Elevated Thresholds Research Articles

His bundle pacing, selective and non-selective: are they equally safe and effective?

Abstract Background Permanent His Bundle Pacing (HBP) is the most physiological form of ventricular pacing. His bundle stimulation can be selective (s-HBP) or non-selective (ns-HBP). Few comparative data in terms of safety and efficacy among the two are available in literature. Purpose Evaluate the safety and efficacy of s-HBP and ns-HBP stimulation and identify predictors of one or the other stimulation. Methods Prospective analysis of patients with HBP implanted between December 2018 and July 2021. The clinical and instrumental parameters were collected at implant and at long-term follow-up. Follow-up data were collected both at outpatient visits and by remote monitoring systems. Results 130 patients in need for antibradyarrhythmia therapy and 26 patients with an indication for cardiac resynchronization therapy were enrolled, 134 (86%) had successful HBP (34% s-HBP and 66% ns-HBP). There were no significant clinical differences between the two populations with the exception of the presence of right bundle branch block (RBBB: 17.4% s-HBP and 34.1% ns-HBP; p = <0.05) and baseline QRS duration (116.5±27.5 ms in s-HBP and 129.9±34.7 ms in ns-HBP; p = <0.05). There were no significant predictors of ns-HBP (Figure 1). At implantation and at an average 16-month follow-up there were no significant differences in the electrical parameters between the two HBP stimulation modalities. Twenty-one patients (15.7% of the population, 24% of s-HBP and 12.5% of ns-HBP; p=0.38) had conduction system disease progression, manifested either by a significant increase in pacing threshold (13.3% of s-HBP and 10.2% of ns-HBP recipients; p=0.64; Figure 2A) or by loss of capture (6.5% of s-HBP and 2.2% of ns-HBP recipients; p=0.69). No statically significant predictors of conduction system disease progression were found (Figure 2B). While seventeen patients who had significant threshold elevation underwent device output reprogramming, four patients, who lost capture, and a single one experiencing lead dislodgment (nS-HBP patient) required lead repositioning (8.7% of s-HBP and 4.5% of ns-HBP recipients; p=0.33). s-HBP was significantly more vulnerable to atrial oversensing that required sensitivity reprogramming (17.4% of s-HBP and 4.5% of ns-HBP recipients; p<0.05). No significant differences in clinical endpoints (cardiovascular death, heart failure, atrial fibrillation, syncope) were observed at follow-up. Conclusions In patients indicated to ventricular stimulation, the potential benefit represented by HBP is burdened by a non-negligible number of complications. Though no significant differences were detected at medium-long term between s-HBP and ns-HBP stimulation, s-HBP stimulation appears to be more affected by pacing threshold increase and progression of conduction tissue disease, which resulted in an almost 2-fold (although statistically not significant) incidence of repeated surgery. Funding Acknowledgement Type of funding sources: None.

Safety and effectiveness of His-bundle pacing and left bundle branch pacing (conduction system pacing) as a first option for cardiac pacing – results of a single-center

Abstract Background Conduction system pacing (CSP) (His bundle pacing and left bundle pacing) is a group of techniques intended to achieve cardiac pacing with a narrow QRS complex through a lead directly inserted in conduction system structures. The safety and effectiveness of this technique are not yet fully understood. Purpose To describe the short-term implant findings and safety profile of CSP as a first option after 4 years in a single center. Methods In a period of 42 months, 214 patients were submitted to CSP as a first strategy to restore AV synchrony (pacemakers for AV block or sinus node dysfunction) or as a resynchronization (CRT) strategy (for patients with heart failure and bundle branch block). CSP lead was implanted in lieu of a conventional right ventricular lead in pacemaker cases, and in addition or in lieu of a coronary sinus lead, in CRT cases, depending on the technical and anatomical possibilities. Results The mean age was 76.7±16.4 years, 65% males. 162 patients implanted a CSP lead for a dual-chamber pacemaker, 3 patients for a single chamber pacemaker, 32 patients for CRT-D (CSP lead replacing the coronary sinus lead with a defibrillator), and 13 patients for an optimized CRT (CSP lead plus coronary sinus lead). In 16 patients (7.4%) the technique of choice was His bundle pacing, two of them presented with subacute elevated thresholds, requiring new lead implantation at the moment of generator pulse replacement. One patient submitted to left bundle branch pacing (0.4%) had subacute lead dislodgement, being submitted to lead revision. Four patients intended for CRT (1.8%) didn't meet the criteria for His bundle pacing or left bundle branch pacing, being submitted to conventional coronary sinus lead placement. There were 10 cases (4.6%) of confirmed lead perforation during the lead septum insertion, with prompt repositioning, all uneventful. No pericardium effusion related to lead perforation was observed. One patient (0.4%) had a pneumothorax, requiring chest tube drainage. Conclusion Conduction system pacing as a first strategy is a feasible, effective and safe technique, both for pacing and for resynchronization purposes, with a complication rate comparable to conventional implantation. Funding Acknowledgement Type of funding sources: None.

