Evaluation of an ambulatory care pathway for patients with nitrous oxide-induced myeloneuropathy.

Introduction: Cases of nitrous oxide (N2O)-induced myeloneuropathy are increasing at UK hospitals. At our centre, a dedicated ambulatory care pathway, endorsed nationally, was established to treat and monitor patients with N2O-myeloneuropathy in 2021 and refined through three audit cycles. We analysed the outcomes of patients on this pathway to better understand factors associated with non-engagement. Alongside, a novel approach using WhatsApp for questionnaire delivery was trialled in an attempt to improve engagement with treatment. Methods: Patients on the N2O ambulatory care pathway were identified from MDT meeting lists from 9 September 2022 to 25 April 2023. Clinical data were collected via electronic clinical records, including the most recent neurological examination and reason for discharge from the pathway. Patients identified from MDT lists from 27 January 2023 to 14 March 2023 were approached to participate in weekly 12-item surveys, delivered via WhatsApp. This was approved as a service development project with approval for WhatsApp use given by the chief clinical information officer. Results: 35/56 (62.5%) patients were discharged from ambulatory care due to non-attendance and 17/56 (30.4%) completed their treatment course. The median time from initial presentation to discharge was 49 days. 24/40 (60.0%) of patients with a final neurological examination documented had a residual deficit, with objective sensory deficits most common. 12 patients were approached to receive weekly questionnaires via WhatsApp. 5/8 who expressed interest returned a consent form. All participants were withdrawn due to non-response or participant choice. 1/5 returned more than two surveys. Conclusion: Despite poor participation in surveys delivered via WhatsApp, novel approaches are needed to improve engagement with patients on the N2O ambulatory care pathway.

Recreational nitrous oxide and thrombotic events: a case series.

Background: The study aimed to elucidate the prevalence of nitrous oxide (N2O) usage in patients with unexplained venous thromboembolism (VTE), highlighting the potential association with hyperhomocysteinaemia (HHcy). Methods: We conducted a retrospective study at the Royal London Hospital, examining cases of N2O-related VTE from March to August 2023. Among 50 patients identified, four (8%) had recent unprovoked VTE. Patient data were collected based on N2O ambulatory emergency care pathway admissions. Results: Among the 50 patients identified, four (8%) had recent or concurrent VTE. Three were male (75%), with an ethnic distribution of 50% Asian or Asian British and 50% Black or Black British. Patients were distributed across quintiles of the index of multiple deprivation. All had actual or functional vitamin B12 deficiency. Discussion: The association between N2O use and VTE requires further investigation, though a plausible mechanism involving HHcy has been proposed. Clinicians should be vigilant for VTE in N2O users, especially those presenting with unexplained symptoms. VTE prophylaxis may be worth considering, particularly if continued exposure to nitrous oxide is anticipated. Conclusion: N2O misuse may increase the risk of VTE, warranting attention from healthcare providers. Further research is needed to elucidate this association and inform preventive strategies. Public awareness about the risks of N2O remains essential.

L-Ergothioneine slows the progression of age-related hearing loss in CBA/CaJ mice.

The naturally occurring amino acid, l-ergothioneine (EGT), has immense potential as a therapeutic, having shown promise in the treatment of other disease models, including neurological disorders. EGT is naturally uptaken into cells via its specific receptor, OCTN1, to be utilized by cells as an antioxidant and anti-inflammatory. In our current study, EGT was administered over a period of 6 months to 25-26-month-old CBA/CaJ mice as a possible treatment for age-related hearing loss (ARHL), since presbycusis has been linked to higher levels of cochlear oxidative stress, apoptosis, and chronic inflammation. Results from the current study indicate that EGT can prevent aging declines of some key features of ARHL. However, we found a distinct sex difference for the response to the treatments, for hearing - Auditory Brainstem Responses (ABRs) and Distortion Product Otoacoustic Emissions (DPOAEs). Males exhibited lower threshold declines in both low dose (LD) and high dose (HD) test groups throughout the testing period and did not display some of the characteristic aging declines in hearing seen in Control animals. In contrast, female mice did not show any therapeutic effects with either treatment dose. Further confirming this sex difference, EGT levels in whole blood sampling throughout the testing period showed greater uptake of EGT in males compared to females. Additionally, RT-PCR results from three tissue types of the inner ear confirmed EGT activity in the cochlea in both males and females. Males and females exhibited significant differences in biomarkers related to apoptosis (Cas-3), inflammation (TNF-a), oxidative stress (SOD2), and mitochondrial health (PGC1a).These changes were more prominent in males as compared to females, especially in stria vascularis tissue. Taken together, these findings suggest that EGT has the potential to be a naturally derived therapeutic for slowing down the progression of ARHL, and possibly other neurodegenerative diseases. EGT, while effective in the treatment of some features of presbycusis in aging males, could also be modified into a general prophylaxis for other age-related disorders where treatment protocols would include eating a larger proportion of EGT-rich foods or supplements. Lastly, the sex difference discovered here, needs further investigation to see if therapeutic conditions can be developed where aging females show better responsiveness to EGT.

