or elevated thresholds (30.6%). There were no Micra removals due to infection noted over the duration of follow-up. At 36 months, the system revision rate was significantly lower with Micra vs. transvenous systems (3.2% vs. 6.6%, P < .001). Long-term outcomes with the Micra leadless pacemaker continue to demonstrate low rates of major complications and system revisions and an extremely low incidence of infection.

Reduced processing efficiency impacts auditory detection of amplitude modulation in children: Evidence from an experimental and modeling study

Auditory detection of the Amplitude Modulation (AM) of sounds, crucial for speech perception, improves until 10 years of age. This protracted development may not only be explained by sensory maturation, but also by improvements in processing efficiency: the ability to make efficient use of available sensory information. This hypothesis was tested behaviorally on 86 6-to-9-year-olds and 15 adults using AM-detection tasks assessing absolute sensitivity, masking, and response consistency in the AM domain. Absolute sensitivity was estimated by the detection thresholds of a sinusoidal AM applied to a pure-tone carrier; AM masking was estimated as the elevation of AM-detection thresholds produced when replacing the pure-tone carrier by a narrowband noise; response consistency was estimated using a double-pass paradigm where the same set of stimuli was presented twice. Results showed that AM sensitivity improved from childhood to adulthood, but did not change between 6 and 9 years. AM masking did not change with age, suggesting that the selectivity of perceptual AM filters was adult-like by 6 years. However, response consistency increased developmentally, supporting the hypothesis of reduced processing efficiency in early childhood. At the group level, double-pass data of children and adults were well simulated by a model of the human auditory system assuming a higher level of internal noise for children. At the individual level, for both children and adults, double-pass data were better simulated when assuming a sub-optimal decision strategy in addition to differences in internal noise. In conclusion, processing efficiency for AM detection is reduced in childhood. Moreover, worse AM detection was linked to both systematic and stochastic inefficiencies, in both children and adults.

Tryptophan metabolism and small fibre neuropathy: a correlation study.

Small nerve fibres located in the epidermis sense pain. Dysfunction of these fibres decreases the pain threshold known as small fibre neuropathy. Diabetes mellitus is accompanied by metabolic changes other than glucose, synergistically eliciting small fibre neuropathy. These findings suggest that various metabolic changes may be involved in small fibre neuropathy. Herein, we explored the correlation between pain sensation and changes in plasma metabolites in healthy Japanese subjects. The pain threshold evaluated from the intraepidermal electrical stimulation was used to quantify pain sensation in a total of 1021 individuals in the 2017 Iwaki Health Promotion Project. Participants with a pain threshold evaluated from the intraepidermal electrical stimulation index <0.20 mA were categorized into the pain threshold evaluated from the intraepidermal electrical stimulation index-low group (n = 751); otherwise, they were categorized into the pain threshold evaluated from the intraepidermal electrical stimulation index-high group (n = 270). Metabolome analysis of plasma was conducted using capillary electrophoresis time-of-flight mass spectrometry. The metabolite set enrichment analysis revealed that the metabolism of tryptophan was significantly correlated with the pain threshold evaluated from the intraepidermal electrical stimulation index in all participants (P < 0.05). The normalized level of tryptophan was significantly decreased in participants with a high pain threshold evaluated from the intraepidermal electrical stimulation index. In addition to univariate linear regression analyses, the correlation between tryptophan concentration and the pain threshold evaluated from the intraepidermal electrical stimulation index remained significant after adjustment for multiple factors (β = -0.07615, P < 0.05). These findings indicate that specific metabolic changes are involved in the deterioration of pain thresholds. Here, we show that abnormal tryptophan metabolism is significantly correlated with an elevated pain threshold evaluated from the intraepidermal electrical stimulation index in the Japanese population. This correlation provides insight into the pathology and clinical application of small fibre neuropathy.

Higher Parametric Thyroid Feedback Quantile-based Index is a predictor of type 2 diabetes in a German population sample.