Temporary threshold shift from continuous 20–40 kHz hyperbolic upsweeps in bottlenose dolphins (Tursiops truncatus)

Naval continuous active sonar (CAS) can operate at high duty cycles and result in sound exposure levels (SELs, in dB re 1 μPa2s) that may induce temporary threshold shift (TTS) in marine mammals. Estimating the impacts of CAS on marine mammal hearing is difficult however, given the scarcity of TTS data for long-duration tonal exposures. For this ongoing study, bottlenose dolphin TTS was measured following exposure to continuous playback of 19-s hyperbolic upsweeps from 20–40 kHz, at multiple sound pressure levels and exposure durations from 2 to 60 min (100% duty cycle). The upsweep was based on characteristics of naval CAS, but frequency-shifted into the dolphin’s range of best hearing to predict how baleen whales might be affected by CAS exposures below 10 kHz. Hearing was measured using both psychophysical and auditory brainstem response measurements. To date, the greatest cumulative exposures of 180 dB SEL (normal-hearing dolphin) and 183 dB SEL (dolphin with elevated hearing thresholds) resulted in less than 6 dB of behavioral TTS. Auditory brainstem response amplitudes for these exposures did not indicate noise-induced fatigue. Future testing will evaluate TTS following exposure to 28-kHz pure tones with comparable SELs. [Work funded by US Navy Living Marine Resources.]

Přínos vysokofrekvenční tónové audiometrie – retrospektivní studie

Summary Introduction: High-frequency audiometry is not usually carried out during routine hearing examinations. It is a frequently used method at the ENT Clinic of the University Hospital Motol (especially in patients being treated for tumours of the pontocerebellar angle), although the exact indicative criteria for this have not been determined. We aimed to characterize a group of patients, using a method which improved the accuracy of the diagnostics. Material and methodology: We analysed 1,515 audiograms retrospectively. These audiograms were performed by using audiometer MADSEN Astera of GN Otometrics during 2011–2018 in 773 adults, aged 16–80 (47.79 ±13.54). They all underwent high-frequency audiometry comprising of all commonly examined frequencies up to 8 kHz, and also at higher frequencies of – 9 kHz, 10 kHz, 11.2 kHz, 12.5 kHz, 14 kHz a 16 kHz. The indication was very diverse – subjective hypacusis/hyperacusis, tinnitus, vestibulopathy, acutrauma, or an already known diagnosis of a pontocerebellar tumour. Results: We identifi ed a clinically signifi cant asymmetry or pathological elevation of the hearing threshold, which was only detectable at frequencies above 8 kHz in 52 patients (6.73%). This group consisted of patients with vestibular schwannoma (48.08%), other tumours and vascular malformations of the temporal region (11.53%), vestibulopathy (3.85%), and patients that had never developed a serious pathology (23.08%). They were mostly patients with straightforward hypacusis or tinnitus. Conclusion: In clinical practice, there are cases of patients with a hearing defect that can only be detected when HFA is performed. HFA clarifi es the diagnosis of hearing disorders and can lead to the detection of potentially life-threatening conditions such as tumours and vascular malformations of the otological area. Key words high-frequency audiometry – hearing loss – tinnitus

The hunt for hidden hearing loss in humans: From preclinical studies to effective interventions.

