Molecular analysis of individual differences in talker search at the cocktail-party.

A molecular (trial-by-trial) analysis of data from a cocktail-party, target-talker search task was used to test two general classes of explanations accounting for individual differences in listener performance: cue weighting models for which errors are tied to the speech features talkers have in common with the target and internal noise models for which errors are largely independent of these features. The speech of eight different talkers was played simultaneously over eight different loudspeakers surrounding the listener. The locations of the eight talkers varied at random from trial to trial. The listener's task was to identify the location of a target talker with which they had previously been familiarized. An analysis of the response counts to individual talkers showed predominant confusion with one talker sharing the same fundamental frequency and timbre as the target and, secondarily, other talkers sharing the same timbre. The confusions occurred for a roughly constant 31% of all of the trials for all of the listeners. The remaining errors were uniformly distributed across the remaining talkers and responsible for the large individual differences in performances observed. The results are consistent with a model in which largely stimulus-independent factors (internal noise) are responsible for the wide variation in performance across listeners.

Complications associated with removal of airway devices under deep anesthesia in children: an analysis of the Wake Up Safe database.

BACKGROUND: Previous studies examining removal of endotracheal tubes and supraglottic devices under deep anesthesia were underpowered to identify rare complications. This study sought to report all adverse events associated with this practice found in a large national database of pediatric anesthesia adverse events. METHODS: An extract of an adverse events database created by the Wake Up Safe database, a multi-institutional pediatric anesthesia quality improvement initiative, was performed for this study. It was screened to identify anesthetics with variables indicating removal of airway devices under deep anesthesia. Three anesthesiologists screened the data to identify events where this practice possibly contributed to the event. Event data was extracted and collated. RESULTS: One hundred two events met screening criteria and 66 met inclusion criteria. Two cardiac etiology events were identified, one of which resulted in the patient's demise. The remaining 97% of events were respiratory in nature (64 events), including airway obstruction, laryngospasm, bronchospasm and aspiration. Some respiratory events consisted of multiple distinct events in series. Nineteen respiratory events resulted in cardiac arrest (29.7%) of which 15 (78.9%) were deemed preventable by local anesthesiologists performing independent review. Respiratory events resulted in intensive care unit admission (37.5%), prolonged intubation and temporary neurologic injury but no permanent harm. Provider and patient factors were root causes in most events. Upon investigation, areas for improvement identified included improving patient selection, ensuring monitoring, availability of intravenous access, and access to emergency drugs and equipment until emergence. CONCLUSIONS: Serious adverse events have been associated with this practice, but no respiratory events were associated with long-term harm.

The Listener Effect in Multitalker Speech Segregation and Talker Identification.

Over six decades ago, Cherry (1953) drew attention to what he called the "cocktail-party problem"; the challenge of segregating the speech of one talker from others speaking at the same time. The problem has been actively researched ever since but for all this time one observation has eluded explanation. It is the wide variation in performance of individual listeners. That variation was replicated here for four major experimental factors known to impact performance: differences in task (talker segregation vs. identification), differences in the voice features of talkers (pitch vs. location), differences in the voice similarity and uncertainty of talkers (informational masking), and the presence or absence of linguistic cues. The effect of these factors on the segregation of naturally spoken sentences and synthesized vowels was largely eliminated in psychometric functions relating the performance of individual listeners to that of an ideal observer, d'ideal. The effect of listeners remained as differences in the slopes of the functions (fixed effect) with little within-listener variability in the estimates of slope (random effect). The results make a case for considering the listener a factor in multitalker segregation and identification equal in status to any major experimental variable.

Natural variation in Caenorhabditis elegans responses to the anthelmintic emodepside.

Treatment of parasitic nematode infections depends primarily on the use of anthelmintics. However, this drug arsenal is limited, and resistance against most anthelmintics is widespread. Emodepside is a new anthelmintic drug effective against gastrointestinal and filarial nematodes. Nematodes that are resistant to other anthelmintic drug classes are susceptible to emodepside, indicating that the emodepside mode of action is distinct from previous anthelmintics. The laboratory-adapted Caenorhabditis elegans strain N2 is sensitive to emodepside, and genetic selection and in vitro experiments implicated slo-1, a large K+ conductance (BK) channel gene, in emodepside mode of action. In an effort to understand how natural populations will respond to emodepside, we measured brood sizes and developmental rates of wild C. elegans strains after exposure to the drug and found natural variation across the species. Some of the observed variation in C. elegans emodepside responses correlates with amino acid substitutions in slo-1, but genetic mechanisms other than slo-1 coding variants likely underlie emodepside resistance in wild C. elegans strains. Additionally, the assayed strains have higher offspring production in low concentrations of emodepside (a hormetic effect). We find that natural variation affects emodepside sensitivity, supporting the suitability of C. elegans as a model system to study emodepside responses across natural nematode populations.

