Effectiveness of Liposomal Bupivacaine With Bupivacaine Hydrochloride vs Bupivacaine Hydrochloride Alone as a Local Anesthetic for Children Undergoing Ambulatory Urologic Surgery: The Baby ORIOLES Randomized Clinical Trial.

PURPOSE: We sought to determine if the addition of liposomal bupivacaine to bupivacaine hydrochloride improves opioid-free rate and postoperative pain scores among children undergoing ambulatory urologic surgery. MATERIALS AND METHODS: A prospective, phase 3, single-blinded, single-center randomized trial with superiority design was conducted in children 6 to 18 years undergoing ambulatory urologic procedures between October 2021 and April 2023. Patients were randomized 1:1 to receive dorsal penile nerve block (penile procedures) or incisional infiltration with spermatic cord block (inguinal/scrotal procedures) with weight-based liposomal bupivacaine plus bupivacaine hydrochloride or bupivacaine hydrochloride alone. The primary outcome was opioid-free rate at 48 hours. Secondary outcomes included parents' postoperative pain measure scores, numerical pain scale scores, and weight-based opioid utilization at 48 hours and 10 to 14 days. RESULTS: We randomized 104 participants, with > 98% (102/104) with complete follow-up data at 48 hours and 10 to 14 days. At interim analysis, there was no significant difference in opioid-free rate at 48 hours between arms (60% in the intervention vs 62% in the control group; estimated difference in proportion -1.9% [95% CI, -20%-16%]; P = .8). We observed no increased odds of patients being opioid-free at 48 hours with the intervention compared to the control group (OR 0.96 [95% CI 0.41-2.3]; P = .9). The trial met the predetermined futility threshold for early stopping. There was no difference in parents' postoperative pain measure scores, numerical pain scale scores, or opioid utilization at 48 hours or 10 to 14 days. No difference in adverse events was observed. CONCLUSIONS: The addition of liposomal bupivacaine to bupivacaine hydrochloride did not significantly improve opioid-sparing effect or postoperative pain compared with bupivacaine hydrochloride alone among children ≥ 6 years undergoing ambulatory urologic surgery.

"Everyone screens to some extent": Barriers and facilitators of developmental screening among children with sickle cell disease: A mixed methods study.

BACKGROUND: Developmental delays are common among children with sickle cell disease (SCD). Existing guidelines support consistent screening to increase the identification of deficits and support referral to rehabilitative interventions, yet adherence remains variable. This study sought to assess current practices and identify barriers and facilitators to improve developmental screening for children 0-3 years with SCD. PROCEDURE: A mixed methods approach, guided by the Exploration and Preparation stages of the Exploration, Preparation, Implementation, and Sustainment (EPIS) framework, assessed developmental screening practices among primary care providers and hematologists. Phase 1 included the SCD Developmental Surveillance and Screening Guideline and Practice Survey. Phase 2 included the SCD Developmental Screening Organizational Survey alongside semi-structured interviews. Descriptive and qualitative methods summarized the findings. RESULTS: Thirty-three providers from general pediatrics and hematology completed phase 1. Use of standardized developmental screening measures was variable, with the most frequently used being the Modified Checklist for Autism in Toddlers (77%) and the Ages and Stages Questionnaire (55%). Fifteen providers participated in phase 2, and reported they were most likely to engage in changes to improve their practice (mean = 4.4/5) and least likely to support spiritual health and well-being (mean = 3.5/5). Three themes emerged:(i) developmental screening is not standardized or specific to SCD, (ii) children with SCD benefit from a multidisciplinary team, and (iii) healthcare system limitations are a barrier. CONCLUSIONS: Developmental screening is inconsistent and insufficient for young children with SCD. Providers are interested in supporting children with SCD, but report a lack of standardized measures and consistent guidance as barriers.

Urological outcomes in adult females born with anorectal malformation or Hirschsprung disease.

