Single-cell genomics and regulatory networks for 388 human brains.

Single-cell genomics is a powerful tool for studying heterogeneous tissues such as the brain. Yet little is understood about how genetic variants influence cell-level gene expression. Addressing this, we uniformly processed single-nuclei, multiomics datasets into a resource comprising >2.8 million nuclei from the prefrontal cortex across 388 individuals. For 28 cell types, we assessed population-level variation in expression and chromatin across gene families and drug targets. We identified >550,000 cell type-specific regulatory elements and >1.4 million single-cell expression quantitative trait loci, which we used to build cell-type regulatory and cell-to-cell communication networks. These networks manifest cellular changes in aging and neuropsychiatric disorders. We further constructed an integrative model accurately imputing single-cell expression and simulating perturbations; the model prioritized ~250 disease-risk genes and drug targets with associated cell types.

The role of long-term target and masker talker familiarity in children's speech-in-speech recognition.

Objectives: This study investigated the influence of long-term talker familiarity on speech-in-speech recognition in school-age children, with a specific emphasis on the role of familiarity with the mother's voice as either the target or masker speech. Design: Open-set sentence recognition was measured adaptively in a two-talker masker. Target and masker sentences were recorded by the adult mothers of the child participants. Each child heard sentences spoken by three adult female voices during testing; their own mother's voice (familiar voice) and two unfamiliar adult female voices. Study sample: Twenty-four school age children (8-13 years) with normal hearing. Results: When the target speech was spoken by a familiar talker (the mother), speech recognition was significantly better compared to when the target was unfamiliar. When the masker was spoken by the familiar talker, there was no difference in performance relative to the unfamiliar masker condition. Across all conditions, younger children required a more favorable signal-to-noise ratio than older children. Conclusion: Implicit long-term familiarity with a talker consistently improves children's speech-in-speech recognition across the age range tested, specifically when the target talker is familiar. However, performance remains unaffected by masker talker familiarity. Additionally, while target familiarity is advantageous, it does not entirely eliminate children's increased susceptibility to competing speech.

Validation of Enhancer Regions in Primary Human Neural Progenitor Cells using Capture STARR-seq.

Genome-wide association studies (GWAS) and expression analyses implicate noncoding regulatory regions as harboring risk factors for psychiatric disease, but functional characterization of these regions remains limited. We performed capture STARR-sequencing of over 78,000 candidate regions to identify active enhancers in primary human neural progenitor cells (phNPCs). We selected candidate regions by integrating data from NPCs, prefrontal cortex, developmental timepoints, and GWAS. Over 8,000 regions demonstrated enhancer activity in the phNPCs, and we linked these regions to over 2,200 predicted target genes. These genes are involved in neuronal and psychiatric disease-associated pathways, including dopaminergic synapse, axon guidance, and schizophrenia. We functionally validated a subset of these enhancers using mutation STARR-sequencing and CRISPR deletions, demonstrating the effects of genetic variation on enhancer activity and enhancer deletion on gene expression. Overall, we identified thousands of highly active enhancers and functionally validated a subset of these enhancers, improving our understanding of regulatory networks underlying brain function and disease.

Single-cell genomics and regulatory networks for 388 human brains.

Single-cell genomics is a powerful tool for studying heterogeneous tissues such as the brain. Yet, little is understood about how genetic variants influence cell-level gene expression. Addressing this, we uniformly processed single-nuclei, multi-omics datasets into a resource comprising >2.8M nuclei from the prefrontal cortex across 388 individuals. For 28 cell types, we assessed population-level variation in expression and chromatin across gene families and drug targets. We identified >550K cell-type-specific regulatory elements and >1.4M single-cell expression-quantitative-trait loci, which we used to build cell-type regulatory and cell-to-cell communication networks. These networks manifest cellular changes in aging and neuropsychiatric disorders. We further constructed an integrative model accurately imputing single-cell expression and simulating perturbations; the model prioritized ~250 disease-risk genes and drug targets with associated cell types.

Catheter-tissue contact optimizes pulsed electric field ablation with a large area focal catheter.

