Search

Auditory perceptual deficits are widely observed among children with developmental language disorder (DLD). Yet, the nature of these deficits and the extent to which they explain speech and language problems remain controversial. In this study, we hypothesize that disruption to the maturation of the basilar membrane may impede the optimization of the auditory pathway from brainstem to cortex, curtailing high-resolution frequency sensitivity and the efficient spectral decomposition and encoding of natural speech. A series of computational simulations involving deep convolutional neural networks that were trained to encode, recognize, and retrieve naturalistic speech are presented to demonstrate the strength of this account. These neural networks were built on top of biologically truthful inner ear models developed to model human cochlea function, which-in the key innovation of the present study-were scheduled to mature at different rates over time. Delaying cochlea maturation qualitatively replicated the linguistic behavior and neurophysiology of individuals with language learning difficulties in a number of ways, resulting in (a) delayed language acquisition profiles, (b) lower spoken word recognition accuracy, (c) word finding and retrieval difficulties, (d) "fuzzy" and intersecting speech encodings and signatures of immature neural optimization, and (e) emergent working memory and attentional deficits. These simulations illustrate many negative cascading effects that a primary maturational frequency discrimination deficit may have on early language development and generate precise and testable hypotheses for future research into the nature and cost of auditory processing deficits in children with language learning difficulties. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Purpose: Amplitude modulations (AMs) are important for speech intelligibility, and deficits in speech intelligibility are a leading source of impairment in childhood listening difficulties (LiD). The present study aimed to explore the relationships between AM perception and speech-in-noise (SiN) comprehension in children and to determine whether deficits in AM processing contribute to childhood LiD. Evoked responses were used to parse the neural origins of AM processing., Method: Forty-one children with LiD and 44 typically developing children, ages 8-16 years, participated in the study. Behavioral AM depth thresholds were measured at 4 and 40 Hz. SiN tasks included the Listening in Spatialized Noise-Sentences Test (LiSN-S) and a coordinate response measure (CRM)-based task. Evoked responses were obtained during an AM change detection task using alternations between 4 and 40 Hz, including the N1 of the acoustic change complex, auditory steady-state response (ASSR), P300, and a late positive response (late potential [LP]). Maturational effects were explored via age correlations., Results: Age correlated with 4-Hz AM thresholds, CRM separated talker scores, and N1 amplitude. Age-normed LiSN-S scores obtained without spatial or talker cues correlated with age-corrected 4-Hz AM thresholds and area under the LP curve. CRM separated talker scores correlated with AM thresholds and area under the LP curve. Most behavioral measures of AM perception correlated with the signal-to-noise ratio and phase coherence of the 40-Hz ASSR. AM change response time also correlated with area under the LP curve. Children with LiD exhibited deficits with respect to 4-Hz thresholds, AM change accuracy, and area under the LP curve., Conclusions: The observed relationships between AM perception and SiN performance extend the evidence that modulation perception is important for understanding SiN in childhood. In line with this finding, children with LiD demonstrated poorer performance on some measures of AM perception, but their evoked responses implicated a primarily cognitive deficit., Supplemental Material: https://doi.org/10.23641/asha.25009103.

Purpose: Amplitude modulations (AM) are important for speech intelligibility, and deficits in speech intelligibility are a leading source of impairment in childhood listening difficulties (LiD). The present study aimed to explore the relationships between AM perception and speech-in-noise (SiN) comprehension in children and to determine whether deficits in AM processing contribute to childhood LiD. Evoked responses were used to parse the neural origin of AM processing., Method: Forty-one children with LiD and forty-four typically-developing children, ages 8-16 y.o., participated in the study. Behavioral AM depth thresholds were measured at 4 and 40 Hz. SiN tasks included the LiSN-S and a Coordinate Response Measure (CRM)-based task. Evoked responses were obtained during an AM Change detection task using alternations between 4 and 40 Hz, including the N1 of the acoustic change complex, auditory steady-state response (ASSR), P300, and a late positive response (LP). Maturational effects were explored via age correlations., Results: Age correlated with 4 Hz AM thresholds, CRM Separated Talker scores, and N1 amplitude. Age-normed LiSN-S scores obtained without spatial or talker cues correlated with age-corrected 4 Hz AM thresholds and area under the LP curve. CRM Separated Talker scores correlated with AM thresholds and area under the LP curve. Most behavioral measures of AM perception correlated with the SNR and phase coherence of the 40 Hz ASSR. AM Change RT also correlated with area under the LP curve. Children with LiD exhibited deficits with respect to 4 Hz thresholds, AM Change accuracy, and area under the LP curve., Conclusions: The observed relationships between AM perception and SiN performance extend the evidence that modulation perception is important for understanding SiN in childhood. In line with this finding, children with LiD demonstrated poorer performance on some measures of AM perception, but their evoked responses implicated a primarily cognitive deficit.