Type 2 diabetes has been described to be associated with hypothyroidism but we recently found that a decrease in pituitary sensitivity to thyroid hormone is associated with diabetes, obesity, and the metabolic syndrome.We aim to assess the longitudinal nature of this association in the population-based Study of Health in Pomerania(SHIP) in Germany. 77% of a population-based sample of 4308 participants between 20 and 79 years was followed for 5 years. We studied 2542 participants without diabetes or thyroid medication at baseline and complete data in the variables of interest. Data of baseline thyroxine(fT4) and thyrotropin(TSH) were used to calculate the Parametric Thyroid Feedback Quantile-based Index(PTFQI), which measures whether TSH remains elevated despite fT4 being high. It uses the average population response as reference. PTFQI association with incidence of type 2 diabetes over 5 years was estimated with Poisson regression models adjusted for age, sex, and body mass index(BMI). Compared with the 1st PTFQI quartile, Incidence Rate Ratios (IRR) for diabetes were 1.54(95% CI 0.97 to 2.46), 1.55(0.94 to 2.57), and 1.97(1.27 to 3.10) for the upper quartiles (p-trend=0.004) after adjusting for age and sex. The association remained statistically significant after additionally adjusting for BMI: 1.64(1.05 to 2.59) for the 4th vs the 1st quartile (p-trend=0.043). An elevation of the pituitary TSH-inhibition threshold is associated with incident type 2 diabetes independently of BMI. The PTFQI might have clinical potential for prognosis and metabolic status monitoring.

Ototoxicity of polystyrene nanoplastics in mice, HEI-OC1 cells and zebrafish.

Polystyrene nanoplastics are a novel class of pollutants. They are easily absorbed by living organisms, and their potential toxicity has raised concerns. However, the impact of polystyrene nanoplastics on auditory organs remains unknown. Here, our results showed that polystyrene nanoplastics entered the cochlea of mice, HEI-OC1 cells, and lateral line hair cells of zebrafish, causing cellular injury and increasing apoptosis. Additionally, we found that exposure to polystyrene nanoplastics resulted in a significant elevation in the auditory brainstem response thresholds, a loss of auditory sensory hair cells, stereocilia degeneration and a decrease in expression of Claudin-5 and Occludin proteins at the blood-lymphatic barrier in mice. We also observed a significant decrease in the acoustic alarm response of zebrafish after exposure to polystyrene nanoplastics. Mechanistic analysis revealed that polystyrene nanoplastics induced up-regulation of the Nrf2/HO-1 pathway, increased levels of malondialdehyde, and decreased superoxide dismutase and catalase levels in cochlea and HEI-OC1 cells. Furthermore, we observed that the expression of ferroptosis-related indicators GPX4 and SLC7A11 decreased as well as increased expression of ACLS4 in cochlea and HEI-OC1 cells. This study also revealed that polystyrene nanoplastics exposure led to increased expression of the inflammatory factors TNF-α, IL-1β and COX2 in cochlea and HEI-OC1 cells. Further research found that the cell apoptosis, ferroptosis and inflammatory reactions induced by polystyrene nanoplastics in HEI-OC1 cells was reversed through the pretreatment with N-acetylcysteine, a reactive oxygen species inhibitor. Overall, our study first discovered and systematically revealed the ototoxicity of polystyrene nanoplastics and its underlying mechanism.

Maximum tree height in European Mountains decreases above a climate-related elevation threshold

Mountain forests face important threats from global change and spatio-temporal variation in tree height can help to monitor these effects. In this study, we used the Global Ecosystem Dynamics Investigation space-borne laser sensor to examine the relationship between maximum tree height and elevation, and the role of climate, in the main European mountain ranges. We found a piecewise relationship between elevation and maximum tree height in all mountain ranges, supporting the existence of a common breakpoint that marks the beginning of tree development limitations. Temperature and precipitation were identified as the most important drivers of tree height variation. Additionally, we predicted significant upward displacement of the breakpoint for the period 2080-2100 under climate change scenarios, potentially increasing the area without growth limitations for trees. These findings contribute to understanding the impacts of global warming on mountain forest ecosystems and provide insights for their monitoring and management.

Mechanisms of cone sensitivity loss in retinitis pigmentosa.