INTRODUCTION: Pulsed electric field (PEF) ablation relies on the intersection of a critical voltage gradient with tissue to cause cell death. Field-based lesion formation with PEF technologies may still depend on catheter-tissue contact (CTC). The purpose of this study was to assess the impact of CTC on PEF lesion formation with an investigational large area focal (LAF) catheter in a preclinical model. METHODS: PEF ablation via a 10-spline LAF catheter was used to create discrete right ventricle (RV) lesions and atrial lesion sets in 10 swine (eight acute, two chronic). Local impedance (LI) was used to assess CTC. Lesions were assigned to three cohorts using LI above baseline: no tissue contact (NTC: ≤∆10 Ω, close proximity to tissue), low tissue contact (LTC: ∆11-29 Ω), and high tissue contact (HTC: ≥∆30 Ω). Acute animals were infused with triphenyl tetrazolium chloride (TTC) and killed ≥2 h post-treatment. Chronic animals were remapped 30 days post-index procedure and stained with infused TTC. RESULTS: Mean (± SD) RV treatment sizes between LTC (n = 14) and HTC (n = 17) lesions were not significantly different (depth: 5.65 ± 1.96 vs. 5.68 ± 2.05 mm, p = .999; width: 15.68 ± 5.22 vs. 16.98 ± 4.45 mm, p = .737), while mean treatment size for NTC lesions (n = 6) was significantly smaller (1.67 ± 1.16 mm depth, 5.97 ± 4.48 mm width, p < .05). For atrial lesion sets, acute and chronic conduction block were achieved with both LTC (N = 7) and HTC (N = 6), and NTC resulted in gaps. CONCLUSIONS: PEF ablation with a specialized LAF catheter in a swine model is dependent on CTC. LI as an indicator of CTC may aid in the creation of consistent transmural lesions in PEF ablation.

Can Playing a Game Improve Children's Speech Recognition? A Preliminary Study of Implicit Talker Familiarity Effects.

PURPOSE: The goal was to evaluate whether implicit talker familiarization via an interactive computer game, designed for this study, could improve children's word recognition in classroom noise. It was hypothesized that, regardless of age, children would perform better when recognizing words spoken by the talker who was heard during the game they played. METHOD: Using a one-group pretest-posttest experimental design, this study examined the impact of short-term implicit voice exposure on children's word recognition in classroom noise. Implicit voice familiarization occurred via an interactive computer game, played at home for 10 min a day for 5 days. In the game, children (8-12 years) heard one voice, intended to become the "familiar talker." Pre- and postfamiliarization, children identified words in prerecorded classroom noise. Four conditions were tested to evaluate talker familiarity and generalization effects. RESULTS: Results demonstrated an 11% improvement when recognizing words spoken by the voice heard in the game ("familiar talker"). This was observed only for words that were heard in the game and did not generalize to unfamiliarized words. Before familiarization, younger children had poorer recognition than older children in all conditions; however, after familiarization, there was no effect of age on performance for familiarized stimuli. CONCLUSIONS: Implicit short-term exposure to a talker has the potential to improve children's speech recognition. Therefore, leveraging talker familiarity through gameplay shows promise as a viable method for improving children's speech-in-noise recognition. However, given that improvements did not generalize to unfamiliarized words, careful consideration of exposure stimuli is necessary to optimize this approach.

Classroom Acoustics for Enhancing Students' Understanding When a Teacher Suffers From a Dysphonic Voice.

PURPOSE: The purpose of this project is to assess the acoustical conditions in which optimal intelligibility and low listening difficulty can be achieved in real classrooms for elementary students, taking into consideration the effects of dysphonic voice and typical classroom noise. METHOD: Speech intelligibility tests were performed in six elementary classrooms with 80 normal-hearing students aged 7-11 years. The speech material was produced by a female actor using a normal voice quality and simulating a dysphonic voice. The stimuli were played by a Head and Torso Simulator. Child babble noise and classrooms with different reverberation times were used to obtain a Speech Transmission Index (STI) range from 0.2 to 0.7, corresponding to the categories bad, poor, fair, and good. RESULTS: The results showed a statistically significant decrease in intelligibility when the speaker was dysphonic, in STI higher than 0.33. The rating of listening difficulty showed a significantly greater difficulty in perceiving the dysphonic voice. In addition, younger children showed poorer performance and greater listening difficulty compared with older children when listening to the normal voice quality. Both groups were equally impacted when the voice was dysphonic. CONCLUSIONS: The results suggested that better acoustic conditions are needed for children to reach a good level of intelligibility and to reduce listening difficulty if the teacher is suffering from voice problems. This was true for children regardless of grade level, highlighting the importance of ensuring more favorable acoustic conditions for children throughout all elementary schools. SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.23504487.

