Targeting adaptive cellular responses to mitochondrial bioenergetic deficiencies in human disease.

Mitochondrial dysfunction is increasingly appreciated as a central contributor to human disease. Oxidative metabolism at the mitochondrial respiratory chain produces ATP and is intricately tied to redox homeostasis and biosynthetic pathways. Metabolic stress arising from genetic mutations in mitochondrial genes and environmental factors such as malnutrition or overnutrition is perceived by the cell and leads to adaptive and maladaptive responses that can underlie pathology. Here, we will outline cellular sensors that react to alterations in energy production, organellar redox, and metabolites stemming from mitochondrial disease (MD) mutations. MD is a heterogeneous group of disorders primarily defined by defects in mitochondrial oxidative phosphorylation from nuclear or mitochondrial-encoded gene mutations. Preclinical therapies that improve fitness of MD mouse models have been recently identified. Targeting metabolic/energetic deficiencies, maladaptive signaling processes, and hyper-oxygenation of tissues are all strategies aside from direct genetic approaches that hold therapeutic promise. A further mechanistic understanding of these curative processes as well as the identification of novel targets will significantly impact mitochondrial biology and disease research.

Peroxisomal-derived ether phospholipids link nucleotides to respirasome assembly.

The protein complexes of the mitochondrial electron transport chain exist in isolation and in higher order assemblies termed supercomplexes (SCs) or respirasomes (SC I+III2+IV). The association of complexes I, III and IV into the respirasome is regulated by unknown mechanisms. Here, we designed a nanoluciferase complementation reporter for complex III and IV proximity to determine in vivo respirasome levels. In a chemical screen, we found that inhibitors of the de novo pyrimidine synthesis enzyme dihydroorotate dehydrogenase (DHODH) potently increased respirasome assembly and activity. By-passing DHODH inhibition via uridine supplementation decreases SC assembly by altering mitochondrial phospholipid composition, specifically elevated peroxisomal-derived ether phospholipids. Cell growth rates upon DHODH inhibition depend on ether lipid synthesis and SC assembly. These data reveal that nucleotide pools signal to peroxisomes to modulate synthesis and transport of ether phospholipids to mitochondria for SC assembly, which are necessary for optimal cell growth in conditions of nucleotide limitation.

Infant Movement Response to Auditory Rhythm.

Rhythmic entrainment occurs when an auditory rhythm drives an internal movement oscillator, thus providing a continuous time reference that improves temporal and spatial movement parameters. Entrainment processes and outcomes are well known for adults, but research is lacking for infants who might benefit from diagnosis and treatment of irregular rhythms within biological, sensorimotor, cognitive, and social domains. The present study used a combination of inertial measurement units and custom-made software to determine the amount, tempo, and regularity of movement in 28 infants aged 6-10 months while they were exposed to silence, an irregular rhythmic cue, or a regular rhythmic cue with tempo changes. We also assessed changes in the infants' movement parameters following a one-week rhythm training protocol. While results revealed no significant effect of auditory condition on amount or tempo of movement, infant movement was significantly more regular when infants were exposed to 120 bpm (beats per minute) than to an irregular rhythmic cue or a 10% faster rhythmic cue (132 bpm). Infants showed no notable changes in movement amount, tempo, or regularity following one week of training involving auditory and physical rhythm. Overall, infants seem to engage in spontaneous movements with or without auditory rhythm but may not show tempo sensitivity through their movements. Increased movement regularity suggests that 120 bpm may be a preferred tempo for infants, at which they are more likely to demonstrate well-timed movements that may reflect interval entrainment. Infants' auditory-motor systems appear not to respond to a 1-week rhythm training protocol.

Recommendation of New Medical Alarms Based on Audibility, Identifiability, and Detectability in a Randomized, Simulation-Based Study.