The Veterans Crisis Line (VCL) is a core component of VA's suicide prevention strategy. Despite the availability and utility of the VCL, many Veterans do not utilize this resource during times of crisis. A brief, psychoeducational behavioral intervention (termed Crisis Line Facilitation [CLF]) was developed to increase utilization of the VCL and reduce suicidal behaviors in high-risk Veterans. The therapist-led session includes educational information regarding the VCL, as well as a chance to discuss the participant's perceptions of contacting the VCL during periods of crisis. The final component of the session is a practice call placed to the VCL by both the therapist and the participant. The CLF intervention was compared to Enhanced Usual Care (EUC) during a multi-site randomized clinical trial for 307 Veteran participants recently hospitalized for a suicidal crisis who reported no contact with the VCL in the prior 12 months. Initial analyses indicated that participants randomized to the CLF intervention were less likely to report suicidal behaviors, including suicide attempts compared to participants randomized to receive EUC over 12-months of follow-up (χ 2  = 18.48/p < 0.0001), however this effect was not sustained when analyses were conducted on an individual level. No significant differences were found between conditions on VCL utilization. Initial evidence suggests a brief CLF intervention has an impact on preventing suicidal behaviors in Veterans treated in inpatient mental health programs; however, it may not change use of the VCL. This brief intervention could be easily adapted into clinical settings to be delivered by standard clinical staff., Competing Interests: Declaration of competing interest All authors declare that they have no conflicts of interest., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Objectives: We completed a registered double-blind randomized control trial to compare acclimatization to two hearing aid fitting algorithms by experienced pediatric hearing aid users with mild to moderate hearing loss. We hypothesized that extended use (up to 13 months) of an adaptive algorithm with integrated directionality and noise reduction, OpenSound Navigator (OSN), would result in improved performance on auditory, cognitive, academic, and caregiver- or self-report measures compared with a control, omnidirectional algorithm (OMNI)., Design: Forty children aged 6 to 13 years with mild to moderate/severe symmetric sensorineural hearing loss completed this study. They were all experienced hearing aid users and were recruited through the Cincinnati Children's Hospital Medical Center Division of Audiology. The children were divided into 20 pairs based on similarity of age (within 1 year) and hearing loss (level and configuration). Individuals from each pair were randomly assigned to either an OSN (experimental) or OMNI (control) fitting algorithm group. Each child completed an audiology evaluation, hearing aid fitting using physically identical Oticon OPN hearing aids, follow-up audiological appointment, and 2 research visits up to 13 months apart. Research visit outcome measures covered speech perception (in quiet and in noise), novel grammar and word learning, cognition, academic ability, and caregiver report of listening behaviors. Analysis of outcome differences between visits, groups, ages, conditions and their interactions used linear mixed models. Between 22 and 39 children provided useable data for each task., Results: Children using the experimental (OSN) algorithm did not show any significant performance differences on the outcome measures compared with those using the control (OMNI) algorithm. Overall performance of all children in the study increased across the duration of the trial on word repetition in noise, sentence repetition in quiet, and caregivers' assessment of hearing ability. There was a significant negative relationship between age at first hearing aid use, final Reading and Mathematical ability, and caregiver rated speech hearing. A significant positive relationship was found between daily hearing aid use and study-long change in performance on the Flanker test of inhibitory control and attention. Logged daily use of hearing aids related to caregiver rated spatial hearing. All results controlled for age at testing/evaluation and false discovery rate., Conclusions: Use of the experimental (OSN) algorithm neither enhanced nor reduced performance on auditory, cognitive, academic or caregiver report measures compared with the control (OMNI) algorithm. However, prolonged hearing aid use led to benefits in hearing, academic skills, attention, and caregiver evaluation., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Listening difficulties (LiD) in people who have normal audiometry are a widespread but poorly understood form of hearing impairment. Recent research suggests that childhood LiD are cognitive rather than auditory in origin. We examined decoding of sentences using a novel combination of behavioral testing and fMRI with 43 typically developing children and 42 age matched (6-13 years old) children with LiD, categorized by caregiver report (ECLiPS). Both groups had clinically normal hearing. For sentence listening tasks, we found no group differences in fMRI brain cortical activation by increasingly complex speech stimuli that progressed in emphasis from phonology to intelligibility to semantics. Using resting state fMRI, we examined the temporal connectivity of cortical auditory and related speech perception networks. We found significant group differences only in cortical connections engaged when processing more complex speech stimuli. The strength of the affected connections was related to the children's performance on tests of dichotic listening, speech-in-noise, attention, memory and verbal vocabulary. Together, these results support the novel hypothesis that childhood LiD reflects difficulties in language rather than in auditory or phonological processing., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: Children presenting at audiology services with caregiver-reported listening difficulties often have normal audiograms. The appropriate approach for the further assessment and clinical management of these children is currently unclear. In this Sensitive Indicators of Childhood Listening Difficulties (SICLiD) study, we assessed listening ability using a reliable and validated caregiver questionnaire (the Evaluation of Children's Listening and Processing Skills [ECLiPS]) in a large (n = 146) and heterogeneous sample of 6- to 13-year-old children with normal audiograms. Scores on the ECLiPS were related to a multifaceted laboratory assessment of the children's audiological, psycho- and physiological-acoustic, and cognitive abilities. This report is an overview of the SICLiD study and focuses on the children's behavioral performance. The overall goals of SICLiD were to understand the auditory and other neural mechanisms underlying childhood listening difficulties and translate that understanding into clinical assessment and, ultimately, intervention., Design: Cross-sectional behavioral assessment of children with "listening difficulties" and an age-matched "typically developing" control group. Caregivers completed the ECLiPS, and the resulting total standardized composite score formed the basis of further descriptive statistics, univariate, and multivariate modeling of experimental data., Results: All scores of the ECLiPS, the SCAN-3:C, a standardized clinical test suite for auditory processing, and the National Institutes of Health (NIH) Cognition Toolbox were significantly lower for children with listening difficulties than for their typically developing peers using group comparisons via t-tests and Wilcoxon Rank-Sum tests. A similar effect was observed on the Listening in Spatialized Noise-Sentences (LiSN-S) test for speech sentence-in-noise intelligibility but only reached significance for the Low Cue and High Cue conditions and the Talker Advantage derived score. Stepwise regression to examine the factors contributing to the ECLiPS Total scaled score (pooled across groups) yielded a model that explained 42% of its variance based on the SCAN-3:C composite, LiSN-S Talker Advantage, and the NIH Toolbox Picture Vocabulary, and Dimensional Change Card Sorting scores (F[4, 95] = 17.35, p < 0.001). High correlations were observed between many test scores including the ECLiPS, SCAN-3:C, and NIH Toolbox composite measures. LiSN-S Advantage measures generally correlated weakly and nonsignificantly with non-LiSN-S measures. However, a significant interaction was found between extended high-frequency threshold and LiSN-S Talker Advantage., Conclusions: Children with listening difficulties but normal audiograms have problems with the cognitive processing of auditory and nonauditory stimuli that include both fluid and crystallized reasoning. Analysis of poor performance on the LiSN-S Talker Advantage measure identified subclinical hearing loss as a minor contributing factor to talker segregation. Beyond auditory tests, evaluations of children with complaints of listening difficulties should include standardized caregiver observations and consideration of broad cognitive abilities., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose This exploratory study assessed the perceptual, cognitive, and academic learning effects of an adaptive, integrated, directionality, and noise reduction hearing aid program in pediatric users. Method Fifteen pediatric hearing aid users (6-12 years old) received new bilateral, individually fitted Oticon Opn hearing aids programmed with OpenSound Navigator (OSN) processing. Word recognition in noise, sentence repetition in quiet, nonword repetition, vocabulary learning, selective attention, executive function, memory, and reading and mathematical abilities were measured within 1 week of the initial hearing aid fitting and 2 months post fit. Caregivers completed questionnaires assessing their child's listening and communication abilities prior to study enrollment and after 2 months of using the study hearing aids. Results Caregiver reporting indicated significant improvements in speech and sound perception, spatial sound awareness, and the ability to participate in conversations. However, there was no positive change in performance in any of the measured skills. Mathematical scores significantly declined after 2 months. Conclusions OSN provided a perceived improvement in functional benefit, compared to their previous hearing aids, as reported by caregivers. However, there was no positive change in listening skills, cognition, and academic success after 2 months of using OSN. Findings may have been impacted by reporter bias, limited sample size, and a relatively short trial period. This study took place during the summer when participants were out of school, which may have influenced the decline in mathematical scores. The results support further exploration with age- and audiogram-matched controls, larger sample sizes, and longer test-retest intervals that correspond to the academic school year.