Many individuals experience hearing problems that are hidden under a normal audiogram. This not only impacts on individual sufferers, but also on clinicians who can offer little in the way of support. Animal studies using invasive methodologies have developed solid evidence for a range of pathologies underlying this hidden hearing loss (HHL), including cochlear synaptopathy, auditory nerve demyelination, elevated central gain, and neural mal-adaptation. Despite progress in pre-clinical models, evidence supporting the existence of HHL in humans remains inconclusive, and clinicians lack any non-invasive biomarkers sensitive to HHL, as well as a standardized protocol to manage hearing problems in the absence of elevated hearing thresholds. Here, we review animal models of HHL as well as the ongoing research for tools with which to diagnose and manage hearing difficulties associated with HHL. We also discuss new research opportunities facilitated by recent methodological tools that may overcome a series of barriers that have hampered meaningful progress in diagnosing and treating of HHL.

Protein kinase C-mediated phosphorylation of transient receptor potential melastatin type 2 Thr738 counteracts the effect of cytosolic Ca2+ and elevates the temperature threshold.

The transient receptor potential melastatin type 2 (TRPM2) channel is a non-selective cation channel that has high Ca2+ permeability. TRPM2 is sensitive to warm temperatures and is expressed in cells and tissues that are maintained at core body temperature. TRPM2 activity is also regulated by endogenous factors including redox signalling, cytosolic Ca2+ and adenosine diphosphate ribose. As a result of its wide expression and function at core body temperature, these endogenous factors could regulate TRPM2 activity at body temperature under physiological and pathophysiological conditions. We previously reported that cellular redox signalling can lower TRPM2 temperature thresholds, although the mechanism that regulates these thresholds is unclear. Here, we used biochemical and electrophysiological techniques to explore another regulatory mechanism for TRPM2 temperature thresholds that is mediated by TRPM2 phosphorylation. Our results show that: (1) the temperature threshold for TRPM2 activation is lowered by cytosolic Ca2+ ; (2) protein kinase C-mediated phosphorylation of TRPM2 counteracts the effect of cytosolic Ca2+ ; and (3) Thr738 in mouse TRPM2 that lies near the Ca2+ binding site in the cytosolic cleft of the transmembrane domain is a potential phosphorylation site that may be involved in phosphorylation-mediated elevation of TRPM2 thresholds. These findings provide structure-based evidence to understand how temperature thresholds of thermo-sensitive TRP channels (thermo-TRPs) are determined and regulated. KEY POINTS: The transient receptor potential melastatin type 2 (TRPM2) ion channel is temperature-sensitive and Ca2+ -permeable. Endogenous factors and pathways such as redox signalling can regulate TRPM2 activity at body temperature under physiological and pathophysiological conditions. In the present study, we report the novel finding that cytosolic Ca2+ lowers the temperature threshold for TRPM2 activation in a concentration-dependent manner. Protein kinase C-mediated phosphorylation of TRPM2 at amino acid Thr782 elevates the temperature threshold for activation by counteracting the effects of cytosolic Ca2+ . These findings provide structure-based evidence to understand how temperature thresholds of thermo-sensitive TRP channels are determined and regulated.

The Clinical Effect and Mechanism of Prostant on Urinary Retention and Anal Pain.

Anal pain and urinary retention are the two most outstanding complications of the procedure for prolapse and hemorrhoids (PPH) surgery. This study intended to assess the clinical effect and mechanism of Prostant on urinary retention and anal pain after the PPH. Here, 30 patients received PPH surgery. The role and mechanism of Prostant in patients and mice with urinary retention and anal pain were evaluated. ANOVA tests were executed and differences between groups were regarded as statistically significant when p < 0.05. Prostant effectively improved the urination status, lower abdomen symptoms, time to urinate and score of VAS, and the reduction of TNF-α and IL-6. Similarly, Prostant can ameliorate the outcome of urodynamics in urinary retention mice. Mechanically, Prostant reversed the urinary retention-elevated the serum level of hs-CRP and TNF-α, reduction of IL-2, imbalance of Treg/Th17, and level of JAK2 and phosphorylated STAT3. Besides, Prostant ameliorated the pain as shown by the reduction of writhing response, and the elevation of threshold of pain and degree of swelling. Moreover, Prostant antagonized the pain-induced dysregulation of Treg/Th17. Therefore, Prostant can treat patients and mice with anal pain and urinary retention by modulating the balance of Th17/Treg to regulate the secretion and production of inflammatory factors. We hope our results can establish a scientific treatment approach for solving anal pain and urinary retention after PPH surgery of mixed hemorrhoids.