The effects of face masks on speech-in-speech recognition for children and adults.

OBJECTIVES: This study explored the effects of different face masks on school-age children's and young adults' word recognition. DESIGN: Speech recognition thresholds were measured adaptively in a two-talker speech masker using a closed-set picture pointing task. Target words were recorded by a female talker in five conditions: no mask, transparent mask, face shield, N95 mask and surgical mask. STUDY SAMPLES: Thirty children (8-12 years) and 25 adults (18-25 years) with normal hearing. RESULTS: Both children's and adults' word recognition was most negatively impacted by the face shield. Children's recognition was also impaired by the transparent mask. No negative effects were observed for the N95 or surgical mask for either age group. CONCLUSION: School-age children, like young adults, are negatively affected by face masks when recognising speech in a two-talker speech masker, but the effects depend on the type of face mask being worn. Acoustic analyses suggest that the reflective materials used for masks impact speech signal quality and impair word recognition.

Effects of Target and Masker Fundamental Frequency Contour Depth on School-Age Children's Speech Recognition in a Two-Talker Masker.

PURPOSE: Maturation of the ability to recognize target speech in the presence of a two-talker speech masker extends into early adolescence. This study evaluated whether children benefit from differences in fundamental frequency (f o) contour depth between the target and masker speech, a cue that has been shown to improve recognition in adults. METHOD: Speech stimuli were recorded from talkers using three speaking styles, with f o contour depths that were Flat, Normal, or Exaggerated. Targets were open-set, declarative sentences produced by a female talker, and maskers were two streams of concatenated sentences produced by a second female talker. Listeners were children (ages 5-17 years) and adults (ages 18-24 years) with normal hearing. Each listener was tested in one of the three masker styles paired with all three target styles. Speech recognition thresholds (SRTs) corresponding to 50% correct were estimated by fitting psychometric functions to adaptive track data. RESULTS: For adults, performance did not differ significantly across conditions with matched speaking styles. A mismatch benefit was observed when combining Flat targets with the Exaggerated masker and Exaggerated targets with the Flat masker, and for both Flat and Exaggerated targets paired with the Normal masker. For children, there was a significant effect of age in all conditions. Flat targets in the Flat masker were associated with lower SRTs than the other two matched conditions, and a mismatch benefit was observed for young children only when the target f o contour was less variable than the masker f o contour. CONCLUSIONS: Whereas child-directed speech often has exaggerated pitch contours, young children were better able to recognize speech with less variable f o. Age effects were observed in the benefit of mismatched speaking styles for some conditions, which could be related to differences in baseline SRTs rather than differences in segregation abilities.

Extended high-frequency hearing and head orientation cues benefit children during speech-in-speech recognition.

While the audible frequency range for humans spans approximately 20 Hz to 20 kHz, children display enhanced sensitivity relative to adults when detecting extended high frequencies (frequencies above 8 kHz; EHFs), as indicated by better pure tone thresholds. The impact that this increased hearing sensitivity to EHFs may have on children's speech recognition has not been established. One context in which EHF hearing may be particularly important for children is when recognizing speech in the presence of competing talkers. In the present study, we examined the extent to which school-age children (ages 5-17 years) with normal hearing were able to benefit from EHF cues when recognizing sentences in a two-talker speech masker. Two filtering conditions were tested: all stimuli were either full band or were low-pass filtered at 8 kHz to remove EHFs. Given that EHF energy emission in speech is highly dependent on head orientation of the talker (i.e., radiation becomes more directional with increasing frequency), two masker head angle conditions were tested: both co-located maskers were facing 45°, or both were facing 60° relative to the listener. The results demonstrated that regardless of age, children performed better when EHFs were present. In addition, a small change in masker head orientation also impacted performance, with better recognition at 60° compared to 45°. These findings suggest that EHF energy in the speech signal above 8 kHz is beneficial for children in complex listening situations. The magnitude of benefit from EHF cues and talker head orientation cues did not differ between children and adults. Therefore, while EHFs were beneficial for children as young as 5 years of age, children's generally better EHF hearing relative to adults did not provide any additional benefit.