Military Veterans are at overall greater risk of suicide than non-Veterans and have experienced increases in rates of suicide that are on par with or exceed those of the general population. The Department of Veterans Affairs has undertaken several initiatives to reduce suicide among Veterans, including the development and expansion of the Veterans Crisis Line (VCL). The VCL has the potential to reduce suicidal behaviors, but it is likely underutilized by high-risk Veterans. This paper describes the development of Crisis Line Facilitation (CLF) a brief intervention, designed to increase use of the VCL in this high-risk population. In a single session, CLF presents psychoeducational information about the VCL, discusses the participant's perceived barriers and facilitators to future use of the VCL, and culminates in the Veteran calling the VCL with the therapist to provide firsthand experiences that may counter negative impressions of the line. The intervention development process, intervention and control condition, and self-reported change indices are presented. Preliminary results (N = 301) suggest Veterans receiving CLF may experience a significant increase in comfort with, and confidence in, using the VCL during future crises compared to those in the control condition.

Selective attention to sound object features such as pitch and location is associated with enhanced brain activity in ventral and dorsal streams, respectively. We examined the role of these pathways in involuntary orienting and conflict resolution using fMRI. Participants were presented with two tones that may, or may not, share the same nonspatial (frequency) or spatial (location) auditory features. In separate blocks of trials, participants were asked to attend to sound frequency or sound location and ignore the change in the task-irrelevant feature. In both attend-frequency and attend-location tasks, RTs were slower when the task-irrelevant feature changed than when it stayed the same (involuntary orienting). This behavioral cost coincided with enhanced activity in the pFC and superior temporal gyrus. Conflict resolution was examined by comparing situations where the change in stimulus features was congruent (both features changed) and incongruent (only one feature changed). Participants were slower and less accurate for incongruent than congruent sound features. This congruency effect was associated with enhanced activity in the pFC and was greater in the right superior temporal gyrus and medial frontal cortex during the attend-location task than during the attend-frequency task. Together, these findings do not support a strict division of "labor" into ventral and dorsal streams but rather suggest interactions between these pathways in situations involving changes in task-irrelevant sound feature and conflict resolution. These findings also validate the Test of Attention in Listening task by revealing distinct neural correlates for involuntary orienting and conflict resolution.

A training method to improve speech hearing in noise has proven elusive, with most methods failing to transfer to untrained tasks. One common approach to identify potentially viable training paradigms is to make use of cross-sectional designs. For instance, the consistent finding that people who chose to avidly engage with action video games as part of their normal life also show enhanced performance on non-game visual tasks has been used as a foundation to test the causal impact of such game play via true experiments (e.g., in more translational designs). However, little work has examined the association between action video game play and untrained auditory tasks, which would speak to the possible utility of using such games to improve speech hearing in noise. To examine this possibility, 80 participants with mixed action video game experience were tested on a visual reaction time task that has reliably shown superior performance in action video game players (AVGPs) compared to non-players (≤ 5 h/week across game categories) and multi-genre video game players (> 5 h/week across game categories). Auditory cognition and perception were tested using auditory reaction time and two speech-in-noise tasks. Performance of AVGPs on the visual task replicated previous positive findings. However, no significant benefit of action video game play was found on the auditory tasks. We suggest that, while AVGPs interact meaningfully with a rich visual environment during play, they may not interact with the games' auditory environment. These results suggest that far transfer learning during action video game play is modality-specific and that an acoustically relevant auditory environment may be needed to improve auditory probabilistic thinking.