INTRODUCTION: Women born with anorectal malformation (ARM) or Hirschsprung disease (HD) may have impaired urologic function resulting in sequelae in adulthood. This study assessed and compared self-reported urinary outcomes in adult females born with ARM or HD to a reference population. METHODS: This was an IRB approved, cross-sectional study of female-born patients with ARM or HD, who completed surveys between November 2021 and August 2022. Female patients between the ages of 18 and 80 years were included. Lower Urinary Tract Symptom Questionnaires were administered through REDCap and the responses were compared to a reference population using Chi-squared or Fisher's exact tests. RESULTS: Sixty-six born female patients answered the questionnaires, two of them identified as non-binary. The response rate was 76%. Median age was 31.6 years. The majority were born with cloaca (56.3%), followed by other type of ARMs (28.1%), complex malformation (9.4%), and HD (6.3%). A history of bladder reconstruction was present for 26.6%. Catheterization through a channel or native urethra was present in 18.8%. Two had ureterostomies and were excluded from the analysis. Seven had chronic kidney disease or end-stage renal disease, three with a history of kidney transplantation. Patients with cloaca had significantly higher rates of urinary incontinence, urinary tract infection, and social problems due to impaired urological functioning, when compared to an age-matched reference population (Table 3). CONCLUSION: This study emphasizes the need for a multi-disciplinary team that includes urology and nephrology following patients with ARM long term, especially within the subgroup of cloaca. LEVEL OF EVIDENCE: III.

Afferent loss, GABA, and Central Gain in older adults: Associations with speech recognition in noise.

Deficits in auditory nerve (AN) function for older adults reduce afferent input to the cortex. The extent to which the cortex in older adults adapts to this loss of afferent input and the mechanisms underlying this adaptation are not well understood. We took a neural systems approach measuring AN and cortical evoked responses within 50 older and 27 younger human adults (59 female) to estimate central gain, or increased cortical activity despite reduced AN activity. Relative to younger adults, older adults' AN response amplitudes were smaller, but cortical responses were not. We used the relationship between AN and cortical response amplitudes in younger adults to predict cortical response amplitudes for older adults from their AN responses. Central gain in older adults was thus defined as the difference between their observed cortical responses and those predicted from the parameter estimates of younger adults. In older adults, decreased afferent input contributed to lower cortical GABA levels, greater central gain, and poorer speech recognition in noise (SIN). These effects on SIN occur in addition to, and independent from, effects attributed to elevated hearing thresholds. Our results are consistent with animal models of central gain and suggest that reduced AN afferent input in some older adults may result in changes in cortical encoding and inhibitory neurotransmission, which contribute to reduced SIN. An advancement in our understanding of the changes that occur throughout the auditory system in response to the gradual loss of input with increasing age may provide potential therapeutic targets for intervention.Significance:Age-related hearing loss is one of the most common chronic conditions of aging, yet little is known about how the cortex adapts to this loss of sensory input. We measured AN and cortical responses to the same stimulus in younger and older adults. In older adults we found hyperexcitability in cortical activity relative to concomitant declines in afferent input that are consistent with central gain Lower levels of cortical GABA, an inhibitory neurotransmitter was associated with greater central gain, which predicted poorer SIN. The results suggest that the cortex in older adults may adapt to attenuated sensory input by reducing inhibition to amplify the cortical response, but this amplification may lead to poorer SIN.

Peripheral Auditory Nerve Impairment in a Mouse Model of Syndromic Autism.

Dysfunction of the peripheral auditory nerve (AN) contributes to dynamic changes throughout the central auditory system, resulting in abnormal auditory processing, including hypersensitivity. Altered sound sensitivity is frequently observed in autism spectrum disorder (ASD), suggesting that AN deficits and changes in auditory information processing may contribute to ASD-associated symptoms, including social communication deficits and hyperacusis. The MEF2C transcription factor is associated with risk for several neurodevelopmental disorders, and mutations or deletions of MEF2C produce a haploinsufficiency syndrome characterized by ASD, language, and cognitive deficits. A mouse model of this syndromic ASD (Mef2c-Het) recapitulates many of the MEF2C haploinsufficiency syndrome-linked behaviors, including communication deficits. We show here that Mef2c-Het mice of both sexes exhibit functional impairment of the peripheral AN and a modest reduction in hearing sensitivity. We find that MEF2C is expressed during development in multiple AN and cochlear cell types; and in Mef2c-Het mice, we observe multiple cellular and molecular alterations associated with the AN, including abnormal myelination, neuronal degeneration, neuronal mitochondria dysfunction, and increased macrophage activation and cochlear inflammation. These results reveal the importance of MEF2C function in inner ear development and function and the engagement of immune cells and other non-neuronal cells, which suggests that microglia/macrophages and other non-neuronal cells might contribute, directly or indirectly, to AN dysfunction and ASD-related phenotypes. Finally, our study establishes a comprehensive approach for characterizing AN function at the physiological, cellular, and molecular levels in mice, which can be applied to animal models with a wide range of human auditory processing impairments.SIGNIFICANCE STATEMENT This is the first report of peripheral auditory nerve (AN) impairment in a mouse model of human MEF2C haploinsufficiency syndrome that has well-characterized ASD-related behaviors, including communication deficits, hyperactivity, repetitive behavior, and social deficits. We identify multiple underlying cellular, subcellular, and molecular abnormalities that may contribute to peripheral AN impairment. Our findings also highlight the important roles of immune cells (e.g., cochlear macrophages) and other non-neuronal elements (e.g., glial cells and cells in the stria vascularis) in auditory impairment in ASD. The methodological significance of the study is the establishment of a comprehensive approach for evaluating peripheral AN function and impact of peripheral AN deficits with minimal hearing loss.