OBJECTIVES: Accurate and timely identification of existing audible medical alarms is not adequate in clinical settings. New alarms that are easily heard, quickly identifiable, and discernable from one another are indicated. The "auditory icons" (brief sounds that serve as metaphors for the events they represent) have been proposed as a replacement to the current international standard. The objective was to identify the best performing icons based on audibility and performance in a simulated clinical environment. DESIGN: Three sets of icon alarms were designed using empirical methods. Subjects participated in a series of clinical simulation experiments that examined the audibility, identification accuracy, and response time of each of these icon alarms. A statistical model that combined the outcomes was used to rank the alarms in overall efficacy. We constructed the "best" and "worst" performing sets based on this ranking and prospectively validated these sets in a subsequent experiment with a new subject sample. SETTING: Experiments were conducted in simulated ICU settings at the University of Miami. SUBJECTS: Medical trainees were recruited from a convenience sample of nursing students and anesthesia residents at the institution. INTERVENTIONS: In Experiment 1 (formative testing), subjects were exposed to one of the three sets of alarms; identical setting and instruments were used throughout. In Experiment 2 (summative testing), subjects were exposed to one of the two sets of alarms, assembled from the best and worst performing alarms from Experiment 1. MEASUREMENTS AND MAIN RESULTS: For each alarm, we determined the minimum sound level to reach audibility threshold in the presence of background clinical noise, identification accuracy (percentage), and response time (seconds). We enrolled 123 medical trainees and professionals for participation (78 with < 6 yr of training). We identified the best performing icon alarms for each category, which matched or exceeded the other candidate alarms in identification accuracy and response time. CONCLUSIONS: We propose a set of eight auditory icon alarms that were selected through formative testing and validated through summative testing for adoption by relevant regulatory bodies and medical device manufacturers.

Auditory Icon Alarms Are More Accurately and Quickly Identified than Current Standard Melodic Alarms in a Simulated Clinical Setting.

BACKGROUND: Current standard audible medical alarms are difficult to learn and distinguish from one another. Auditory icons represent a new type of alarm that has been shown to be easier to learn and identify in laboratory settings by lay subjects. In this study, we test the hypothesis that icon alarms are easier to learn and identify than standard alarms by anesthesia providers in a simulated clinical setting. METHODS: Twenty anesthesia providers were assigned to standard or icon groups. Experiments were conducted in a simulated intensive care unit. After a brief group-specific alarm orientation, subjects identified patient-associated alarm sounds during the simulation and logged responses via a tablet computer. Each subject participated in the simulation twice and was exposed to 32 alarm annunciations. Primary outcome measures were response accuracy and response times. Secondary outcomes included assessments of perceived fatigue and task load. RESULTS: Overall accuracy rate in the standard alarm group was 43% (mean) and in the icon group was 88% (mean). Subjects in the icon group were 26.1 (odds ratio [98.75% CI, 8.4 to 81.5; P < 0.001]) times more likely to correctly identify an alarm. Response times in the icon group were shorter than in the standard alarm group (12 vs. 15 s, difference 3 s [98.75% CI ,1 to 5; P < 0.001]). CONCLUSIONS: Under our simulated conditions, anesthesia providers more correctly and quickly identified icon alarms than standard alarms. Subjects were more likely to perceive higher fatigue and task load when using current standard alarms than icon alarms.

Factors Affecting Acoustics and Speech Intelligibility in the Operating Room: Size Matters.

INTRODUCTION: Noise in health care settings has increased since 1960 and represents a significant source of dissatisfaction among staff and patients and risk to patient safety. Operating rooms (ORs) in which effective communication is crucial are particularly noisy. Speech intelligibility is impacted by noise, room architecture, and acoustics. For example, sound reverberation time (RT60) increases with room size, which can negatively impact intelligibility, while room objects are hypothesized to have the opposite effect. We explored these relationships by investigating room construction and acoustics of the surgical suites at our institution. METHODS: We studied our ORs during times of nonuse. Room dimensions were measured to calculate room volumes (VR). Room content was assessed by estimating size and assigning items into 5 volume categories to arrive at an adjusted room content volume (VC) metric. Psychoacoustic analyses were performed by playing sweep tones from a speaker and recording the impulse responses (ie, resulting sound fields) from 3 locations in each room. The recordings were used to calculate 6 psychoacoustic indices of intelligibility. Multiple linear regression was performed using VR and VC as predictor variables and each intelligibility index as an outcome variable. RESULTS: A total of 40 ORs were studied. The surgical suites were characterized by a large degree of construction and surface finish heterogeneity and varied in size from 71.2 to 196.4 m (average VR = 131.1 [34.2] m). An insignificant correlation was observed between VR and VC (Pearson correlation = 0.223, P = .166). Multiple linear regression model fits and ß coefficients for VR were highly significant for each of the intelligibility indices and were best for RT60 (R = 0.666, F(2, 37) = 39.9, P < .0001). For Dmax (maximum distance where there is <15% loss of consonant articulation), both VR and VC ß coefficients were significant. For RT60 and Dmax, after controlling for VC, partial correlations were 0.825 (P < .0001) and 0.718 (P < .0001), respectively, while after controlling for VR, partial correlations were -0.322 (P = .169) and 0.381 (P < .05), respectively. CONCLUSIONS: Our results suggest that the size and contents of an OR can predict a range of psychoacoustic indices of speech intelligibility. Specifically, increasing OR size correlated with worse speech intelligibility, while increasing amounts of OR contents correlated with improved speech intelligibility. This study provides valuable descriptive data and a predictive method for identifying existing ORs that may benefit from acoustic modifiers (eg, sound absorption panels). Additionally, it suggests that room dimensions and projected clinical use should be considered during the design phase of OR suites to optimize acoustic performance.