Galectin-3 protects auditory function in female mice

Sex differences in the development of sensorineural hearing loss have been recognized in various inner ear disorders, but the molecular basis for such differences is poorly understood. Autosomal genes have been shown to cause sex differences in disease susceptibility, but many genes exerting sex-dependent effects on auditory function remain to be identified. Galectin-3 (Gal-3), a protein encoded by the autosomal gene Lgals3, is a member of the β-galactoside-binding protein family, and has been linked to multiple biological processes, including immune responses, apoptosis, and cell adhesion. Here, we investigated auditory function and hair cell integrity in Gal-3 knockout (KO, Lgals3−/−) and wild-type (WT, Lgals3+/+) mice from age 1 to 6 months. KO mice show a more rapid age-related increase in ABR thresholds compared to WT mice. Noticeably, the threshold deterioration in female KO mice is significantly greater than in the male KO and WT mice. The ABR threshold elevation manifests over a broad frequency range in female KO mice, whereas the threshold elevations are confined to high frequencies in the male KO and WT mice. Moreover, DPOAE input/output functions reveal a similar pattern of auditory dysfunction, with the female KO mice displaying a significantly greater reduction in DPOAE amplitudes than male KO mice and WT mice of both sexes. Finally, age-related outer hair cell loss is greater for female KO mice compared to male KO mice and WT mice of both sexes. Together, these results indicate that Gal-3 deficiency exacerbates age-related cochlear degeneration and auditory dysfunction in female mice. Our study identifies Gal-3 as a sex-dependent molecule for maintaining female cochlear integrity.

Transcutaneous electrical nerve inhibition using medium frequency alternating current

Transcutaneous medium-frequency alternating electrical current is defined as an alternating current between 1 and 10 kHz and is capable of producing an instant, reversible block. This study aims to evaluate the efficacy of sensory perception and force production of the index and middle finger after transcutaneous medium-frequency alternating electrical current stimulation of the distal median nerve. A single-center prospective interventional cohort study was conducted in adult healthy volunteers at the Jessa Hospital, Hasselt, Belgium. Two different electrodes (PALS & 3M) were placed on the distal median nerve, which was located using a Sonosite X-Porte Ultrasound transducer, with the first electrode being placed on the skin at the level of the transverse carpal ligament and the second electrode 7 cm proximally to the first electrode. The tactile sensation was evaluated with Semmes–Weinstein monofilament test and sensation of pressure/pain was evaluated with an algometer. Peak force production was assessed with an electronic dynamometer. All measurements were performed at baseline and tMFAEC stimulation frequencies of 2 and 10 kHz in a randomized manner. Statistical analysis was performed with a one-way ANOVA with repeated measures test or a Friedman rank sum test, followed by the Wilcoxon signed rank test adjusted with Bonferroni correction. A p-value < 0.05 was considered statistically significant. From 9 to 13th of April 2021, 25 healthy volunteers were included in the Jessa Hospital, Hasselt, Belgium. A statistically significant reduction in tactile sensation during 2 kHz and 10 kHz stimulation compared to baseline was observed (2.89 ± 0.22 (PALS2); 3.35 ± 0.25 (3M2) and 2.14 ± 0.12 (PALS10); 2.38 ± 0.12 (3M10) versus − 1.75 ± 0.09 (baseline), p < 0.0001). 3M electrodes showed a tendency towards the elevation of pressure pain threshold compared to baseline. No significant difference in mean peak forces of the index and middle fingers after transcutaneous medium-frequency alternating electrical current stimulation with 2 and 10 kHz was found. This study demonstrates that transcutaneous medium-frequency alternating electrical current stimulation on the distal median nerve inhibits tactile sensory nerve activity in the index and middle finger when stimulation of 2 kHz and, to a lesser extent, 10 kHz was applied. A reduction of motor nerve activity was not observed but force production measurements may be prone to error.Trial registration: clinicaltrials.gov on 01/04/2021. NCT-Number: NCT04827173.

Afferent Loss, GABA, and Central Gain in Older Adults: Associations with Speech Recognition in Noise.