Listening difficulties (LiD) are common in children with and without hearing loss. Impaired interactions between the two ears have been proposed as an important component of LiD when there is no hearing loss, also known as auditory processing disorder (APD). We examined the ability of 6-13 year old (y.o.) children with normal audiometric thresholds to identify and selectively attend to dichotically presented CV syllables using the Bergen Dichotic Listening Test (BDLT; www.dichoticlistening.com). Children were recruited as typically developing (TD; n = 39) or having LiD ( n = 35) based primarily on composite score of the ECLiPS caregiver report. Different single syllables (ba, da, ga, pa, ta, ka) were presented simultaneously to each ear (6 × 36 trials). Children reported the syllable heard most clearly (non-forced, NF) or the syllable presented to the right [forced right (FR)] or left [forced left (FL)] ear. Interaural level differences (ILDs) manipulated bottom-up perceptual salience. Dichotic listening (DL) data [correct responses, laterality index (LI)] were analyzed initially by group (LiD, TD), age, report method (NF, FR, FL), and ILD (0, ± 15 dB) and compared with speech-in-noise thresholds (LiSN-S) and cognitive performance (NIH Toolbox). fMRI measured brain activation produced by a receptive speech task that segregated speech, phonetic, and intelligibility components. Some activated areas [planum temporale (PT), inferior frontal gyrus (IFG), and orbitofrontal cortex (OFC)] were correlated with dichotic results in TD children only. Neither group, age, nor report method affected the LI of right/left recall. However, a significant interaction was found between ear, group, and ILD. Laterality indices were small and tended to increase with age, as previously reported. Children with LiD had significantly larger mean LIs than TD children for stimuli with ILDs, especially those favoring the left ear. Neural activity associated with Speech, Phonetic, and Intelligibility sentence cues did not differ significantly between groups. Significant correlations between brain activity level and BDLT were found in several frontal and temporal locations for the TD but not for the LiD group. Overall, the children with LiD had only subtle differences from TD children in the BDLT, and correspondingly minor changes in brain activation., (Copyright © 2020 Moore, Hugdahl, Stewart, Vannest, Perdew, Sloat, Cash and Hunter.)

Introduction: Hearing loss is common and associated with poorer health and impeded communication. Little is known about the association between hearing loss and substance use disorders in the general population. The objective of this study was to assess substance use disorder prevalence among individuals with hearing loss, versus those without hearing loss, in a nationally representative sample of adults., Methods: Two years (2015 and 2016) of National Survey on Drug Use and Health (unweighted N=86,186) were combined to compare substance use disorders among adults with and without self-reported hearing loss. Statistical analysis included descriptive frequencies, chi-square tests, and multiple logistic regressions. Analyses were performed in 2018., Results: Hearing loss prevalence across all age groups was 5.2%. Among younger age groups, after adjusting for sociodemographics, hearing loss was independently associated with an increased likelihood of experiencing a substance use disorder (ages 18-34 years, AOR=1.34, 95% CI=1.10, 1.64 vs 35-49 years, AOR=1.87, 95% CI=1.39, 2.53). Hearing loss was also associated with a greater likelihood of a prescription opioid use disorder (AOR=2.85, 95% CI=1.86, 4.39) in the group aged 18-34 years and, for the group aged 35-49 years, hearing loss increased the likelihood of both an alcohol use disorder (AOR=1.87, 95% CI=1.39, 2.53) and a prescription opioid use disorder (AOR=1.99, 95% CI=1.01, 3.91)., Conclusions: Hearing loss is independently associated with substance use disorders among those aged 49 years and younger; these associations are particularly pronounced for prescription opioid use disorders in the group aged 18-34 years. Given the concern of inappropriate use of prescription opioids, this information may have implications for healthcare providers' pain management for patients with hearing loss., (Copyright © 2018 American Journal of Preventive Medicine. Published by Elsevier Inc. All rights reserved.)

Dissecting neural circuitry in non-human primates (NHP) is crucial to identify potential neuromodulation anatomical targets for the treatment of pharmacoresistant neuropsychiatric diseases by electrical neuromodulation. How targets of deep brain stimulation (DBS) and cortical targets of transcranial magnetic stimulation (TMS) compare and might complement one another is an important question. Combining optogenetics and tractography may enable anatomo-functional characterization of large brain cortico-subcortical neural pathways. For the proof-of-concept this approach was used in the NHP brain to characterize the motor cortico-subthalamic pathway (m&#95;CSP) which might be involved in DBS action mechanism in Parkinson's disease (PD). Rabies-G-pseudotyped and Rabies-G-VSVg-pseudotyped EIAV lentiviral vectors encoding the opsin ChR2 gene were stereotaxically injected into the subthalamic nucleus (STN) and were retrogradely transported to the layer of the motor cortex projecting to STN. A precise anatomical mapping of this pathway was then performed using histology-guided high angular resolution MRI tractography guiding accurately cortical photostimulation of m&#95;CSP origins. Photoexcitation of m&#95;CSP axon terminals or m&#95;CSP cortical origins modified the spikes distribution for photosensitive STN neurons firing rate in non-equivalent ways. Optogenetic tractography might help design preclinical neuromodulation studies in NHP models of neuropsychiatric disease choosing the most appropriate target for the tested hypothesis.

In everyday situations auditory selective attention requires listeners to suppress task-irrelevant stimuli and to resolve conflicting information in order to make appropriate goal-directed decisions. Traditionally, these two processes (i.e. distractor suppression and conflict resolution) have been studied separately. In the present study we measured neuroelectric activity while participants performed a new paradigm in which both processes are quantified. In separate block of trials, participants indicate whether two sequential tones share the same pitch or location depending on the block's instruction. For the distraction measure, a positive component peaking at ~250 ms was found - a distraction positivity. Brain electrical source analysis of this component suggests different generators when listeners attended to frequency and location, with the distraction by location more posterior than the distraction by frequency, providing support for the dual-pathway theory. For the conflict resolution measure, a negative frontocentral component (270-450 ms) was found, which showed similarities with that of prior studies on auditory and visual conflict resolution tasks. The timing and distribution are consistent with two distinct neural processes with suppression of task-irrelevant information occurring before conflict resolution. This new paradigm may prove useful in clinical populations to assess impairments in filtering out task-irrelevant information and/or resolving conflicting information.