Development of benchmark datasets for text mining and sentiment analysis to accelerate regulatory literature review.

In the field of regulatory science, reviewing literature is an essential and important step, which most of the time is conducted by manually reading hundreds of articles. Although this process is highly time-consuming and labor-intensive, most output of this process is not well transformed into machine-readable format. The limited availability of data has largely constrained the artificial intelligence (AI) system development to facilitate this literature reviewing in the regulatory process. In the past decade, AI has revolutionized the area of text mining as many deep learning approaches have been developed to search, annotate, and classify relevant documents. After the great advancement of AI algorithms, a lack of high-quality data instead of the algorithms has recently become the bottleneck of AI system development. Herein, we constructed two large benchmark datasets, Chlorine Efficacy dataset (CHE) and Chlorine Safety dataset (CHS), under a regulatory scenario that sought to assess the antiseptic efficacy and toxicity of chlorine. For each dataset, ∼10,000 scientific articles were initially collected, manually reviewed, and their relevance to the review task were labeled. To ensure high data quality, each paper was labeled by a consensus among multiple experienced reviewers. The overall relevance rate was 27.21% (2,663 of 9,788) for CHE and 7.50% (761 of 10,153) for CHS, respectively. Furthermore, the relevant articles were categorized into five subgroups based on the focus of their content. Next, we developed an attention-based classification language model using these two datasets. The proposed classification model yielded 0.857 and 0.908 of Area Under the Curve (AUC) for CHE and CHS dataset, respectively. This performance was significantly better than permutation test (p < 10E-9), demonstrating that the labeling processes were valid. To conclude, our datasets can be used as benchmark to develop AI systems, which can further facilitate the literature review process in regulatory science.

Mapping parents' journey following prenatal diagnosis of CHD: a qualitative study.

OBJECTIVE: To better understand parents' accounts of their prenatal and postnatal experience after prenatal diagnosis of CHD - particularly emotional processing and coping mechanisms - to identify strategies to improve support. METHODS: This single-centre, longitudinal qualitative study included pregnant mothers and their support persons seen in Fetal Cardiology Clinic at Vanderbilt Children's Hospital from May through August 2019 for probable complex CHD. Twenty-seven individuals from 17 families participated in 62 phone interviews during pregnancy and postpartum: 27 conducted after the initial prenatal cardiology consultation, 15 after a follow-up prenatal visit, and 20 after birth. Applied thematic analysis approach was used to code and analyse transcribed interviews. Coding and codebook revisions occurred iteratively; intercoder reliability was >80%. RESULTS: Patients included mothers (16 [59%]), fathers (8 [30%]), and other support persons (3 [11%]). Initial fetal diagnoses included a range of moderate to severe CHD. Prenatally, parents sought to maintain hope while understanding the diagnosis; planning for the future rather than focusing on day-to-day was more common if prognoses were better. Postnatally, with confirmation of prenatal diagnoses, parents' sense of control expanded, and they desired more active engagement in clinical decision making. CONCLUSIONS: To enhance effective communication and support, understanding how parents conceptualise hope in relation to diagnosis and how that may evolve over time is critical. Expectant parents whose child has a significant risk of mortality may demonstrate hope by focusing on positivity. As prognostic uncertainty diminishes postpartum, the parental role on the team may shift, requiring clinicians to provide different support.

Neural Presbyacusis in Humans Inferred from Age-Related Differences in Auditory Nerve Function and Structure.