Age-related changes of auditory sensitivity across the life span of CBA/CaJ mice.

The inbred mouse strain CBA/CaJ is a frequently used animal model of age-related hearing loss in humans. These mice display significant hearing loss at a relatively advanced age, similar to most humans, with progressive loss of hearing as the mouse continues to age. While important descriptions of hearing loss in this mouse strain at multiple ages have previously been published, shortcomings persist in the data for hearing over the lifespan of the mouse. Therefore, we analyzed auditory brainstem response threshold data from records maintained by our research group to yield an extensive database of thresholds over nearly the entire life span of the CBA/CaJ mouse (from 79 to 1085 days). Data was collected from in-house bred mice of CBA/CaJ stock, initially from The Jackson Laboratory. Data was collected using BiosigRZ software and TDT System III hardware. Thresholds were routinely measured in conjunction with behavioral and electrophysiological experiments; only responses from baseline or experimentally naïve animals were analyzed. The resulting data set comprised 376 female mice and 441 males. At the lowest and highest frequencies (8 & 32 kHz), initial thresholds were just under 30 dB SPL and increased slowly until they were significantly different at 16-18 months compared to 1-3 months age, with the difference increasing over subsequent ages. At the middle frequencies (12 & 16 kHz), initial thresholds were just under 20 dB SPL and increased until they became different from initial at 16-18 months. At 24 kHz, initial thresholds were just above 20 dB and became different from initial at 13-16 months of age. The rate of change of thresholds with age were similar for all frequencies until about 30 months of age, when 32 kHz threshold changes lagged behind other frequencies. Generally, CBA/CaJ mice in our colony display relatively low thresholds until approximately 16 months of age, depending on frequency. After 16-18 months, thresholds become significantly worse. After approximately 20-22 months thresholds increase linearly with age.

Nitrous oxide-induced subacute combined degeneration of the cord: diagnosis and treatment.

Recreational use of nitrous oxide (N2O) has increased rapidly in recent years and is now the second most commonly used recreational drug among young people in the UK. There has been a corresponding rise in cases of nitrous oxide-induced subacute combined degeneration of the cord (N2O-SACD), a pattern of myeloneuropathy usually associated with severe vitamin B12 deficiency. This can cause serious and permanent disability in young people but, if recognised early, may be effectively treated. All neurologists should be aware of N2O-SACD and its treatment; however, there are currently no agreed guidelines. Based on our experience in East London, an area of high N2O use, we provide practical advice on its recognition, investigation and treatment.

Universal automated classification of the acoustic startle reflex using machine learning.

The startle reflex (SR), a robust, motor response elicited by an intense auditory, visual, or somatosensory stimulus has been widely used as a tool to assess psychophysiology in humans and animals for almost a century in diverse fields such as schizophrenia, bipolar disorder, hearing loss, and tinnitus. Previously, SR waveforms have been ignored, or assessed with basic statistical techniques and/or simple template matching paradigms. This has led to considerable variability in SR studies from different laboratories, and species. In an effort to standardize SR assessment methods, we developed a machine learning algorithm and workflow to automatically classify SR waveforms in virtually any animal model including mice, rats, guinea pigs, and gerbils obtained with various paradigms and modalities from several laboratories. The universal features common to SR waveforms of various species and paradigms are examined and discussed in the context of each animal model. The procedure describes common results using the SR across species and how to fully implement the open-source R implementation. Since SR is widely used to investigate toxicological or pharmaceutical efficacy, a detailed and universal SR waveform classification protocol should be developed to aid in standardizing SR assessment procedures across different laboratories and species. This machine learning-based method will improve data reliability and translatability between labs that use the startle reflex paradigm.