Effects of Hearing Loss on School-Aged Children's Ability to Benefit From F0 Differences Between Target and Masker Speech.

OBJECTIVES: The objectives of the study were to (1) evaluate the impact of hearing loss on children's ability to benefit from F0 differences between target/masker speech in the context of aided speech-in-speech recognition and (2) to determine whether compromised F0 discrimination associated with hearing loss predicts F0 benefit in individual children. We hypothesized that children wearing appropriately fitted amplification would benefit from F0 differences, but they would not show the same magnitude of benefit as children with normal hearing. Reduced audibility and poor suprathreshold encoding that degrades frequency discrimination were expected to impair children's ability to segregate talkers based on F0. DESIGN: Listeners were 9 to 17 year olds with bilateral, symmetrical, sensorineural hearing loss ranging in degree from mild to severe. A four-alternative, forced-choice procedure was used to estimate thresholds for disyllabic word recognition in a 60-dB-SPL two-talker masker. The same male talker produced target and masker speech. Target words had either the same mean F0 as the masker or were digitally shifted higher than the masker by three, six, or nine semitones. The F0 benefit was defined as the difference in thresholds between the shifted-F0 conditions and the unshifted-F0 condition. Thresholds for discriminating F0 were also measured, using a three-alternative, three-interval forced choice procedure, to determine whether compromised sensitivity to F0 differences due to hearing loss would predict children's ability to benefit from F0. Testing was performed in the sound field, and all children wore their personal hearing aids at user settings. RESULTS: Children with hearing loss benefited from an F0 difference of nine semitones between target words and masker speech, with older children generally benefitting more than younger children. Some children benefitted from an F0 difference of six semitones, but this was not consistent across listeners. Thresholds for discriminating F0 improved with increasing age and predicted F0 benefit in the nine-semitone condition. An exploratory analysis indicated that F0 benefit was not significantly correlated with the four-frequency pure-tone average (0.5, 1, 2, and 4 kHz), aided audibility, or consistency of daily hearing aid use, although there was a trend for an association with the low-frequency pure-tone average (0.25 and 0.5 kHz). Comparisons of the present data to our previous study of children with normal hearing demonstrated that children with hearing loss benefitted less than children with normal hearing for the F0 differences tested. CONCLUSIONS: The results demonstrate that children with mild-to-severe hearing loss who wear hearing aids benefit from relatively large F0 differences between target and masker speech during aided speech-in-speech recognition. The size of the benefit increases with increasing age, consistent with previously reported age effects for children with normal hearing. However, hearing loss reduces children's ability to capitalize on F0 differences between talkers. Audibility alone does not appear to be responsible for this effect; aided audibility and degree of loss were not primary predictors of performance. The ability to benefit from F0 differences may be limited by immature central processing or aspects of peripheral encoding that are not characterized in standard clinical assessments.

Independent and Combined Effects of Fundamental Frequency and Vocal Tract Length Differences for School-Age Children's Sentence Recognition in a Two-Talker Masker.