A common complaint of older adults is difficulty understanding speech, particularly in challenging listening conditions. Accumulating evidence suggests that these difficulties may reflect a loss and/or dysfunction of auditory nerve (AN) fibers. We used a novel approach to study age-related changes in AN structure and several measures of AN function, including neural synchrony, in 58 older adults and 42 younger adults. AN activity was measured in response to an auditory click (compound action potential; CAP), presented at stimulus levels ranging from 70 to 110 dB pSPL. Poorer AN function was observed for older than younger adults across CAP measures at higher but not lower stimulus levels. Associations across metrics and stimulus levels were consistent with age-related AN disengagement and AN dyssynchrony. High-resolution T2-weighted structural imaging revealed age-related differences in the density of cranial nerve VIII, with lower density in older adults with poorer neural synchrony. Individual differences in neural synchrony were the strongest predictor of speech recognition, such that poorer synchrony predicted poorer recognition of time-compressed speech and poorer speech recognition in noise for both younger and older adults. These results have broad clinical implications and are consistent with an interpretation that age-related atrophy at the level of the AN contributes to poorer neural synchrony and may explain some of the perceptual difficulties of older adults.SIGNIFICANCE STATEMENT Differences in auditory nerve (AN) pathophysiology may contribute to the large variations in hearing and communication abilities of older adults. However, current diagnostics focus largely on the increase in detection thresholds, which is likely because of the absence of indirect measures of AN function in standard clinical test batteries. Using novel metrics of AN function, combined with estimates of AN structure and auditory function, we identified age-related differences across measures that we interpret to represent age-related reductions in AN engagement and poorer neural synchrony. Structure-function associations are consistent with an explanation of AN deficits that arise from age-related atrophy of the AN. Associations between neural synchrony and speech recognition suggest that individual and age-related deficits in neural synchrony contribute to speech recognition deficits.

Two distinct types of nodes of Ranvier support auditory nerve function in the mouse cochlea.

The auditory nerve (AN) of the inner ear is the primary conveyor of acoustic information from sensory hair cells to the brainstem. Approximately 95% of peripheral AN fibers are myelinated by glial cells. The integrity of myelin and the glial-associated paranodal structures at the node of Ranvier is critical for normal AN activity and axonal survival and function in the central auditory nervous system. However, little is known about the node of Ranvier's spatiotemporal development in the AN, how the aging process (or injury) affects the activity of myelinating glial cells, and how downstream alterations in myelin and paranodal structure contribute to AN degeneration and sensorineural hearing loss. Here, we characterized two types of Ranvier nodes-the axonal node and the ganglion node-in the mouse peripheral AN, and found that they are distinct in several features of postnatal myelination and age-related degeneration. Cellular, molecular, and structure-function correlations revealed that the two node types are each critical for different aspects of peripheral AN function. Neural processing speed and synchrony is associated with the length of the axonal node, while stimulus level-dependent amplitude growth and action potentials are associated with the ganglion node. Moreover, our data indicate that dysregulation of glial cells (e.g., satellite cells) and degeneration of the ganglion node structure are an important new mechanism of age-related hearing loss.

Sensory tetanisation to induce long-term-potentiation-like plasticity: A review and reassessment of the approach.

There is great interest in developing non-invasive approaches for studying cortical plasticity in humans. High-frequency presentation of auditory and visual stimuli, or sensory tetanisation, can induce long-term-potentiation-like (LTP-like) changes in cortical activity. However, contrasting effects across studies suggest that sensory tetanisation may be unreliable. We review these contrasting effects, conduct our own study of auditory and visual tetanisation, and perform meta-analyses to determine the average effect of sensory tetanisation across studies. We measured auditory-evoked amplitude changes in a group of younger (18-29 years of age) and older (55-83 years of age) adults following tetanisation to 1 and 4 kHz tone bursts and following a slow-presentation control. We also measured visual-evoked amplitude changes following tetanisation to horizontal and vertical sign gradients. Auditory and visual response amplitudes decreased following tetanisation, consistent with some studies but contrasting with others finding amplitude increases (i.e. LTP-like changes). Older adults exhibited more modest auditory-evoked amplitude decreases, but visual-evoked amplitude decreases like those of younger adults. Changes in response amplitude were not specific to tetanised stimuli. Importantly, slow presentation of auditory tone bursts produced response amplitude changes approximating those observed following tetanisation in younger adults. Meta-analyses of visual and auditory tetanisation studies found that the overall effect of sensory tetanisation was not significant across studies or study sites. The results suggest that sensory tetanisation may not produce reliable changes in cortical responses and more work is needed to determine the validity of sensory tetanisation as a method for inducing human cortical plasticity in vivo.

Assessing COVID-19 testing strategies in K-12 schools in underserved populations: study protocol for a cluster-randomized trial.