Deficits in auditory nerve (AN) function for older adults reduce afferent input to the cortex. The extent to which the cortex in older adults adapts to this loss of afferent input and the mechanisms underlying this adaptation are not well understood. We took a neural systems approach measuring AN and cortical evoked responses within 50 older and 27 younger human adults (59 female) to estimate central gain or increased cortical activity despite reduced AN activity. Relative to younger adults, older adults' AN response amplitudes were smaller, but cortical responses were not. We used the relationship between AN and cortical response amplitudes in younger adults to predict cortical response amplitudes for older adults from their AN responses. Central gain in older adults was thus defined as the difference between their observed cortical responses and those predicted from the parameter estimates of younger adults. In older adults, decreased afferent input contributed to lower cortical GABA levels, greater central gain, and poorer speech recognition in noise (SIN). These effects on SIN occur in addition to, and independent from, effects attributed to elevated hearing thresholds. Our results are consistent with animal models of central gain and suggest that reduced AN afferent input in some older adults may result in changes in cortical encoding and inhibitory neurotransmission, which contribute to reduced SIN. An advancement in our understanding of the changes that occur throughout the auditory system in response to the gradual loss of input with increasing age may provide potential therapeutic targets for intervention.SIGNIFICANCE STATEMENT Age-related hearing loss is one of the most common chronic conditions of aging, yet little is known about how the cortex adapts to this loss of sensory input. We measured AN and cortical responses to the same stimulus in younger and older adults. In older adults we found hyperexcitability in cortical activity relative to concomitant declines in afferent input that are consistent with central gain. Lower levels of cortical GABA, an inhibitory neurotransmitter, were associated with greater central gain, which predicted poorer SIN. The results suggest that the cortex in older adults may adapt to attenuated sensory input by reducing inhibition to amplify the cortical response, but this amplification may lead to poorer SIN.

FCHSD2 is required for stereocilia maintenance in mouse cochlear hair cells.

Stereocilia are F-actin-based protrusions on the apical surface of inner-ear hair cells and are indispensable for hearing and balance perception. The stereocilia of each hair cell are organized into rows of increasing heights, forming a staircase-like pattern. The development and maintenance of stereocilia are tightly regulated, and deficits in these processes lead to stereocilia disorganization and hearing loss. Previously, we showed that the F-BAR protein FCHSD2 is localized along the stereocilia of cochlear hair cells and cooperates with CDC42 to regulate F-actin polymerization and cell protrusion formation in cultured COS-7 cells. In the present work, Fchsd2 knockout mice were established to investigate the role of FCHSD2 in hearing. Our data show that stereocilia maintenance is severely affected in cochlear hair cells of Fchsd2 knockout mice, which leads to progressive hearing loss. Moreover, Fchsd2 knockout mice show increased acoustic vulnerability. Noise exposure causes robust stereocilia degeneration as well as enhanced hearing threshold elevation in Fchsd2 knockout mice. Lastly, Fchsd2/Cdc42 double knockout mice show more severe stereocilia deficits and hearing loss, suggesting that FCHSD2 and CDC42 cooperatively regulate stereocilia maintenance.

Hydrogen Gas Inhalation Attenuates Acute Impulse Noise Trauma: A Preclinical In Vivo Study.

Molecular hydrogen (H2) has shown therapeutic potential in several oxidative stress-related conditions in humans, is well-tolerated, and is easily administered via inhalation.The aim of this preclinical in vivo study was to investigate whether impulse noise trauma can be prevented by H2 when inhaled immediately after impulse noise exposure. Guinea pigs (n = 26) were subjected to impulse noise (n = 400; 156 dB SPL; 0.33/s; n = 11; the Noise group), to impulse noise immediately followed by H2 inhalation (2 mol%; 500 ml/min; 1 hour; n = 10; the Noise + H2 group), or to H2 inhalation (n = 5; the H2 group). The acoustically evoked ABR threshold at 3.15, 6.30, 12.5, 20.0, and 30.0 kHz was assessed before and 4 days after impulse noise and/or H2 exposure. The cochleae were harvested after the final ABR assessment for quantification of hair cells. Noise exposure caused ABR threshold elevations at all frequencies (median 35, 35, 30, 35, and 35 dB SPL, the Noise group; 20, 25, 10, 13, and 20 dB SPL, the Noise + H2 group; P < .05) but significantly less so in the Noise + H2 group (P < .05). Outer hair cell (OHC) loss was in the apical, mid, and basal regions 8.8%, 53%, and 14% in the Noise group and 3.5%, 22%, and 1.2% in the Noise + H2 group. The corresponding inner hair cell (IHC) loss was 0.1%, 14%, and 3.5% in the Noise group and 0%, 2.8%, and 0% in the Noise + H2 group. The difference between the groups was significant in the basal region for OHCs (P = .003) and apical (P = .033) and basal (P = .048) regions for IHCs. Acute acoustic trauma can be reduced by H2 when inhaled immediately after impulse noise exposure.