PBRM1, SETD2 and BAP1 - the trinity of 3p in clear cell renal cell carcinoma.

Biallelic inactivation of the tumour suppressor gene Von Hippel-Lindau (VHL) occurs in the vast majority of clear cell renal cell carcinoma (ccRCC) instances, disrupting cellular oxygen-sensing mechanisms to yield a state of persistent pseudo-hypoxia, defined as a continued hypoxic response despite the presence of adequate oxygen levels. However, loss of VHL alone is often insufficient to drive oncogenesis. Results from genomic studies have shown that co-deletions of VHL with one (or more) of three genes encoding proteins involved in chromatin modification and remodelling, polybromo-1 gene (PBRM1), BRCA1-associated protein 1 (BAP1) and SET domain-containing 2 (SETD2), are common and important co-drivers of tumorigenesis. These genes are all located near VHL on chromosome 3p and are often altered following cytogenetic rearrangements that lead to 3p loss and precede the establishment of ccRCC. These three proteins have multiple roles in the regulation of crucial cancer-related pathways, including protection of genomic stability, antagonism of polycomb group (PcG) complexes to maintain a permissive transcriptional landscape in physiological conditions, and regulation of genes that mediate responses to immune checkpoint inhibitor therapy. An improved understanding of these mechanisms will bring new insights regarding cellular drivers of ccRCC growth and therapy response and, ultimately, will support the development of novel translational therapeutics.

Small molecule modulation of the large-conductance calcium-activated potassium channel suppresses salicylate-induced tinnitus in mice.

Tinnitus is the phantom perception of sound that has no external source. A neurological signature of tinnitus, and the frequently associated hyperacusis, is an imbalance between excitatory and inhibitory activity in the central auditory system (CAS), leading to dysregulated network excitability. The large conductance, calcium-activated potassium (BK) channel is a key player in pre- and post-synaptic excitability through its mediation of K+ currents. Changes in BK channel activity are associated with aberrant network activity in sensory regions of the CNS, raising the possibility that BK channel modulation could regulate activity associated with tinnitus and hyperacusis. To test whether BK channel openers are able to suppress biomarkers of drug-induced tinnitus and hyperacusis, the 1,3,4 oxadiazole BMS-191011 was given to young adult CBA mice that had been administered 250 mg/kg sodium salicylate (SS). Systemic treatment with BMS-191011 reduced behavioral manifestations of SS-induced tinnitus, but not hyperacusis, probed via the gap-in-noise startle response method. Systemic BMS-191011 treatment did not influence SS-induced increases in auditory brainstem response functions, but local application at the inferior colliculus did reverse SS-suppressed spontaneous activity, particularly in the frequency region of the tinnitus percept. Thus, action of BMS-191011 in the inferior colliculus may contribute to the reduction in behaviorally measured tinnitus. Together, these findings support the utility of BK channel openers in reducing central auditory processing changes associated with the formation of the tinnitus percept.

A BK channel-targeted peptide induces age-dependent improvement in behavioral and neural sound representation.

Recent evidence suggests that modulation of the large-conductance, calcium-activated potassium (BK) channel regulates auditory processing in the brain. Because ion channel expression often changes during aging, this could be a factor in age-related hearing loss. The current study explored how the novel BK channel modulator LS3 shapes central auditory processing in young and old adult mice. In vivo extracellular recordings in the auditory midbrain demonstrated that LS3 differentially modulates neural processing along the tonotopic axis. Though sound-evoked activity was reduced in the mid and ventral tonotopic regions, LS3 enhanced excitatory drive and sound-evoked responses for some neurons in the dorsal, low-frequency region. Behavioral assessment using acoustic reflex modification audiometry indicated improved tone salience following systemic LS3 administration. Moderation of these responses with aging correlated with an age-related decline in BK channel expression. These findings suggest that targeting the BK channel enhances responsivity to tonal sounds, providing the potential to improve hearing acuity and treat hearing loss.