To explore the mechanisms of cone sensitivity loss in retinitis pigmentosa by combining two-colour perimetry with threshold versus intensity (tvi) testing. Seven subjects with autosomal recessive retinitis pigmentosa and 10 normal subjects were recruited and underwent perimetric testing of one eye using 480- and 640-nm Goldman size V targets presented under scotopic conditions (no background illumination) and against a white background ranging in luminance from -1.5 to 2 log cd m-2 in 0.5 log cd m-2 steps. Data were fitted with tvi functions of the form logT = logT0 + log ((A + A0)/A0)n, where T is the threshold, T0 is the absolute threshold, A is the background intensity, A0 is the 'dark-light' constant and n is a gain constant. Reliable tvi functions could not be obtained within the region of the visual field corresponding to loss of the ellipsoid zone on optical coherence tomography. At fixation, changes in both T0 and A0 were observed, consistent with a d1 mechanism loss, which resulted in an upwards and rightwards shift of the tvi function. Losses at [±3°, ±3°] demonstrated changes in T0, consistent with a d3 mechanism loss, resulting in an upwards translation of the tvi curve. Although the absolute cone threshold was elevated at each location, shifts in the tvi function (so-called d1 mechanism loss) at fixation minimise threshold elevation in the presence of white adapting backgrounds, such as those typically employed in standard two-colour perimetry. At more peripheral testing locations, changes in threshold occurred independent of background luminance (so-called d3 mechanism loss). These findings suggest that backgrounds which selectively adapt rods while maintaining cones at, or near, absolute threshold may be preferable to conventional two-colour perimetry for assessing loss of cone sensitivity, especially at the point of fixation.

Complete Restoration of Hearing Loss and Cochlear Synaptopathy via Minimally Invasive, Single-Dose, and Controllable Middle Ear Delivery of Brain-Derived Neurotrophic Factor-Poly(dl-lactic acid-co-glycolic acid)-Loaded Hydrogel.

Noise-induced hearing loss (NIHL) often accompanies cochlear synaptopathy, which can be potentially reversed to restore hearing. However, there has been little success in achieving complete recovery of sensorineural deafness using nearly noninvasive middle ear drug delivery before. Here, we present a study demonstrating the efficacy of a middle ear delivery system employing brain-derived neurotrophic factor (BDNF)-poly-(dl-lactic acid-co-glycolic acid) (PLGA)-loaded hydrogel in reversing synaptopathy and restoring hearing function in a mouse model with NIHL. The mouse model achieved using the single noise exposure (NE, 115 dBL, 4 h) exhibited an average 20 dBL elevation of hearing thresholds with intact cochlear hair cells but a loss of ribbon synapses as the primary cause of hearing impairment. We developed a BDNF-PLGA-loaded thermosensitive hydrogel, which was administered via a single controllable injection into the tympanic cavity of noise-exposed mice, allowing its presence in the middle ear for a duration of 2 weeks. This intervention resulted in complete restoration of NIHL at frequencies of click, 4, 8, 16, and 32 kHz. Moreover, the cochlear ribbon synapses exhibited significant recovery, whereas other cochlear components (hair cells and auditory nerves) remained unchanged. Additionally, the cochlea of NE treated mice revealed activation of tropomyosin receptor kinase B (TRKB) signaling upon exposure to BDNF. These findings demonstrate a controllable and minimally invasive therapeutic approach that utilizes a BDNF-PLGA-loaded hydrogel to restore NIHL by specifically repairing cochlear synaptopathy. This tailored middle ear delivery system holds great promise for achieving ideal clinical outcomes in the treatment of NIHL and cochlear synaptopathy.

Effects of Astragaloside IV on Hearing, Inflammatory Factors, and Intestinal Flora in Mice Exposed to Noise.

Long-term exposure to noise can cause irreversible hearing loss. Considering that there is no effective drug treatment, it is important to seek preventive treatment for noise-induced hearing loss (NIHL). Although astragaloside IV (AS-IV) protects against NIHL by reducing serum inflammatory factors, there is scarce information on the regulation of inflammatory factors by AS-IV to prevent NIHL. We investigated the hearing thresholds and relationship between the serum levels of inflammatory cytokines and intestinal microbiota of c57bl/6j mice exposed to noise (103 dB SPL 4 h·d-1) for 7 days, treated with or without AS-IV. Our results revealed a lower hearing threshold and lower serum levels of TNF-α, TNF-γ, IL-6, IL-1β, and IFN-γ in the mice treated with AS-IV. Additionally, AS-IV increased the abundance levels of the phylum Firmicutes, class Bacillus, order Lactobacillus, and family Lactobacillus (p < 0.05), and decreased those of the phylum Bacteroidetes and order Bacteroidales (p < 0.05). Lactobacillus and Bacilli negatively correlated with TNF-α, TNF-γ, and IL-1β; Erysipelotrichaceae negatively correlated with INF-γ; and Clostridiales positively correlated with IL-1β. In conclusion, AS-IV reduces the elevation of hearing thresholds in mice, preventing hearing loss in mice exposed to noise, and under the intervention of AS-IV, changes in the levels of inflammatory factors correlate with intestinal flora. We suggest that AS-IV improves intestinal flora and reduces inflammation levels in c57bl/6j mice exposed to noise.