Purpose The purpose of this study was to examine the independent and combined contributions of fundamental frequency (F0) and vocal tract length (VTL) differences on children's speech-in-speech recognition in the presence of a competing two-talker masker. Method Participants were 64 children (5-17 years old) and 25 adults (18-39 years old). Sentence recognition thresholds were measured in a two-talker masker. Target sentences had either the same mean F0 and VTL of the masker or were digitally altered so that the target and masker differed in F0 (Experiment 1), differed in VTL (Experiment 2), or differed in both F0 and VTL (Experiment 3). To determine the benefit, masking release was computed by subtracting thresholds in each shifted condition from the threshold in the unshifted condition. Results Results demonstrate that children's ability to benefit from either F0 or VTL differences (Experiments 1 and 2) depended on listener age, with younger children showing less improvement in speech reception thresholds compared to older children and adults. Age effects were also evident in the combined-cue conditions (Experiment 3), but children showed greater improvements compared to F0-only or VTL-only manipulations. Conclusions There was a prolonged pattern of development in children's ability to benefit from F0 or VTL differences between target and masker speech. Young children failed to capitalize on F0 and VTL differences to the same extent as older children and adults but did show a robust benefit when the cues were combined, supporting the hypothesis that younger children rely more heavily on redundant cues compared to older children and adults.

Attitudes, Provider and Treatment Selection of Complementary and Integrative Health among Individuals with Pain-Related Conditions.

Complementary and integrative therapies are used by people to address many conditions, including pain-related conditions. There has been concern about the quality of online health information, including information pertaining to complementary and integrative health (CIH). In this qualitative interview study, we sought to investigate how individuals interact with CIH-related information online and how this might affect their subsequent behavior. We conducted semi-structured interviews with 14 individuals with chronic pain conditions. We report findings based on three main themes: individuals' beliefs about CIH; approach to CIH, including how people view provider information and personalize their CIH use strategy; and factors that affect trust in the information encountered. Overall, study participants believed there was value in CIH therapies and that treatments were effective. Many described experiences that had influenced their views of complementary therapies over time. We also found that individuals form impressions of CIH providers based on structural and personal characteristics, particularly cost and proximity, that are conveyed in information to which they are exposed. These findings have various implications. First, over time individuals with chronic pain conditions develop their own beliefs and attitudes, which play a role in their selection of providers and modalities relating to CIH. Health care providers should consider how people view information relating to, and make decisions about, CIH therapies and work collaboratively with patients to develop effective health management strategies. Information services should also consider patients' perspectives in developing websites and other informational materials.

Patients' Health Information Practices and Perceptions of Provider Knowledge in the Case of the Newly Discovered Alpha-gal Food Allergy.

BACKGROUND: Alpha-gal food allergy is a life-threatening, newly discovered condition with limited presence in authoritative information sources. Sufferers seeking diagnosis are likely to encounter clinicians unfamiliar with the condition. OBJECTIVE: To understand information practices of individuals diagnosed with alpha-gal allergy, how they obtained diagnosis, and their perceptions of health-care providers' awareness of the condition. METHODS: Semistructured interviews with open- and closed-ended questions were completed with a chronological systematic sample of 28 adults (11% of alpha-gal clinic patients at the time) diagnosed with alpha-gal allergy and treated at University of North Carolina Allergy and Immunology Clinic. RESULTS: The majority of patients determined they had alpha-gal allergy through nontraditional health information channels. Three-quarters of patients rated their primary care provider as having little to no knowledge. In 25 specialists' encounters, 23 were rated as having little to no knowledge. CONCLUSION: With new conditions, information is often available through informal networks before appearing in the vetted medical literature. In this study, social connections were the primary pathway to successful diagnosis. Health practitioners need to develop mechanisms to understand that process.

Effects of Adaptive Hearing Aid Directionality and Noise Reduction on Masked Speech Recognition for Children Who Are Hard of Hearing.