A Wirelessly Controlled Scalable 3D-Printed Microsystem for Drug Delivery.

Here we present a 3D-printed, wirelessly controlled microsystem for drug delivery, comprising a refillable microreservoir and a phase-change peristaltic micropump. The micropump structure was inkjet-printed on the back of a printed circuit board around a catheter microtubing. The enclosure of the microsystem was fabricated using stereolithography 3D printing, with an embedded microreservoir structure and integrated micropump. In one configuration, the microsystem was optimized for murine inner ear drug delivery with an overall size of 19 × 13 × 3 mm3. Benchtop results confirmed the performance of the device for reliable drug delivery. The suitability of the device for long-term subcutaneous implantation was confirmed with favorable results of implantation of a microsystem in a mouse for six months. The drug delivery was evaluated in vivo by implanting four different microsystems in four mice, while the outlet microtubing was implanted into the round window membrane niche for infusion of a known ototoxic compound (sodium salicylate) at 50 nL/min for 20 min. Real-time shifts in distortion product otoacoustic emission thresholds and amplitudes were measured during the infusion, demonstrating similar results with syringe pump infusion. Although demonstrated for one application, this low-cost design and fabrication methodology is scalable for use in larger animals and humans for different clinical applications/delivery sites.

Rescuing Auditory Temporal Processing with a Novel Augmented Acoustic Environment in an Animal Model of Congenital Hearing Loss.

Congenital sensorineural hearing loss (SNHL) affects thousands of infants each year and results in significant delays in speech and language development. Previous studies have shown that early exposure to a simple augmented acoustic environment (AAE) can limit the effects of progressive SNHL on hearing sensitivity. However, SNHL is also accompanied by hearing loss that is not assessed on standard audiological examinations, such as reduced temporal processing acuity. To assess whether sound therapy may improve these deficits, a mouse model of congenital SNHL was exposed to simple or temporally complex AAE. The DBA/2J mouse strain develops rapid, base to apex, progressive SNHL beginning at birth and is functionally deaf by six months of age. Hearing sensitivity and auditory brainstem function was measured using otoacoustic emissions, auditory brainstem response (ABR) and extracellular recording from the inferior colliculus (IC) in mice following exposure to 30 d of continuous AAE. Peripheral function and sound sensitivity in auditory midbrain neurons improved following exposure to both types of AAE. However, exposure to a novel, temporally complex AAE more strongly improved a measure of temporal processing acuity, neural gap-in-noise detection in the auditory midbrain. These experiments suggest that targeted sound therapy may be harnessed to improve hearing outcomes for children suffering from congenital SNHL.

Machine learning, waveform preprocessing and feature extraction methods for classification of acoustic startle waveforms.

The acoustic startle response (ASR) is an involuntary muscle reflex that occurs in response to a transient loud sound and is a highly-utilized method of assessing hearing status in animal models. Currently, a high level of variability exists in the recording and interpretation of ASRs due to the lack of standardization for collecting and analyzing these measures. An ensembled machine learning model was trained to predict whether an ASR waveform is a startle or non-startle using highly-predictive features extracted from normalized ASR waveforms collected from young adult CBA/CaJ mice. Features were extracted from the normalized waveform as well as the power spectral density estimates and continuous wavelet transforms of the normalized waveform. Machine learning models utilizing methods from different families of algorithms were individually trained and then ensembled together, resulting in an extremely robust model.•ASR waveforms were normalized using the mean and standard deviation computed before the startle elicitor was presented•9 machine learning algorithms from 4 different families of algorithms were individually trained using features extracted from the normalized ASR waveforms•Trained machine learning models were ensembled to produce an extremely robust classifier.

Aldosterone up-regulates voltage-gated potassium currents and NKCC1 protein membrane fractions.