Periprocedural myocardial infarction and injury.

Periprocedural myocardial infarction (PMI) and injury, pertinent to both cardiac and non-cardiac procedures, have gained increasing recognition in clinical practice. Over time, diverse definitions for diagnosing PMI have been developed and validated among patient populations undergoing coronary revascularization. However, this variety in definitions presents considerable challenges in clinical settings and complicates both the design and interpretation of clinical trials. The necessity to accurately diagnose PMI has spurred significant interest in establishing universally accepted and prognostically meaningful thresholds for cardiac biomarkers elevation and supportive ancillary criteria. In fact, elevations in cardiac biomarkers in line with the 4th Universal Definition of Myocardial Infarction, have been extensively confirmed to be associated with increased mortality and cardiovascular events. In the context of non-coronary cardiac procedures, such as Transcatheter Aortic Valve Implantation, there is a growing acknowledgment of both the high incidence rates and the adverse impact of PMI on patient outcomes. Similarly, emerging research underscores the significance of PMI and injury in non-cardiac surgery, highlighting the urgent need for effective prevention and risk management strategies in this domain.

Distinguishing fibromyalgia syndrome from small fiber neuropathy: a clinical guide.

Fibromyalgia syndrome (FMS) and small fiber neuropathy (SFN) are distinct pain conditions that share commonalities and may be challenging as for differential diagnosis. To comprehensively investigate clinical characteristics of women with FMS and SFN to determine clinically applicable parameters for differentiation. We retrospectively analyzed medical records of 158 women with FMS and 53 with SFN focusing on pain-specific medical and family history, accompanying symptoms, additional diseases, and treatment. We investigated data obtained using standardized pain, depression, and anxiety questionnaires. We further analyzed test results and findings obtained in standardized small fiber tests. FMS patients were on average ten years younger at symptom onset, described higher pain intensities requiring frequent change of pharmaceutics, and reported generalized pain compared to SFN. Pain in FMS was accompanied by irritable bowel or sleep disturbances, and in SFN by paresthesias, numbness, and impaired glucose metabolism (P < 0.01 each). Family history was informative for chronic pain and affective disorders in FMS (P < 0.001) and for neurological disorders in SFN patients (P < 0.001). Small fiber pathology in terms of skin denervation and/or thermal sensory threshold elevation was present in 110/158 (69.7 %) FMS patients and 39/53 (73.6 %) SFN patients. FMS patients mainly showed proximally reduced skin innervation and higher corneal nerve branch densities (p<0.001) whereas SFN patients were characterized by reduced cold detection and prolonged electrical A-delta conduction latencies (P < 0.05). Our data show that FMS and SFN differ substantially. Detailed pain, drug and family history, investigating blood glucose metabolism, and applying differential small fiber tests may help to improve diagnostic differentiation and targeted therapy.

Auditory Neuropathy Spectrum Disorder in Individuals with Sickle Cell Anemia: Case Study.

The present study attempted to understand the association between Auditory neuropathy spectrum disorder (ANSD) and Sickle cell anemia (SCA) and to recognize possible causative factors for the presence of ANSD in SCA individuals. Two cases, 24 years male and 17years female with a laboratory-confirmed diagnosis of Sickle cell anemia underwent detailed audiological evaluation i.e., pure tone audiometry, speech audiometry, immittance audiometry, otoacoustic emission, and auditory brainstem responses. Audiological evaluation revealed a bilateral moderate low-frequency sensorineural hearing loss in male and bilateral moderately severe sensorineural Hearing loss in female case with elevated Speech Recognition Threshold and poor Speech Identification Scores. 'A' type tympanogram with the absence of Acoustic reflexes and the presence of Otoacoustic emission with no distinct and reproducible peak V in Auditory Brainstem Response (ABR) at 90 dBnHL with the presence of ringing cochlear microphonics on polarity reversal collectively indicating bilateral ANSD in both cases. ANSD and SCA are reported to have a genetic basis of etiology. There might be possibilities that one genetic condition may be common in manifesting both conditions or one genetic condition can cause the presence of another genetic condition or can exaggerate the evolution of another genetic condition. Also, abnormal ABR findings indicate the possibility of neuropathological involvement in isolation or in combination with genetic abnormalities that need detailed investigation to understand non-genetic causative factors. Thus, paved the path for further research in this line and might provide better rehabilitative options.