Two novel loci underlie natural differences in Caenorhabditis elegans abamectin responses.

Parasitic nematodes cause a massive worldwide burden on human health along with a loss of livestock and agriculture productivity. Anthelmintics have been widely successful in treating parasitic nematodes. However, resistance is increasing, and little is known about the molecular and genetic causes of resistance for most of these drugs. The free-living roundworm Caenorhabditis elegans provides a tractable model to identify genes that underlie resistance. Unlike parasitic nematodes, C. elegans is easy to maintain in the laboratory, has a complete and well annotated genome, and has many genetic tools. Using a combination of wild isolates and a panel of recombinant inbred lines constructed from crosses of two genetically and phenotypically divergent strains, we identified three genomic regions on chromosome V that underlie natural differences in response to the macrocyclic lactone (ML) abamectin. One locus was identified previously and encodes an alpha subunit of a glutamate-gated chloride channel (glc-1). Here, we validate and narrow two novel loci using near-isogenic lines. Additionally, we generate a list of prioritized candidate genes identified in C. elegans and in the parasite Haemonchus contortus by comparison of ML resistance loci. These genes could represent previously unidentified resistance genes shared across nematode species and should be evaluated in the future. Our work highlights the advantages of using C. elegans as a model to better understand ML resistance in parasitic nematodes.

Additivity of segregation cues in simulated cocktail-party listening.

An approach is borrowed from Measurement Theory [Krantz et al. (1971). Foundations of Measurement (Academic, New York), Vol. 1] to evaluate the interaction of voice fundamental frequency and spatial cues in the segregation of talkers in simulated cocktail-party listening. The goal is to find a mathematical expression whereby the combined effect of cues can be simply related to their individual effects. On each trial, the listener judged whether an interleaved sequence of four vowel triplets (heard over headphones) were spoken by the same (MMM) or different (FMF) talkers. The talkers had nominally different fundamental frequencies and spoke from nominally different locations (simulated using head-related transfer functions). Natural variation in these cues was simulated by adding a small, random perturbation to the nominal values independently for each vowel on each trial. Psychometric functions (PFs) relating d' performance to the difference in nominal values were obtained for the cues presented individually and in combination. The results revealed a synergistic interaction of cues wherein the PFs for cues presented in combination exceeded the simple vector sum of the PFs for the cues presented individually. The results are discussed in terms of their implications for possible emergent properties of cues affecting performance in simulated cocktail-party listening.

A test of model classes accounting for individual differences in the cocktail-party effect.

Listeners differ widely in the ability to follow the speech of a single talker in a noisy crowd-what is called the cocktail-party effect. Differences may arise for any one or a combination of factors associated with auditory sensitivity, selective attention, working memory, and decision making required for effective listening. The present study attempts to narrow the possibilities by grouping explanations into model classes based on model predictions for the types of errors that distinguish better from poorer performing listeners in a vowel segregation and talker identification task. Two model classes are considered: those for which the errors are predictably tied to the voice variation of talkers (decision weight models) and those for which the errors occur largely independently of this variation (internal noise models). Regression analyses of trial-by-trial responses, for different tasks and task demands, show overwhelmingly that the latter type of error is responsible for the performance differences among listeners. The results are inconsistent with models that attribute the performance differences to differences in the reliance listeners place on relevant voice features in this decision. The results are consistent instead with models for which largely stimulus-independent, stochastic processes cause information loss at different stages of auditory processing.

Deep sampling of Hawaiian Caenorhabditis elegans reveals high genetic diversity and admixture with global populations.

Hawaiian isolates of the nematode species Caenorhabditis elegans have long been known to harbor genetic diversity greater than the rest of the worldwide population, but this observation was supported by only a small number of wild strains. To better characterize the niche and genetic diversity of Hawaiian C. elegans and other Caenorhabditis species, we sampled different substrates and niches across the Hawaiian islands. We identified hundreds of new Caenorhabditis strains from known species and a new species, Caenorhabditis oiwi. Hawaiian C. elegans are found in cooler climates at high elevations but are not associated with any specific substrate, as compared to other Caenorhabditis species. Surprisingly, admixture analysis revealed evidence of shared ancestry between some Hawaiian and non-Hawaiian C. elegans strains. We suggest that the deep diversity we observed in Hawaii might represent patterns of ancestral genetic diversity in the C. elegans species before human influence.