Pharmacological dopamine replacement therapies provide the most well-established treatments for Parkinson's disease (PD). However, these long-term treatments can lead to motor complications and off-target effects. ProSavin(®), a lentiviral vector (LV)-based gene therapy approach aimed at restoring local and continuous dopamine production, through delivery of three enzymes in the dopamine biosynthesis pathway, was demonstrated to be safe and well-tolerated in a phase I/II clinical study of patients with advanced PD. Although improvements in motor behaviour were observed, the data indicated that higher levels of dopamine replacement might be required to maximize benefit. We attempted to increase production of dopamine, and its precursor L-Dopa in LV-transduced cells, by optimizing the gene order in the ProSavin expression cassette, and by creating fusions of two or three of the transgenes, using linker sequences. In vitro analysis showed that several gene arrangements provided significantly increased dopamine and/or L-Dopa production compared with ProSavin, and that LV titers and transgene expression were not affected by introducing gene fusions. One vector, equine infectious anemia virus (EIAV)-TCiA, was selected for further characterization and showed significant improvements in dopamine and L-Dopa production compared with ProSavin, in human neuronal cells. Further characterization of EIAV-TCiA demonstrated expression of all three dopamine enzymes in vivo and faithful delivery and integration of the expected gene expression cassette within the genome of target cells, as assessed by Northern and Southern blotting. In conclusion, we have developed a novel LV vector with an increased capacity for L-Dopa and dopamine production compared with the current ProSavin vector. Clinical evaluation of this vector will be performed to assess the benefits in patients with PD.

Objective: To establish the modality specificity and generality of selective attention networks., Method: Forty-eight young adults completed a battery of four auditory and visual selective attention tests based upon the Attention Network framework: the visual and auditory Attention Network Tests (vANT, aANT), the Test of Everyday Attention (TEA), and the Test of Attention in Listening (TAiL). These provided independent measures for auditory and visual alerting, orienting, and conflict resolution networks. The measures were subjected to an exploratory factor analysis to assess underlying attention constructs., Results: The analysis yielded a four-component solution. The first component comprised of a range of measures from the TEA and was labeled "general attention." The third component was labeled "auditory attention," as it only contained measures from the TAiL using pitch as the attended stimulus feature. The second and fourth components were labeled as "spatial orienting" and "spatial conflict," respectively-they were comprised of orienting and conflict resolution measures from the vANT, aANT, and TAiL attend-location task-all tasks based upon spatial judgments (e.g., the direction of a target arrow or sound location)., Conclusions: These results do not support our a-priori hypothesis that attention networks are either modality specific or supramodal. Auditory attention separated into selectively attending to spatial and non-spatial features, with the auditory spatial attention loading onto the same factor as visual spatial attention, suggesting spatial attention is supramodal. However, since our study did not include a non-spatial measure of visual attention, further research will be required to ascertain whether non-spatial attention is modality-specific.

It is a current regulatory requirement to demonstrate absence of detectable replication-competent lentivirus (RCL) in lentiviral vector products prior to use in clinical trials. Immune Design previously described an HIV-1-based integration-deficient lentiviral vector for use in cancer immunotherapy (VP02). VP02 is enveloped with E1001, a modified Sindbis virus glycoprotein which targets dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN) expressed on dendritic cells in vivo. Vector enveloped with E1001 does not transduce T-cell lines used in standard HIV-1-based RCL assays, making current RCL testing formats unsuitable for testing VP02. We therefore developed a novel assay to test for RCL in clinical lots of VP02. This assay, which utilizes a murine leukemia positive control virus and a 293F cell line expressing the E1001 receptor DC-SIGN, meets a series of evaluation criteria defined in collaboration with US regulatory authorities and demonstrates the ability of the assay format to amplify and detect a hypothetical RCL derived from VP02 vector components. This assay was qualified and used to test six independent GMP production lots of VP02, in which no RCL was detected. We propose that the evaluation criteria used to rationally design this novel method should be considered when developing an RCL assay for any lentiviral vector.

Embryonic stem cells (ESCs) are maintained in an undifferentiated state through expression of the core transcriptional factors Nanog, Oct4, and Sox2. However, the epigenetic regulation of pluripotency is poorly understood. Differentiation of ESCs is accompanied by a global reduction of panacetylation of histones H3 and H4 suggesting that histone acetylation plays an important role in maintenance of ESC pluripotency. Acetylated lysine residues on histones are read by members of the bromodomain family that includes BET (bromodomain and extraterminal domain) proteins for which highly potent and selective inhibitors have been developed. In this study we demonstrate that the pan-BET bromodomain inhibitor JQ1 induces rapid spontaneous differentiation of murine ESCs by inducing marked transcriptional downregulation of Nanog as well as the stemness markers Lefty1 and Lefty2, but not Myc, often used as a marker of BET inhibitor activity in cancer. We show that the effects of JQ1 are recapitulated by knockdown of the BET family member BRD4 implicating this protein in Nanog regulation. These data are also supported by chromatin immunoprecipitation experiments which confirm BRD4 binding at the Nanog promoter that is known to require acetylation by the histone acetyltransferase MOF for transcriptional activity. In further support of our findings, we show that JQ1 antagonizes the stem cell-promoting effects of the histone deacetylase inhibitors sodium butyrate and valproic acid. Our data suggest that BRD4 is critical for the maintenance of ESC pluripotency and that this occurs primarily through the maintenance of Nanog expression.

Purpose: The study explored whether visual information improves speech identification in typically developing children with normal hearing when the auditory signal is spectrally degraded., Method: Children (n=69) and adults (n=15) were presented with noise-vocoded sentences from the Children's Co-ordinate Response Measure (Rosen, 2011) in auditory-only or audiovisual conditions. The number of bands was adaptively varied to modulate the degradation of the auditory signal, with the number of bands required for approximately 79% correct identification calculated as the threshold., Results: The youngest children (4- to 5-year-olds) did not benefit from accompanying visual information, in comparison to 6- to 11-year-old children and adults. Audiovisual gain also increased with age in the child sample., Conclusions: The current data suggest that children younger than 6 years of age do not fully utilize visual speech cues to enhance speech perception when the auditory signal is degraded. This evidence not only has implications for understanding the development of speech perception skills in children with normal hearing but may also inform the development of new treatment and intervention strategies that aim to remediate speech perception difficulties in pediatric cochlear implant users.