The correlation between the body shape and otolithic function in patients with obstructive sleep apnea

ObjectiveTo identify the typical pattern of changes of vestibular-evoked myogenic potentials (VEMPs) and explore the relationship between VEMPs and the anthropometry factors in patients with obstructive sleep apnea (OSA). MethodsPatients diagnosed as OSA after overnight polysomnography (PSG) tests were enrolled as the study group. Healthy volunteers were recruited as the control group. Anthropometry data of the body shape and VEMPs results were collected completely. The correlation analysis was conducted among those parameters. ResultsForty-nine patients with OSA who were diagnosed in the Therapy Center of Sleep-disordered Breathing in our hospital and sex- and age-matched healthy controls as well. Significant changes in ocular and cervical VEMPs (oVEMP and cVEMP) in the study group were observed, which were reduced response rates, elevated thresholds, decreased amplitudes, and prolonged first wave latencies. In oVEMP, the first wave (n1) latency was significantly correlated with weight, body mass index (BMI), neck circumference, waist circumference, hip circumference, and apnea hypopnea index (AHI). In a tentative application, combined use of BMI and oVEMP n1 latency increased the detection rate during OSA screening prior to PSG. ConclusionOSA can negatively affect function of otolithic organs and their pathways. The first wave latency of the VEMPs waveform may be another important parameter to define peripheral nervous system lesions caused by systemic diseases as OSA.

Cardiomyopathy correlates to nerve damage in p.A117Slate‐onset transthyretin amyloid polyneuropathy

ObjectiveLate‐onset hereditary transthyretin amyloidosis with polyneuropathy (ATTRv‐PN) is often associated with heart involvement. Recent advances in cardiac imaging allow the detection of cardiac amyloidosis. This study aimed to explore cardiomyopathy by cardiac imaging and its clinical correlates with polyneuropathy in late‐onset ATTRv‐PN.MethodsPolyneuropathy was assessed by intraepidermal nerve fiber (IENF) density, nerve conduction study (NCS), autonomic function tests, quantitative sensory testing, and clinical questionnaires. Cardiomyopathy was evaluated by echocardiography, 99mTc‐pyrophosphate (PYP) single‐photon emission computed tomography (SPECT) imaging, cardiac magnetic resonance imaging (CMR), and serum Pro‐B‐type natriuretic peptide. Healthy controls and patients with Brugada syndrome were enrolled for comparison of CMR.ResultsFifty late‐onset ATTRv‐PN patients (38 men, 46 with p. A117S mutation), aged 63.7 ± 5.5 years, of polyneuropathy disability stage 1–4 were enrolled. All patients presented polyneuropathy in NCS, and 74.5% of patients had reduced IENF density in distal legs. All patients showed significant radiotracer uptake in the heart on 99mTc‐PYP SPECT imaging, and 87.8% of patients had abnormally increased left ventricular (LV) septum thickness on echocardiography. CMR showed longer myocardial native T1, larger extracellular volume, greater LV mass index, and higher LV mass to end‐diastolic volume ratio in ATTRv‐PN patients than healthy controls and patients with Brugada syndrome. These CMR parameters were associated with skin denervation, absent sympathetic skin responses, elevated thermal thresholds, worsened NCS profiles, and functional deficits of polyneuropathy.InterpretationLate‐onset ATTRv‐PN coexisted with cardiomyopathy regardless of the clinical severity of polyneuropathy. The cardiac amyloid burden revealed by CMR was correlated with pathophysiology and clinical disability of nerve degeneration.

Comparison of the safety and efficacy of YEARS, PEGeD, 4PEPS or the sole item "PE is the most likely diagnosis" strategies for the diagnosis of pulmonary embolism in the emergency department: post-hoc analysis of two European cohort studies.