Implication of lncRNA MSTRG.81401 in Hippocampal Pyroptosis Induced by P2X7 Receptor in Type 2 Diabetic Rats with Neuropathic Pain Combined with Depression.

Major depressive disorder (MDD) is a common complication of diabetes and is often observed alongside diabetic neuropathic pain (DNP) as a comorbidity in diabetic patients. Long non-coding RNA (lncRNA) plays an important role in various pathophysiological processes. The P2X7 receptor is responsible for triggering inflammatory responses, such as pyroptosis, linked to pain and depression. The aim of this study was to investigate the effect of lncRNA MSTRG.81401 on hippocampal pyroptosis induced by the P2X7 receptor in diabetic rats with DNP combined with MDD (DNP + MDD). Our results showed that the expression of lncRNA MSTRG.81401 was significantly elevated in the hippocampus of DNP + MDD rats compared with the control group. Following the administration of shRNA targeting lncRNA MSTRG.81401, a notable elevation in mechanical and thermal pain thresholds was observed in rats with comorbid DNP and MDD. Additionally, significant improvements in depression-like behaviors were evident in the open-field test (OFT), sucrose preference test (SPT), and forced swim test (FST). In the DNP + MDD rats, elevated levels in hippocampal P2X7 receptor mRNA and protein were observed, along with increased co-expression of P2X7 and the astrocytic marker glial fibrillary acidic protein (GFAP). Meanwhile, in DNP + MDD rats, the heightened mRNA expression of NOD-like receptor protein 3 (NLRP3), apoptosis-associated speck-like protein (ASC), pyroptosis-related protein Gasdermin D (GSDMD), caspase-1, IL-1β, IL-18, and TNF-α was detected, in addition to increased serum levels of IL-1β, IL-18 and TNF-α. After shRNA treatment with lncRNA MSTRG.81401, the above abnormal changes in indicators for pyroptosis and inflammation were improved. Therefore, our study demonstrates that shRNA of lncRNA MSTRG.81401 can alleviate the pain and depression-like behaviors in diabetic rats associated with the comorbidity of DNP and MDD by inhibiting the hippocampal P2X7 receptor-mediated pyroptosis pathway and pro-inflammatory responses. This suggests that the P2X7R/NLRP3/caspase-1 implicated pyroptosis and inflammatory scenario may serve as a potential target for the management of comorbid DNP and MDD in diabetes.

Model and remote-sensing-guided experimental design and hypothesis generation for monitoring snow-soil–plant interactions

In this study, we develop a machine-learning (ML)-enabled strategy for selecting hillslope-scale ecohydrological monitoring sites within snow-dominated mountainous watersheds, with a particular focus on snow-soil–plant interactions. Data layers rely on spatial data layers from both remote sensing and hydrological model simulations. Specifically, a Landsat-based foresummer drought sensitivity index is used to define the dependency of the annual peak plant productivity on the Palmer drought severity index in the early growing season. Hydrological simulations provide the spatiotemporal dynamics of near-surface soil moisture and snow depth. In this framework, a regression analysis identifies the key hydrological variables relevant to the spatial heterogeneity of drought sensitivity. We then apply unsupervised clustering to these key variables, using the Gaussian mixture model, to group hillslopes into several zones that have divergent relationships regarding soil moisture, snow dynamics, and drought sensitivity. Using the datasets collected in the East River Watershed (Crested Butte, Colorado, United States), results show that drought sensitivity is significantly correlated with model-derived soil moisture and snow-free timing over space and time. The relationship is, however, non-linear, such that the correlation decreases above a threshold elevation and in a heavy snow year due to large snowpacks, lateral flow, and soil storage limitations. Clustering is then able to define the zones that have high or low sensitivity to drought, as well as the mid-elevation regions where sensitivity is associated with the topographic aspect and net potential radiation. In addition, the algorithm identifies the most representative hillslopes with road/trail access within each zone for installing monitoring sites. Our method also aims to significantly increase the use of ML and model-simulation results to guide critical zone and watershed monitoring activities.