Refractory cancer pain affects 10–20% of patients with advanced malignancies and is not adequately controlled by opioids. The intrathecal therapy is an effective interventional procedure for referral, but the implanted infusion pumps are costly and the refilling requires technical expertise. Hypophysectomy, in its three stages—surgical, chemical, and radiosurgical—has emerged as an alternative for managing this pain. However, the underlying mechanism remains elusive, with existing hypotheses unable to comprehensively account for both the initial and long-term analgesic effects. This literature review explores the historical evolution, clinical outcomes, and hypothesized mechanisms of hypophysectomy for pain relief. Surgical hypophysectomy initially demonstrated an 85.5% success rate but carried significant risks like diabetes insipidus and hypopituitarism. Chemical hypophysectomy reduced invasiveness, achieving 75.1% pain relief with fewer complications. Modern pituitary radiosurgery has improved safety while maintaining high efficacy (initial relief: 95.9%, long-term: 73.5%). The mechanisms underlying pain relief remain unclear but include tumor regression, increased β -endorphins, neuroendocrine modulation, and hypothalamic involvement. A new hypothesis suggests that radiosurgery induces hormone redistribution (e.g., oxytocin, vasopressin) through hypothalamic–pituitary modulation, contributing to both immediate and long-term analgesia. Despite its potential, unresolved issues such as optimal radiation dose, pain assessment standardization, and precise mechanisms limit widespread adoption. This review underscores the need for larger, homogenous studies to validate the safety and efficacy of hypophysectomy in treating refractory cancer pain. These findings offer a promising avenue for improving palliative care in oncology. [ABSTRACT FROM AUTHOR]

Context: Antral follicle count (AFC) is reflective of ovarian reserve and linked to reproductive performance in mammalian females. We previously demonstrated earlier upregulation of endometrial oxytocin receptor transcription in heifers with low AFC, indicating an earlier onset of luteolysis. Aims: We aimed to support the earlier onset of luteolysis in non-pregnant heifers with a low number of antral ovarian follicles (Open Low AFC) and hypothesized a reduced abundance of luteinizing hormone/choriogonadotropin receptor (LH/CG-R) and increased abundance of thrombospondin-1 (THBS1) in luteal tissue of those heifers. We further investigated if classical interferon stimulated genes (ISGs) are already upregulated in response to conceptus-derived interferon tau. Methods: For 4 years, 10 heifers with the highest (High AFC) and 10 heifers with the lowest AFC (Low AFC) of the population (n = 120/year) were selected, synchronized and inseminated. On day 15 or 16 after insemination, reproductive tracts were collected, and pregnancy status was determined. Corpora lutea were isolated, weighed and underwent transcriptomic analysis. Key results: Transcript abundance of LH/CG-R was lower in Open Low AFC heifers compared to all other subgroups. Transcript abundance of THBS1 was upregulated in Open vs Pregnant heifers and showed greater abundance in Low vs High AFC heifers. Luteal weights and abundance of ISGs did not differ between heifers of differing AFC groups or pregnancy status. Conclusions: The patterns of luteal LH / CG-R and THBS1 abundance support the concept of earlier onset of luteolysis in Open heifers with diminished AFC. Implications: This may result in a shorter window for maternal recognition of pregnancy and contribute to inferior reproductive performance. Livestock production systems rely on efficient reproduction. Selection of heifers with a high number of antral ovarian follicles can be applied with the aim of improving reproductive efficiency. The herein presented results support an earlier onset of luteolysis in non-pregnant heifers with a low number of antral follicles. This indicates a shorter time period for the recognition of pregnancy by the dam, which might contribute to inferior reproductive performance in heifers with a low number of antral ovarian follicles. Image by MK, created with biorender.com. This article belongs to the collection: The biology of the ovary – Honouring the contributions of Ken P McNatty and Rex J Scaramuzzi. [ABSTRACT FROM AUTHOR]

Background: Breast thermography originated in the 1950s but was later abandoned due to the contradictory results obtained in the following decades. However, advances in infrared technology and image processing algorithms in the twenty-first century led to a renewed interest in thermography. This work aims to provide an updated and objective picture of the recent scientific evidence on its effectiveness, both as a screening and as a diagnostic tool. Methods: We searched for clinical studies published between 2001 and May 31, 2023, in the databases PubMed and Scopus, that aimed to evaluate the effectiveness of digital, long-wave infrared imaging for detecting breast cancer. Additional documents were retrieved from the studies included in the systematic reviews that resulted from the search and by searching for the names of commercial systems. We limited our selection to studies that reported the sensitivity and specificity of breast thermography (or the data needed to calculate them) using images collected by themselves, with at least five breast cancer cases. Studies that considered breast diseases other than cancer to be positive or that did not use standard tests to set the ground truth diagnosis were excluded, as well as articles written in a language other than English and documents we could not access. We also conducted meta-analyses of proportions of the sensitivity and specificity values reported in the selected studies and a bivariate meta-analysis to account for the correlation between these metrics. Results: Our systematic search resulted in 22 studies, with an average pooled sensitivity and specificity of 88.5% and 71.8%, respectively. However, the differences in patient recruitment, sample size, imaging protocol, equipment, and interpretation criteria yielded a high heterogeneity measure (79.3% and 99.1% I 2 value, respectively). Conclusions: Overall, thermography showed a high sensitivity in the selected studies, whereas specificity started off lower and increased over time. The most recent studies reported a combination of sensitivity and specificity comparable to standard diagnostic tests. Most of the selected studies were small and tend to include only patients with a suspicious mass that requires biopsy. However, larger studies with a wider variety of patient types (asymptomatic, women with dense breasts, etc.) have been published in the latest years. [ABSTRACT FROM AUTHOR]