Na+-K+-2Cl- Cotransporter (NKCC1) is a protein that aids in the active transport of sodium, potassium, and chloride ions across cell membranes. It has been shown that long-term systemic treatment with aldosterone (ALD) can enhance NKCC1 protein expression and activity in the aging cochlea resulting in improved hearing. In the present work, we used a cell line with confirmed NKCC1 expression to demonstrate that in vitro application of ALD increased outward voltage-gated potassium currents significantly, and simultaneously upregulated whole lysate and membrane portion NKCC1 protein expression. These ALD-induced changes were blocked by applying the mineralocorticoid receptor antagonist eplerenone. However, application of the NKCC1 inhibitor bumetanide or the potassium channel antagonist Tetraethyl ammonium had no effect. In addition, NKKC1 mRNA levels remained stable, indicating that ALD modulates NKCC1 protein expression via the activation of mineralocorticoid receptors and post-transcriptional modifications. Further, in vitro electrophysiology experiments, with ALD in the presence of NKCC1, K+ channel and mineralocorticoid receptor inhibitors, revealed interactions between NKCC1 and outward K+ channels, mediated by a mineralocorticoid receptor-ALD complex. These results provide evidence of the therapeutic potential of ALD for the prevention/treatment of inner ear disorders such as age-related hearing loss.

A 3D-Printed Modular Microreservoir for Drug Delivery.

Reservoir-based drug delivery microsystems have enabled novel and effective drug delivery concepts in recent decades. These systems typically comprise integrated storing and pumping components. Here we present a stand-alone, modular, thin, scalable, and refillable microreservoir platform as a storing component of these microsystems for implantable and transdermal drug delivery. Three microreservoir capacities (1, 10, and 100 µL) were fabricated with 3 mm overall thickness using stereolithography 3D-printing technology, enabling the fabrication of the device structure comprising a storing area and a refill port. A thin, preformed dome-shaped storing membrane was created by the deposition of parylene-C over a polyethylene glycol sacrificial layer, creating a force-free membrane that causes zero forward flow and insignificant backward flow (2% of total volume) due to membrane force. A septum pre-compression concept was introduced that enabled the realization of a 1-mm-thick septa capable of ~65000 leak-free refill punctures under 100 kPa backpressure. The force-free storing membrane enables using normally-open micropumps for drug delivery, and potentially improves the efficiency and precision of normally-closed micropumps. The ultra-thin septum reduces the thickness of refillable drug delivery devices, and is capable of thousands of leak-free refills. This modular and scalable device can be used for drug delivery in different laboratory animals and humans, as a sampling device, and for lab-on-a-chip and point-of-care diagnostics applications.

Automated classification of acoustic startle reflex waveforms in young CBA/CaJ mice using machine learning.

BACKGROUND: The acoustic startle response (ASR) is a simple reflex that results in a whole body motor response after animals hear a brief loud sound and is used as a multisensory tool across many disciplines. Unfortunately, a method of how to record, process, and analyze ASRs has yet to be standardized, leading to high variability in the collection, analysis, and interpretation of ASRs within and between laboratories. NEW METHOD: ASR waveforms collected from young adult CBA/CaJ mice were normalized with features extracted from the waveform, the resulting power spectral density estimates, and the continuous wavelet transforms. The features were then partitioned into training and test/validation sets. Machine learning methods from different families of algorithms were used to combine startle-related features into robust predictive models to predict whether an ASR waveform is a startle or non-startle. RESULTS: An ensemble of several machine learning models resulted in an extremely robust model to predict whether an ASR waveform is a startle or non-startle with a mean ROC of 0.9779, training accuracy of 0.9993, and testing accuracy of 0.9301. COMPARISON WITH EXISTING METHODS: ASR waveforms analyzed using the threshold and RMS techniques resulted in over 80% of accepted startles actually being non-startles when manually classified versus 2.2% for the machine learning method, resulting in statistically significant differences in ASR metrics (such as startle amplitude and pre-pulse inhibition) between classification methods. CONCLUSIONS: The machine learning approach presented in this paper can be adapted to nearly any ASR paradigm to accurately process, sort, and classify startle responses.

Cochlear pharmacokinetics - Micro-computed tomography and learning-prediction modeling for transport parameter determination.