Purpose The purpose of this study was to evaluate speech-in-noise and speech-in-speech recognition associated with activation of a fully adaptive directional hearing aid algorithm in children with mild to severe bilateral sensory/neural hearing loss. Method Fourteen children (5-14 years old) who are hard of hearing participated in this study. Participants wore laboratory hearing aids. Open-set word recognition thresholds were measured adaptively for 2 hearing aid settings: (a) omnidirectional (OMNI) and (b) fully adaptive directionality. Each hearing aid setting was evaluated in 3 listening conditions. Fourteen children with normal hearing served as age-matched controls. Results Children who are hard of hearing required a more advantageous signal-to-noise ratio than children with normal hearing to achieve comparable performance in all 3 conditions. For children who are hard of hearing, the average improvement in signal-to-noise ratio when comparing fully adaptive directionality to OMNI was 4.0 dB in noise, regardless of target location. Children performed similarly with fully adaptive directionality and OMNI settings in the presence of the speech maskers. Conclusions Compared to OMNI, fully adaptive directionality improved speech recognition in steady noise for children who are hard of hearing, even when they were not facing the target source. This algorithm did not affect speech recognition when the background noise was speech. Although the use of hearing aids with fully adaptive directionality is not proposed as a substitute for remote microphone systems, it appears to offer several advantages over fixed directionality, because it does not depend on children facing the target talker and provides access to multiple talkers within the environment. Additional experiments are required to further evaluate children's performance under a variety of spatial configurations in the presence of both noise and speech maskers.

Internet searching produces misleading findings regarding violent deaths in crisis settings: short report.

Donor and agency priorities are influenced by a variety of political, social, and media-related forces that can have a profound impact on response and resource provision. We have attempted to assess how well internet searches articulate the span of violent death rates for five current "crisis" settings. In three graduate classes (2 public health, 1 information science) at US universities, during a four month period in 2017-2018, we asked approximately 60 graduate students to conduct an internet search to determine which of five countries had the highest and lowest "violence specific mortality rate": Venezuela, Syria, Yemen, Central African Republic (CAR), or Mali. Students were divided into groups of three, and within each group explored this question by three approaches. Many graduate students in all groups could not determine the relative rates, especially which country had the lowest violence specific mortality rate. Of the 34 searches that identified a highest violent death rate country, 27.5 (81%) concluded it was Venezuela, followed by Syria (4.5; 13%), Mali (1; 3%) and CAR (1; 3%). Of the 26 searches that identified a least violent death rate 21.5 (83%) reported either CAR or Mali, followed by Yemen (2.5; 10%) and Syria (2; 8%). Aside from lack of data on CAR and Mali, students were perplexed about whether to include suicides or executions in the measure. This resulted in almost half of all inquiries unable to estimate a highest and lowest rate among these five countries. Where conclusions were drawn, it is likely the internet drew students to the opposite conclusion from reality. There are several reasons for this discordance, such as differing categories of violent deaths as defined by the World Health Organization, and search engine algorithms. It is probable, however, that larger issues of connectivity of individual societies with each other and the outside world are playing a profound role in the deceptive results found in this exercise. This insight emphasizes the internet's under-reporting in the world's most poor and remote locations, and highlights the importance of primary data collection and reporting in such settings.

Unpacking healthcare waste management at rural village health clinics in the Ntcheu District (Malawi).

Management of healthcare waste in low- and middle-income countries lacks a straightforward solution, especially where rural health services are provided. The purpose of our case study was to explore the knowledge and practices of health surveillance assistants operating at rural village health clinics in Ntcheu District, Malawi, with regard to the collection, segregation, transportion, treatment, and disposal of healthcare waste. Data were collected from 81 clinics. The results indicated that while general gaps in both knowledge and practice were observed, sharps (e.g., needles) management was generally being done well. An opportunity for scale-up was found in one clinic, in which local materials had been used to construct a low-cost innovative sharps disposal receptacle that had been modified from a pit latrine design. This study recommends waste management training suitable for rural settings, the promotion of low-cost sharps disposal receptacles using local materials, further opportunities for low-cost incinerators, central waste collection, and encouraging grassroots innovation in healthcare waste management.

Public Libraries: A Community-Level Resource to Advance Population Health.

Policy makers and public health practitioners rarely consider public libraries to be part of the health system, even though they possess several characteristics that suggest unrealized potential to advance population health. This scoping review uses an adapted social determinants framework to categorize current health-related work conducted by public libraries in the United States and to discuss libraries' potential as 'meso-level' community resources to improve population health. Our discussion of libraries contributes to scholarship on place-based health disparities, by emphasizing the potential impact of institutions that are modifiable through social policy-e.g., parks, community centers, schools-and which have a conceptually clear or empirically documented relationship to health.