Organizational agility is the ability of an organization to swiftly and efficiently respond to changes in the organization's environment. However, the literature demonstrates the interchangeability of agility, flexibility, adaptability, and versatility. Therefore, confusion and conceptual overlap persist. As a result, this study aimed to provide further conceptual clarity about organizational agility by synthesizing organizational agility, flexibility, adaptability, and versatility. A systematic review of 40 articles published in business and management-related journals between 1991 and 2022 in ABI/INFORMS, Since Direct, Emerald databases are employed. Findings from thematic analysis and content analysis using Leximancer text mining analysis show that versatility, adaptability, and flexibility are closely connected with their focus on coping with change in the business environment. However, agility is distinct due to its emphasis on organizational ability, capability, and changeability, as well as how it conceptualizes these attributes. This review contributes to developing organizational agility theory and practice by disentangling organizational agility from related concepts. Specifically, it contributes to scientific communication by referring to the same phenomena as organizational agility. Finally, the study concludes by highlighting future research directions. [ABSTRACT FROM AUTHOR]

Background: To determine whether, when primary breast cancer is treated by local excision supported by systemic therapy appropriate to the oestrogen receptor status (ER) of the tumour, local radiotherapy can be avoided.Methods: We carried out a randomised controlled trial in 585 patients aged less than 70 years with primary breast cancers of 4 cm or less in size in four specialist units and seven other hospitals in Scotland. After local excision of the tumour (1 cm margin) and an axillary lymph-node clearance or sample, all patients received systemic therapy with oral tamoxifen 20 mg daily or six 3-weekly intravenous bolus injections of cyclophosphamide 600 mg, methotrexate 50 mg, and fluorouracil 600 mg per m2, depending upon the ER concentration in the primary tumour. Patients were then randomly allocated to postoperative radical radiotherapy (50 Gy to breast with boost to the tumour bed) or to no further local treatment. The median follow-up of living patients was 5.7 years. The primary analysis was by intention to treat but since some patients did not receive systemic therapy appropriate to their ER status, a subsidiary analysis was restricted to 464 patients in whom all details of the protocol had been observed.Findings: In the primary analysis survival was equal in the radiotherapy and non-radiotherapy groups (hazard ratio [HR] 0.98, 95% CI 0.67-1.44). Event-free survival showed an advantage in the irradiated patients (HR 0.54, 95% CI 0.39-0.74), largely due to fewer loco-regional relapses (HR 0.20, 95% CI 0.12-0.33). The relapse rate in the ipsilateral breast was 24.5% in the non-irradiated group and 5.8% following breast irradiation. The subsidiary analysis confirmed these findings and indicated the advantage of radiotherapy irrespective of ER concentration. There was a non-significant trend towards fewer distant metastases in the irradiated group.Interpretation: After local excision of a primary breast cancer, we conclude that radiotherapy to the residual breast tissue is advisable even when selective adjuvant systemic therapy is given. [ABSTRACT FROM AUTHOR]

The bromodomain and extra terminal (BET) family protein bromodomain containing protein 4 (BRD4) is an epigenetic regulator recently identified as a therapeutic target for several hematological cancers, notably mixed lineage leukemia-fusion acute myeloid leukemia (MLL-AML). Here, we show that the BRD4 bromodomain inhibitor JQ1 is highly active against the p53-wild-type Ontario Cancer Institute (OCI)-AML3 cell line which carries mutations in nucleophosmin (NPM1) and DNA methyltransferase 3 (DNMT3A) genes commonly associated with poor prognostic disease. We find that JQ1 causes caspase 3/7-mediated apoptosis and DNA damage response in these cells. In combination studies, we show that histone deacetylase (HDAC) inhibitors, the HDM2 inhibitor Nutlin-3, and the anthracycline daunorubicin all enhance the apoptotic response of JQ1. These compounds all induce activation of p53 suggesting that JQ1 might sensitize AML cells to p53-mediated cell death. In further experiments, we show that BRD4 associates with acetylated p53 but that this association is not inhibited by JQ1 indicating that the protein-protein interaction does not involve bromodomain binding of acetylated lysines. Instead, we propose that JQ1 acts to prevent BRD4-mediated recruitment of p53 to chromatin targets following its activation in OCI-AML3 cells resulting in cell cycle arrest and apoptosis in a c-MYC-independent manner. Our data suggest that BET bromodomain inhibition might enhance current chemotherapy strategies in AML, notably in poor-risk DNMT3A/NPM1-mutated disease., (© 2013 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Imitation is a potentially crucial aspect of social cognitive development. Although deficits in imitation ability have been widely demonstrated in autism spectrum disorder (ASD), the specificity and significance of the findings is unclear, due largely to methodological limitations. We developed a novel assessment of imitation ability, using objective movement parameters (path length and action duration) derived from a touch-sensitive tablet laptop during drawing actions on an identical tablet. By direct comparison of the kinematics of a model's actions with those of the participant who observed them, measures of imitation accuracy were obtained. By replaying the end-point of the movement as a spot on the screen, imitation accuracy was compared against a "ghost control" condition, with no human actor but only the end-point of the movement seen [object movement reenactment (OMR)]. Hence, demands of the control task were closely matched to the experimental task with respect to motor, memory, and attentional abilities. Adolescents with ASD showed poorer accuracy for copying object size and action duration on both the imitation and OMR tasks, but were significantly more impaired for imitation of object size. Our results provide evidence that some of the imitation deficit in ASD is specific to a self-other mapping problem, and cannot be explained by general factors such as memory, spatial reasoning, motor control, or attention, nor related to the social demands of the testing situation., (© 2013 International Society for Autism Research, Wiley Periodicals, Inc.)

Background: Multiple myeloma is a plasma cell disorder that is characterised by clonal proliferation of malignant plasma cells in the bone marrow, monoclonal paraprotein in the blood or urine and associated organ dysfunction. It accounts for approximately 1% of cancers and 13% of haematological cancers. Myeloma arises from an asymptomatic proliferation of monoclonal plasma cells termed monoclonal gammopathy of undetermined significance (MGUS)., Methods: MicroRNA expression profiling of serum samples was performed on three patient groups as well as normal controls. Validation of the nine microRNAs detected as promising biomarkers was carried out using TaqMan quantitative reverse transcription PCR. MicroRNA levels in serum were normalised using standard curves to determine the numbers of microRNAs per μl of serum., Results: Three serum microRNAs, miR-720, miR-1308 and miR-1246, were found to have potential as diagnostic biomarkers in myeloma. Use of miR-720 and miR-1308 together provides a powerful diagnostic tool for distinguishing normal healthy controls, as well as patients with unrelated illnesses, from pre-cancerous myeloma and myeloma patients. In addition, the combination of miR-1246 and miR-1308 can distinguish MGUS from myeloma patients., Conclusion: We have developed a biomarker signature using microRNAs extracted from serum, which has potential as a diagnostic and prognostic tool for multiple myeloma.