GNSS-IR water level monitoring toward particular narrow scenarios: Application to South-to-North Water Diversion Project in China

River water level monitoring plays a crucial role in hydrological practice. Global Navigation Satellite Systems Interferometry Reflectometry (GNSS-IR) has been demonstrated to help retrieve absolute water levels in expansive and unobstructed scenarios. However, how to measure in rivers remains a significant challenge for practical use due to the restricted reflection area. To address these issues, we propose the Dynamic Masking Elevation Threshold Selection Method (DMETSM), which effectively broadens the selection of available reflective signals. Through analyzing actual field data collected along the South-to-North Water Diversion Project, we have found that DMETSM almost doubles the effective monitoring area compared to the classical method. Furthermore, the multi-GNSS water level retrievals at two sites can achieve high accuracy, with root-mean-square errors of 1.36 cm and 2.57 cm, respectively. Results show that it improves accuracy by 30.6 % and 42.6 %. This highlights the considerable potential and value of applications in narrow and irregular areas.

Resveratrol Improves Mechanical Allodynia and Inflammation: Focus on Sex Differences in Rats

Inflammatory pain is a complex phenomenon arising from various etiological factors, resulting in diverse symptoms that can lead to persistent debilitations. The management of chronic inflammatory pain predominantly involves non-steroidal anti-inflammatory drugs, despite their association with adverse cardiovascular and gastrointestinal effects. Consequently, the pursuit of innovative therapeutic avenues for pain intervention is of paramount importance. Resveratrol, renowned for its anti-inflammatory and anti-oxidative attributes, emerges as a promising candidate in this regard. In this work, we assessed the potential of resveratrol to elicit anti-nociceptive and anti-inflammatory effects in two distinct models of peripheral inflammation: carrageenan and complete Freund’s adjuvant, conducted in male and female rats. In rats treated with carrageen, resveratrol administration yielded an elevation in mechanical thresholds in both sexes, concurrently inducing a reduction in paw diameter specifically among male rats. Furthermore, the administration of resveratrol in complete Freund’s adjuvant–treated rats led to an analogous increase of mechanical thresholds, a response observed in both male and female subjects. These compelling outcomes underscore the analgesic and anti-inflammatory attributes inherent to resveratrol, thereby offering a fresh insight into the intricate realm of sex-related variances in two well-characterized pharmacodynamics models of inflammatory pain.Graphical

A Guinea Pig Model Suggests That Objective Assessment of Acoustic Hearing Preservation in Human Ears With Cochlear Implants Is Confounded by Shifts in the Spatial Origin of Acoustically Evoked Potential Measurements Along the Cochlear Length.