The optimal strategy for the diagnosis of pulmonary embolism (PE) in the emergency department (ED) remains debated. To reduce the need of imaging testing, several rules have been recently validated using an elevated D-dimer threshold. To validate the safety of different diagnostic strategies and compare the efficacy in terms of chest imaging testing. Post-hoc analysis of individual data of 3330 adult patients without a high clinical probability of PE in the ED followed-up at 3 months in France and Spain (1916 from the PROPER cohort, 1414 from the MODIGLIANI cohort). Four diagnostic strategies with an elevated D-dimer threshold if PE is unlikely. The YEARS combined with Pulmonary Embolism Rule-out Criteria (PERC) the pulmonary embolism graduated D-dimer (PEGeD) combined with PERC and the 4-level pulmonary embolism probability score (4PEPS) rules were assessed. A modified simplified (MODS) rule with a simplified YEARS reduced to the sole item of "Is PE the most likely diagnosis" combined with PERC was also tested. The primary outcome was the proportion of diagnosed PE or deep venous thrombosis at 3 months in patients in whom PE could have been excluded without chest imaging according to the tested strategy. The safety of a strategy was confirmed if the failure rate was less than 1.85%. The secondary outcome was the use of imaging testing according to each rule. Among 3330 analyzed patients, 150 (4.5%) had a PE. The number of missed PEs were 25, 29, 30 and 26 for the PERC+YEARS, PERC+PEGeD, 4PEPS and MODS rules respectively, with a failure rate of 0.75% (95% CI 0.51% to 1.10%), 0.87% (0.61% to 1.25%), 0.90% (0.63% to 1.28%) and 0.78% (0.53% to 1.14%) respectively. There was no significant difference in the failure rate between rules. Except for a significant lower use of chest imaging for 4PEPS compared to YEARS (14.9% vs 16.3%, difference -1.4% [95%CI -2.1% to -0.8%]), there was no difference in the proportion of imaging testing. In this post-hoc analysis of patients with suspicion of PE, YEARS and PEGeD combined with PERC, and 4PEPS were safe to exclude PE. The safety of the modified simplified MODS strategy was also confirmed. There was no significant difference of the failure rate between strategies.

Recovery from amblyopia with cholinesterase inhibition

An elevated threshold for neuroplasticity limits visual gains with treatment of residual amblyopia in late childhood and adulthood. Donepezil, an acetylcholinesterase inhibitor, can enable visual neuroplasticity and promote recovery from amblyopia in adult mice. Motivated by these promising findings, we sought to determine whether donepezil can enable recovery in older children and adults with residual amblyopia.

The Role of Efferent Reflexes in the Efficient Encoding of Speech by the Auditory Nerve.

To avoid information loss, the auditory system must adapt the broad dynamic range of natural sounds to the restricted dynamic range of auditory nerve fibers. How it solves this dynamic range problem is not fully understood. Recent electrophysiological studies showed that dynamic-range adaptation occurs at the auditory nerve level, but the amount of adaptation found was insufficient to prevent information loss. We used the physiological MATLAB Auditory Periphery model to study the contribution of efferent reflexes to dynamic range adaptation. Simulating the healthy human auditory periphery provided adaptation predictions that suggest that the acoustic reflex shifts rate-level functions toward a given context level and the medial olivocochlear reflex sharpens the response of nerve fibers around that context level. A simulator of hearing was created to decode model-predicted firing of the auditory nerve back into an acoustic signal, for use in psychophysical tasks. Speech reception thresholds in noise obtained with a normal-hearing implementation of the simulator were just 1 dB above those measured with unprocessed stimuli. This result validates the simulator for speech stimuli. Disabling efferent reflexes elevated thresholds by 4 dB, reaching thresholds found in mild-to-moderately hearing-impaired individuals. Overall, our studies suggest that efferent reflexes may contribute to overcoming the dynamic range problem. Because specific sensorineural pathologies can be inserted in the model, the simulator can be used to obtain the psychophysical signatures of each pathology, thereby laying a path to differential diagnosis.SIGNIFICANCE STATEMENT The saturation of auditory nerve fibers at moderate sound levels seen in rate-level functions challenges our understanding of how sounds of wide dynamic range are encoded. Our physiologically inspired simulations suggest that efferent reflexes may play a major role in dynamic range adaptation, with the acoustic reflex moving auditory nerve rate-level function toward a given context level and the medial olivocochlear reflex increasing fiber sensitivity around that context level. A psychophysical task using advanced simulations showed how the existence of the efferent system could prevent unrecoverable information loss and severe impairment of speech-in-noise intelligibility. These findings illustrate how important the precise modeling of peripheral compression is to both simulations and the understanding of normal and impaired hearing.