Hearing level equalized otoacoustic emissions acquired by swept-tones: intensity characteristics.

Otoacoustic emissions (OAE), which are acoustic responses produced by the cochlea, can be recorded with a microphone in the ear canal to give diagnostic information regarding cochlear functioning. Recently, the researchers developed a novel stimulus for the acquisition of OAE using a hearing-level equalized (HL(eq)) swept-tone signal. The objective of this study was to observe OAE characteristics at a multitude of intensities to track the changes in temporal and spectral morphology. An increase in high-frequency emissions was found as stimulation intensity decreased. Furthermore, it was found that hearing level equalized swept-tone OAEs (HL(eq) sTEAOE) can be acquired at very low intensities, which is not typical under current acquisition modalities. This may result in clinical improvements by providing a fast and cheap method for contributing to the detection of auditory thresholds.

Swept-tone transient-evoked otoacoustic emissions.

Transient-evoked otoacoustic emissions (TEOAE) are responses generated within the inner ear in response to acoustic stimuli and are indicative of normal cochlear function. They are commonly acquired by averaging post-stimulus acoustic responses recorded near the eardrum in response to brief stimuli such as clicks or tone pips. In this study a new long duration stimulus consisting of a frequency swept tone is introduced for the acquisition of TEOAEs. Like stimulus frequency generated OAEs, swept-tone responses contain embedded OAEs. With swept-tone analysis, OAEs can be recovered by convolving it with a time reversed swept-tone signal resulting in time-compression. In addition, higher order nonlinear OAE responses were removed from the linear TEOAE. The results show comparable phase and time-frequency properties between the click and swept-tone evoked OAEs. Swept-tone acquisition of TEOAEs has beneficial noise properties, improving the signal to noise ratio by 6 dB compared to click evoked responses thus offering testing time savings. Additionally, swept-tone analysis removed synchronized spontaneous OAE activity from the recordings of subjects exhibiting such responses in conventional click TEOAEs. Since swept-tone stimulus consists of a single frequency component at any instantaneous moment, its analysis also provides for direct comparison with stimulus-frequency OAEs and click evoked OAEs.

High-frequency transient evoked otoacoustic emissions acquisition with auditory canal compensated clicks using swept-tone analysis.

The meatus (auditory canal) plays a role in altering the waveform of incident sound, distorting time- and frequency-domain characteristics. Often in transient-evoked otoacoustic emission (TEOAE) recording protocols, a 75 mus click is utilized to elicit a click-evoked response. TEOAEs are recorded by a probe microphone placed in the meatus and last for about 20 ms. Time-domain ringing in the meatal response (MR) creates a stimulus artifact that lasts up to 5+ ms, obscuring early-latency TEOAEs. This research is motivated by the need for a real-time, ear and probe placement dependent method for minimizing the magnitude and phase distortions of the meatus. The MR is first obtained using swept-tone analysis, from which a compensated stimulus is created. Usage of a compensated click from normally hearing adult subjects show an improvement to the flatness of the magnitude response and linearization of the phase response. Furthermore, a reduction in effective duration of the MR is found, attenuating the meatal artifact for click stimuli. The high frequency TEOAE content found in the early latencies of the response that is typically obscured by the MR artifact is revealed with the use of a compensated click.

High resolution system for improved transient-evoked otoacoustic emission acquisition.

Transient-evoked otoacoustic emissions (TEOAE) are generated by the cochlea in response to clicks. They are obtained by averaging post-onset acoustic responses which are composed of the stimulus-related meatal response (MR) and the TEOAEs. TEOAEs are typically below normal hearing thresholds and are obstructed by the MR, which is several orders of magnitude higher. For click stimuli, MRs typically last about 5 ms and obstruct the early latency emissions. TEOAEs become compressively nonlinear as the MR increases, and this property is commonly exploited by obtaining a derived nonlinear response (DNLR) which reduces the MR artifact. In this study we report the development of a high-resolution system which linearly acquires both MRs and TEOAEs. Results show that the duration of the artifact can be reduced, making the high frequency content of TEOAEs observable.