Extreme allelic heterogeneity at a Caenorhabditis elegans beta-tubulin locus explains natural resistance to benzimidazoles.

Benzimidazoles (BZ) are essential components of the limited chemotherapeutic arsenal available to control the global burden of parasitic nematodes. The emerging threat of BZ resistance among multiple nematode species necessitates the development of novel strategies to identify genetic and molecular mechanisms underlying this resistance. All detection of parasitic helminth resistance to BZ is focused on the genotyping of three variant sites in the orthologs of the ß-tubulin gene found to confer resistance in the free-living nematode Caenorhabditis elegans. Because of the limitations of laboratory and field experiments in parasitic nematodes, it is difficult to look beyond these three sites to identify additional mechanisms that might contribute to BZ resistance in the field. Here, we took an unbiased genome-wide mapping approach in the free-living nematode species C. elegans to identify the genetic underpinnings of natural resistance to the commonly used BZ, albendazole (ABZ). We found a wide range of natural variation in ABZ resistance in natural C. elegans populations. In agreement with known mechanisms of BZ resistance in parasites, we found that a majority of the variation in ABZ resistance among wild C. elegans strains is caused by variation in the ß-tubulin gene ben-1. This result shows empirically that resistance to ABZ naturally exists and segregates within the C. elegans population, suggesting that selection in natural niches could enrich for resistant alleles. We identified 25 distinct ben-1 alleles that are segregating at low frequencies within the C. elegans population, including many novel molecular variants. Population genetic analyses indicate that ben-1 variation arose multiple times during the evolutionary history of C. elegans and provide evidence that these alleles likely occurred recently because of local selective pressures. Additionally, we find purifying selection at all five ß-tubulin genes, despite predicted loss-of-function variants in ben-1, indicating that BZ resistance in natural niches is a stronger selective pressure than loss of one ß-tubulin gene. Furthermore, we used genome-editing to show that the most common parasitic nematode ß-tubulin allele that confers BZ resistance, F200Y, confers resistance in C. elegans. Importantly, we identified a novel genomic region that is correlated with ABZ resistance in the C. elegans population but independent of ben-1 and the other ß-tubulin loci, suggesting that there are multiple mechanisms underlying BZ resistance. Taken together, our results establish a population-level resource of nematode natural diversity as an important model for the study of mechanisms that give rise to BZ resistance.

Validating a new grading scale for emergency general surgery diseases.

BACKGROUND: The American Association for the Surgery of Trauma (AAST) recently developed a grading scale for measuring anatomic severity of emergency general surgery (EGS) diseases. Grades were developed by expert consensus and have not been validated. The study purpose was to measure inter-rater reliability of the grading scale using colonic diverticulitis and to measure the association between disease grade and patient outcomes. METHODS: All charts were reviewed and independently assigned AAST grades based on specific disease criteria. Inter-rater reliability was measured using a kappa coefficient. Multivariate regression models were used to determine the relationship between AAST disease grade and patient outcomes adjusted for age, comorbidities, and patient physiology. RESULTS: Over 70% of patients demonstrated mild disease (grades I and II). No deaths were encountered. Inter-rater reliability for grade assignment was moderate (kappa coefficient, 0.43; 95% confidence interval, 0.31-0.56), with 67% concordance in grades. Compared to grade I, complications were similar in grade II but increased significantly with higher grades (grade III odds ratio [OR], 3.13 [1.32-7.41]; grade IV OR, 8.18 [2.09-32.0]; and grade V OR, 10.2 [2.68-38.90]). Compared to grade I, length of stay increased with higher grades (grade II incidence rate ratio [IRR], 1.30 [1.07-1.60]; grade III IRR, 2.4 [1.93-2.98]; grade IV IRR, 3.2 [2.27-4.60]; and grade V IRR, 2.6 [1.82-3.60]). CONCLUSIONS: The EGS grading scale for diverticulitis demonstrated moderate inter-rater reliability. Higher grades were independently associated with complications and length of stay. The findings provide a positive validation that the EGS scale is easily used and effective.