Inner ear disorders such as sensorineural deafness and genetic diseases may one day be treated with local drug delivery to the inner ear. Current pharmacokinetic models have been based on invasive methods to measure drug concentrations, limiting them in spatial resolution, and restricting the research to larger rodents. We developed an intracochlear pharmacokinetic model based on an imaging, learning-prediction (LP) paradigm for learning transport parameters in the murine cochlea. This was achieved using noninvasive micro-computed tomography imaging of the cochlea during in vivo infusion of a contrast agent at the basal end of scala tympani through a cochleostomy. Each scan was registered in 3-D to a cochlear atlas to segment the cochlear regions with high accuracy, enabling concentrations to be extracted along the length of each scala. These spatio-temporal concentration profiles were used to learn a concentration dependent diffusion coefficient, and transport parameters between the major scalae and to clearance. The LP model results are comparable to the current state of the art model, and can simulate concentrations for cases involving different infusion molecules and different drug delivery protocols. Forward simulation results with pulsatile delivery suggest the pharmacokinetic model can be used to optimize drug delivery protocols to reduce total drug delivered and the potential for toxic side effects. While developed in the challenging murine cochlea, the processes are scalable to larger animals and different drug infusion paradigms.

Sodium salicylate alters temporal integration measured through increasing stimulus presentation rates.

OBJECTIVE: High doses of sodium salicylate (SS) are known to induce tinnitus, general hyperexcitability in the central auditory system, and to cause mild hearing loss. We used the auditory brainstem response (ABR) to assess the effects of SS on auditory sensitivity and temporal processing in the auditory nerve and brainstem. ABRs were evoked using tone burst stimuli varying in frequency and intensity with presentation rates from 11/s to 81/s. DESIGN: ABRs were recorded and analysed prior to and after SS treatment in each animal, and peak 1 and peak 4 amplitudes and latencies were determined along with minimal response threshold. STUDY SAMPLE: Nine young adult CBA/CaJ mice were used in a longitudinal within-subject design. RESULTS: No measurable effects of presentation rate were found on ABR threshold prior to SS; however, following SS administration increasing stimulus rates lowered ABR thresholds by as much as 10 dB and compressed the peak amplitude by intensity level functions. CONCLUSIONS: These results suggest that SS alters temporal integration and compressive nonlinearity, and that varying the stimulus rate of the ABR may prove to be a useful diagnostic tool in the study of hearing disorders that involve hyperexcitability.

A nanoliter resolution implantable micropump for murine inner ear drug delivery.

Advances in protective and restorative biotherapies have created new opportunities to use site-directed, programmable drug delivery systems to treat auditory and vestibular disorders. Successful therapy development that leverages the transgenic, knock-in, and knock-out variants of mouse models of human disease requires advanced microsystems specifically designed to function with nanoliter precision and with system volumes suitable for implantation. Here we present results for a novel biocompatible, implantable, scalable, and wirelessly controlled peristaltic micropump. The micropump configuration included commercially available catheter microtubing (250 µm OD, 125 µm ID) that provided a biocompatible leak-free flow path while avoiding complicated microfluidic interconnects. Peristaltic pumping was achieved by sequentially compressing the microtubing via expansion and contraction of a thermal phase-change material located in three chambers integrated adjacent to the microtubing. Direct-write micro-scale printing technology was used to build the mechanical components of the micropump around the microtubing directly on the back of a printed circuit board assembly (PCBA). The custom PCBA was fabricated using standard commercial processes providing microprocessor control of actuation and Bluetooth wireless communication through an Android application. The results of in vitro characterization indicated that nanoliter resolution control over the desired flow rates of 10-100 nL/min was obtained by changing the actuation frequency. Applying 10× greater than physiological backpressures and ±â€¯3 °C ambient temperature variation did not significantly affect flow rates. Three different micropumps were tested on six mice for in vivo implantation of the catheter microtubing into the round window membrane niche for infusion of a known ototoxic compound (sodium salicylate) at 50 nL/min for 20 min. Real-time shifts in distortion product otoacoustic emission thresholds and amplitudes were measured during the infusion. There were systematic increases in distortion product threshold shifts during the 20-min perfusions; the mean shift was 15 dB for the most basal region. A biocompatibility study was performed to evaluate material suitability for chronic subcutaneous implantation and clinical translational development. The results indicated that the micropump components successfully passed key biocompatibility tests. A micropump prototype was implanted for one month without development of inflammation or infection. Although tested here on the small murine cochlea, this low-cost design and fabrication methodology is scalable for use in larger animals and for clinical applications in children and adults by appropriate scaling of the microtubing diameter and actuator volume.

A structured tool for delivering feedback on medical student clinical clerkings.