Our recent empirical findings have shown that the auditory nerve compound action potential (CAP) evoked by a low-level tone burst originates from a narrow cochlear region tuned to the tone burst frequency. At moderate to high sound levels, the origins shift to the most sensitive audiometric regions rather than the extended high-frequency regions of the cochlear base. This means that measurements evoked from extended high-frequency sound stimuli can shift toward the apex with increasing level. Here we translate this study to understand the spatial origin of acoustically evoked responses from ears that receive cochlear implants, an emerging area of research and clinical practice that is not completely understood. An essential step is to first understand the influence of the cochlear implant in otherwise naive ears. Our objective was to understand how function of the high-frequency cochlear base, which can be excited by the intense low-frequency sounds that are frequently used for objective intra- and postoperative monitoring, can be influenced by the presence of the cochlear implant. We acoustically evoked responses and made measurements with an electrode placed near the guinea pig round window. The cochlear implant was not utilized for either electrical stimulation or recording purposes. With the cochlear implant in situ, CAPs were acoustically evoked from 2 to 16 kHz tone bursts of various levels while utilizing the slow perfusion of a kainic acid solution from the cochlear apex to the cochlear aqueduct in the base, which sequentially reduced neural responses from finely spaced cochlear frequency regions. This cochlear perfusion technique reveals the spatial origin of evoked potential measurements and provides insight on what influence the presence of an implant has on acoustical hearing. Threshold measurements at 3 to 11 kHz were elevated by implantation. In an individual ear, thresholds were elevated and lowered as cochlear implant was respectively inserted and removed, indicative of "conductive hearing loss" induced by the implant. The maximum threshold elevation occurred at most sensitive region of the naive guinea pig ear (33.66 dB at 8 kHz), making 11 kHz the most sensitive region to acoustic sounds for guinea pig ears with cochlear implants. Conversely, the acute implantation did not affect the low-frequency, 500 Hz thresholds and suprathreshold function, as shown by the auditory nerve overlapped waveform. As the sound pressure level of the tone bursts increased, mean data show that the spatial origin of CAPs along the cochlear length shifted toward the most sensitive cochlear region of implanted ears, not the extended high-frequency cochlear regions. However, data from individual ears showed that after implantation, measurements from moderate to high sound pressure levels originate in places that are unique to each ear. Alterations to function of the cochlear base from the in situ cochlear implant may influence objective measurements of implanted ears that are frequently made with intense low-frequency sound stimuli. Our results from guinea pigs advance the interpretation of measurements used to understand how and when residual acoustic hearing is lost in human ears receiving a cochlear implant.

SR9883 is a novel small-molecule enhancer of α4β2* nicotinic acetylcholine receptor signaling that decreases intravenous nicotine self-administration in rats.

Most smokers attempting to quit will quickly relapse to tobacco use even when treated with the most efficacious smoking cessation agents currently available. This highlights the need to develop effective new smoking cessation medications. Evidence suggests that positive allosteric modulators (PAM) and other enhancers of nicotinic acetylcholine receptor (nAChR) signaling could have therapeutic utility as smoking cessation agents. 3-[3-(3-pyridyl)-1,2,4-oxadiazol-5-yl]benzonitrile (NS9283) was used as a starting point for medical chemistry efforts to develop novel small molecule enhancers of α4β2* nAChR stoichiometries containing a low-affinity agonist binding site at the interface of α4/α4 and α4/α5 subunits. The NS9283 derivative SR9883 enhanced the effect of nicotine on α4β2* nAChR stoichiometries containing low-affinity agonist binding sites, with EC50 values from 0.2-0.4 μM. SR9883 had no effect on α3β2* or α3β4* nAChRs. SR9883 was bioavailable after intravenous (1 mg kg-1) and oral (10-20 mg kg-1) administration and penetrated into the brain. When administered alone, SR9883 (5-10 mg kg-1) had no effect on locomotor activity or intracranial self-stimulation (ICSS) thresholds in mice. When co-administered with nicotine, SR9883 enhanced locomotor suppression and elevations of ICSS thresholds induced by nicotine. SR9883 (5 and 10 mg kg-1) decreased responding for intravenous nicotine infusions (0.03 mg kg-1 per infusion) but had no effect on responding for food rewards in rats. These data suggest that SR9883 is useful for investigating behavioral processes regulated by certain α4β2* nAChR stoichiometries. SR9883 and related compounds with favorable drug-like physiochemical and pharmacological properties hold promise as novel treatments of tobacco use disorder.

Visualization and analysis of multi-channel dynamic range compression in hearing aids

One main functionality of hearing aids is restoring audibility. This means that low sound pressure levels are amplified above the elevated hearing threshold, and higher sound pressure levels do not exceed the individual uncomfortable loudness level (UCL). To this end, hearing aids provide frequency-dependent dynamic range compression which is denoted as hearing aid channels (HACs) in the recently published standard IEC 60118-16. As an increasing number of HACs, among other features, is one main feature to differentiate between price or technology levels, IEC 60118-16 includes a measurement procedure to verify the number of HACs. In this work, we verify this test procedure with a research hearing aid (RHA), and evaluate six commercial hearing aids of three different manufacturers and two technology levels. These results demonstrate the possibilities and limitations of the new test procedure. Furthermore, we introduced an extension of this test procedure with a channel-specific compression setting to overcome limitations and to get a deeper insight into the functionality of HACs in hearing aids. These results show that many HACs of commercial devices are coupled to neighboring frequencies, and that different strategies are used across manufacturers to adapt the number of HACs for different technology levels.