Reference equivalent threshold sound pressure levels for the Wireless Automated Hearing Test System.

This paper presents reference equivalent threshold sound pressure levels (RETSPLs) for the Wireless Automated Hearing Test System (WAHTS), a recently commercialized device developed for use as a boothless audiometer. Two initial studies were conducted following the ISO 389-9 standard [ISO 389-9 (2009). "Acoustics-Reference zero for the calibration of audiometric equipment. Part 9: Preferred test conditions for the determinations of reference hearing threshold levels" (International Organization for Standardization, Geneva)]. Although the standard recruitment criteria are intended to yield otologically normal test subjects, the recruited populations appeared to have slightly elevated thresholds [5-10 dB hearing level (HL)]. Comparison of WAHTS thresholds to other clinical audiometric equipment revealed bias errors that were consistent with the elevated thresholds of the RETSPL populations. As the objective of RETSPLs is to ensure consistent thresholds regardless of the equipment, this paper presents the RETSPLs initially obtained following ISO 389-9:2009 and suggested correction to account for the elevated HLs of the originally recruited populations. Two additional independent studies demonstrate the validity of these corrected thresholds.

Speech-specific perceptual adaptation deficits in children and adults with dyslexia.

According to several influential theoretical frameworks, phonological deficits in dyslexia result from reduced sensitivity to acoustic cues that are essential for the development of robust phonemic representations. Some accounts suggest that these deficits arise from impairments in rapid auditory adaptation processes that are either speech-specific or domain-general. Here, we examined the specificity of auditory adaptation deficits in dyslexia using a nonlinguistic tone anchoring (adaptation) task and a linguistic selective adaptation task in children and adults with and without dyslexia. Children and adults with dyslexia had elevated tone-frequency discrimination thresholds, but both groups benefited from anchoring to repeated stimuli to the same extent as typical readers. Additionally, although both dyslexia groups had overall reduced accuracy for speech sound identification, only the child group had reduced categorical perception for speech. Across both age groups, individuals with dyslexia had reduced perceptual adaptation to speech. These results highlight broad auditory perceptual deficits across development in individuals with dyslexia for both linguistic and nonlinguistic domains, but speech-specific adaptation deficits. Finally, mediation models in children and adults revealed that the causal pathways from basic perception and adaptation to phonological awareness through speech categorization were not significant. Thus, rather than having causal effects, perceptual deficits may co-occur with the phonological deficits in dyslexia across development. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Effect of oxytocin pretreatment on the development of morphine tolerance and dependence in rats

Increased opioid synthesis and release, and enhanced alpha-2 adrenoceptor signaling have been suggested to mediate repeated oxytocin-induced long-lasting effects including elevated pain threshold in rats. This study evaluated whether oxytocin pretreatment would influence development of dependence and tolerance to the nociceptive and body temperature responses to morphine and enhance effects of alpha-2 adrenergic agonist clonidine on nociceptive threshold, body temperature and morphine withdrawal signs. Rats injected subcutaneously with saline or 1 mg/kg oxytocin for 5 days were implanted with placebo or morphine pellets 24 h after the treatment period. Body temperature and nociception were assessed, with nociception determined via by hot plate and tail immersion tests, before and 4, 24 and 48 h after pellet implantation, and following a challenge dose of morphine. Withdrawal signs were determined after naloxone administration. Oxytocin produced analgesia, as evidenced by increased paw withdrawal latency in the hot plate test. Morphine increased body temperature and nociceptive threshold which declined over time. Morphine challenge could not demonstrate tolerance to the body temperature response. Analgesic tolerance was observed in the hot plate test in saline and in both tests in oxytocin pretreated rats. Naloxone-precipitated withdrawal appeared to be less severe in oxytocin pretreatment. Clonidine was ineffective on the withdrawal signs but decreased body temperature and increased tail flick latency in the tail immersion test in oxytocin pretreated animals. These results, while producing evidence for a hyperresponsiveness in alpha-2 adrenoceptors, provide contrasting effects on morphine tolerance and dependence, and their partial mediation by opioidergic and adrenergic activation in repeated oxytocin treatment.