This article was migrated. The article was marked as recommended. Introduction: The initial history and examination is a fundamental aspect of clinical practice. Most medical students cultivate this skill through regular undertaking of 'clerkings' during their clinical placements. We designed a written, structured, proforma-based approach to delivery of feedback on student clerkings which also promoted the undertaking of a 'complete clerking' encouraging students to maintain a whole-system holistic approach. Within this paper, we present our findings following its introduction at a London teaching hospital. Methods: Sixty-one medical students on their first clinical attachment within acute medicine were asked to submit at least one full medical clerking for objective appraisal using the structured clerking feedback proforma by a clinical teaching fellow. Students completed a 'pre' and 'post' assessment using Likert Scales at the time of receiving their clerking feedback. Structured interviews of randomly selected students and senior medical educators were also undertaken. Results: Following introduction of the structured feedback proforma, there was a significant increase across all indices of student-perceived utility and satisfaction compared to previously received feedback (which was mostly ad-hoc verbal). Using Likert Scales (1 to 10: 1 representing least effect and 10 representing greatest effect) student assessment of usefulness was 9.0 (versus 6.34 for previous feedback); likelihood of influencing future practice was 8.8 (versus 6.47); extent to which it reinforced the message of a complete clerking was 9.5 (versus 6.13) and extent to which the feedback would encourage them to undertake complete clerkings was 9.0. Free text comments and subsequent interviews of randomly selected students and senior medical educators reinforced the positive perception of this approach. Conclusions: The introduction of a structured clerking feedback proforma can improve the quality and utility of the feedback delivered to medical students on their acute medical clerkings and can promote and reinforce the value of maintaining a whole-system holistic approach.

Noise-Induced Hearing Loss in Mice: Effects of High and Low Levels of Noise Trauma in CBA Mice.

Acoustic trauma can induce temporary or permanent noise-induced hearing loss (NIHL). Noise exposed animal models allow us to study the effects of various noise trauma insults on the cochlea and auditory pathways. Here we studied the short-term and long-term functional changes occurring in the auditory system following exposure to two different noise traumas. Several measures of hearing function known to change following noise exposure were examined: Temporary (TTS) and permanent (PTS) threshold shifts were measured using auditory brainstem responses (ABR), outer hair cell function was examined using distortion product otoacoustic emissions (DPOAEs), and auditory temporal processing was assessed using a gap-in-noise (GIN) ABR paradigm. Physiological measures were made before and after the exposure (24 hours, 2 weeks, 4 weeks, and 1 year). The animals were perfused and their brain, and cochlea were collected for future biomarker studies. Young adult mice were exposed to 110 dB and 116 dB octave-band noise levels for 45 minutes, and both groups demonstrated significant threshold shifts 1 day post-noise exposure across all frequencies. However 2 weeks postexposure, PTS within the 110 dB group was significantly reduced compared to 1 day post trauma, this improvement in thresholds was not as great in the 116 dB exposure group. At 2 weeks post-trauma, differences between the measured PTS in the two groups was significant for 4 of the 7 measured frequencies. At this 1 year time point after exposure, mice in the 110 dB group showed very minor PTS, but the 116 dB group showed a large PTS comparable to their 2 and 4 week PTS. At this time point, PTS variation between the two groups was significant across all frequencies. DPOAE amplitudes measured 2 weeks post exposure showed recovery for all frequencies within 10 dB (average) of the baseline in the 110 dB group, however for the 116 dB exposure DP amplitudes were elevated by about 30 dB. The differences in DPOAE amplitudes between the 110 dB and 116 dB groups were significant at 2 weeks, 4 weeks, and 1 year post-trauma in the mid frequency range. At 2 weeks, 4 weeks, and 1 year, DPOAE thresholds returned to within 10 dB of the baseline for the 110 dB group in the low and mid frequency range, whereas the 116 dB group still showed shifts of 30 dB for all frequency ranges. For Gap ABRs, there was a significant decrease in both noise burst 1 (NB1) and noise burst 2 (NB2) amplitudes for peaks 1 and 4 in the 116 dB group relative to the 110 dB group when measured at 1 year post trauma. These results indicate that a 6 dB increase in noise exposure intensity results in a significant increased ototrauma in both the peripheral and central auditory systems.