In-stent restenosis is a clinical complication following coronary angioplasty caused by the implantation of the metal device in the atherosclerotic vessel. Histological examination has shown a clear contribution of both inflammatory and smooth muscle cells (SMCs) to the deposition of an excess of neointimal tissue. However, the sequence of events leading to clinically relevant restenosis is unknown. This paper aims to study the phenotype of SMCs when adhering on substrates and exposed to biochemical stimuli typical of the early phases of stent implantation. In particular, human SMC phenotype was studied when adhering on extracellular matrix-like material (collagen-rich gel), thrombus-like material (fibrin gel) and stent material (stainless steel) in the presence or absence of a platelet-derived growth factor (PDGF) stimulus. Cells on the collagen and fibrin-rich substrates maintained their contractile phenotype. By contrast, cells on stainless steel acquired a secretory phenotype with a proliferation rate 50 per cent higher than cells on the natural substrates. Cells on stainless steel also showed an increase in PDGF-BB receptor expression, thus explaining the increase in proliferation observed when cells were subject to PDGF-BB stimuli. The stainless steel substrate also promoted a different pattern of β1-integrin localization and an altered expression of hyaluronan (HA) synthase isoforms where the synthesis of high-molecular-weight HA seemed to be favoured. These findings highlighted the induction of a phenotypic pattern in SMC by the stainless steel substrate whereby the formation of a HA-rich neointimal tissue is enhanced.

Objective: Polo-like kinase 1 (Plk1) is a regulator of the cell cycle that has been implicated in the pathology of many cancers. We have investigated whether this kinase plays a role in multiple myeloma (MM) using the Plk1 inhibitor BI 2536., Materials and Methods: We have used six MM cell lines and six patient-derived samples to determine the effects of the Plk1 inhibitor, BI 2536, on cell viability, apoptosis, and cytokinesis. We have also examined the effect of the microenvironment on these parameters and the effects of BI 2536 in combination with other antimyeloma agents., Results: We show that MM cell lines and patient samples express PLK1 and that cell death by apoptosis occurs when Plk1 is inhibited. Cells treated with BI 2536 accumulate in the G(2)/M phase of the cell cycle causing endoduplication. The effects of BI 2536 are not abrogated when cells are cultured on extracellular matrix components, in the presence of interleukin-6, or with bone marrow stromal cells., Conclusions: Plk1 inhibition leads to cell death in MM cell lines and patient myeloma samples. Our data suggest that inhibition of Plk1 may have potential use as a therapeutic strategy in multiple myeloma., (Copyright © 2011 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.)

ProSavin is an equine infectious anemia virus vector-based gene therapy for Parkinson's disease for which inducible HEK293T-based producer cell lines (PCLs) have been developed. These cell lines demonstrate stringent tetracycline-regulated expression of the packaging components and yield titers comparable to the established transient production system. A prerequisite for the use of PCL-derived lentiviral vectors (LVs) in clinical applications is the thorough characterization of both the LV and respective PCL with regard to identity and genetic stability. We describe the detailed characterization of two ProSavin PCLs (PS5.8 and PS46.2) and resultant ProSavin vector. The two cell lines demonstrate stable production of vector over a time period sufficient to allow generation of master and working cell banks, and subsequent large-scale vector production. ProSavin generated from the PCLs performs comparably in vivo to that produced by the standard transient transfection process with respect to transduction efficiency and immunogenicity. The development of ProSavin PCLs, and the detailed characterization described here, will aid the advancement of ProSavin for clinical application.

Galectin-1, the prototype of a family of beta-galactoside-binding proteins, has been implicated in a wide variety of biological processes. Data presented herein show that galectin-1 stimulates monocyte migration in a dose-dependent manner but is not chemotactic for macrophages. Galectin-1-induced monocyte chemotaxis is blocked by lactose and inhibited by an anti-galectin-1 antibody but not by nonspecific antibodies. Furthermore, galectin-1-mediated monocyte migration was significantly inhibited by MEK inhibitors in a rapid, time-dependent manner suggesting that MAP kinase pathways are involved in galectin-1. Migration was also almost completely blocked by pertussis toxin implying G-protein involvement in the galectin-1-induced chemotaxis. These results demonstrate a role for galectin-1 in monocyte chemotaxis which differs from galectin-3 in that macrophages are nonresponsive. Furthermore, our observations suggest that galectin-1 may be involved in chemoattraction at sites of inflammation in vivo and may contribute to disease processes such as atherosclerosis.

Stented coronary angioplasty is the procedure of choice to re-establish patency in obstructed coronary arteries. However, the stent implantation procedure often leads to in-stent restenosis, a process that is characterized by stent strut colonization by macrophages and smooth muscle cells and by neointima formation. The present in vitro study investigates the effect of stent materials on the phenotypical features of monocyte/macrophages. Human peripheral blood monocytes from healthy donors (n = 7) were cultured up to 7 days on substrates mimicking: (i) the stent surface (i.e., electropolished stainless steel), (ii) the de-endothelialized vessel wall (collagen-based extracellular matrix gel), and (iii) thrombus (i.e., fibrin gel). The cells were analyzed by immunocytochemistry for their ability to express alpha-actin, a typical myofibroblast marker, by ELISA to determine PDGF-BB and TGF-beta1 secretion and by PCR to evaluate hyaluronan synthase 1, 2, and 3 genes expression. Data were statistically analyzed by ANOVA (Dunnett's test) and data considered significantly different at p