BACKGROUND: Since March 2020, COVID-19 has disproportionately impacted communities of color within the United States. As schools have shifted from virtual to in-person learning, continual guidance is necessary to understand appropriate interventions to prevent SARS-CoV-2 transmission. Weekly testing of students and staff for SARS-CoV-2 within K-12 school setting could provide an additional barrier to school-based transmission, especially within schools unable to implement additional mitigation strategies and/or are in areas of high transmission. This study seeks to understand the role that weekly SARS-CoV-2 testing could play in K-12 schools. In addition, through qualitative interviews and listening sessions, this research hopes to understand community concerns and barriers regarding COVID-19 testing, COVID-19 vaccine, and return to school during the COVID-19 pandemic. METHODS/DESIGN: Sixteen middle and high schools from five school districts have been randomized into one of the following categories: (1) Weekly screening + symptomatic testing or (2) Symptomatic testing only. The primary outcome for this study will be the average of the secondary attack rate of school-based transmission per case. School-based transmission will also be assessed through qualitative contact interviews with positive contacts identified by the school contact tracers. Lastly, new total numbers of weekly cases and contacts within a school-based quarantine will provide guidance on transmission rates. Qualitative focus groups and interviews have been conducted to provide additional understanding to the acceptance of the intervention and barriers faced by the community regarding SARS-CoV-2 testing and vaccination. DISCUSSION: This study will provide greater understanding of the benefit that weekly screening testing can provide in reducing SARS-CoV-2 transmission within K-12 schools. Close collaboration with community partners and school districts will be necessary for the success of this and similar studies. TRIAL REGISTRATION: NCT04875520 . Registered May 6, 2021.

Optimizing non-invasive functional markers for cochlear deafferentation based on electrocochleography and auditory brainstem responses.

Accumulating evidence suggests that cochlear deafferentation may contribute to suprathreshold deficits observed with or without elevated hearing thresholds, and can lead to accelerated age-related hearing loss. Currently there are no clinical diagnostic tools to detect human cochlear deafferentation in vivo. Preclinical studies using a combination of electrophysiological and post-mortem histological methods clearly demonstrate cochlear deafferentation including myelination loss, mitochondrial damages in spiral ganglion neurons (SGNs), and synaptic loss between inner hair cells and SGNs. Since clinical diagnosis of human cochlear deafferentation cannot include post-mortem histological quantification, various attempts based on functional measurements have been made to detect cochlear deafferentation. So far, those efforts have led to inconclusive results. Two major obstacles to the development of in vivo clinical diagnostics include a lack of standardized methods to validate new approaches and characterize the normative range of repeated measurements. In this overview, we examine strategies from previous studies to detect cochlear deafferentation from electrocochleography and auditory brainstem responses. We then summarize possible approaches to improve these non-invasive functional methods for detecting cochlear deafferentation with a focus on cochlear synaptopathy. We identify conceptual approaches that should be tested to associate unique electrophysiological features with cochlear deafferentation.

Benzo(a)pyrene-induced cytotoxicity, cell proliferation, DNA damage, and altered gene expression profiles in HT-29 human colon cancer cells.

In the US alone, around 60,000 lives/year are lost to colon cancer. In order to study the mechanisms of colon carcinogenesis, in vitro model systems are required in addition to in vivo models. Towards this end, we have used the HT-29 colon cancer cells, cultured in Dulbecco's Modified Eagle Medium (DMEM), which were exposed to benzo(a)pyrene (BaP), a ubiquitous and prototypical environmental and dietary toxicant at 1, 10, 100 nM and 1, 5, 10, and 25 µM concentrations for 96 h. Post-BaP exposure, growth, cytotoxicity, apoptosis, and cell cycle changes were determined. The BaP metabolite concentrations in colon cells were identified and measured. Furthermore, the BaP biotransformation enzymes were studied at the protein and mRNA levels. The BaP exposure-induced damage to DNA was assessed by measuring the oxidative damage to DNA and the concentrations of BaP-DNA adducts. To determine the whole repertoire of genes that are up- or downregulated by BaP exposure, mRNA transcriptome analysis was conducted. There was a BaP exposure concentration (dose)-dependent decrease in cell growth, cytotoxicity, and modulation of the cell cycle in the treatment groups compared to untreated or dimethylsulfoxide (DMSO: vehicle for BaP)-treated categories. The phase I biotransformation enzymes, CYP1A1 and 1B1, showed BaP concentration-dependent expression. On the other hand, phase II enzymes did not exhibit any marked variation. Consistent with the expression of phase I enzymes, elevated concentrations of BaP metabolites were generated, contributing to the formation of DNA lesions and stable DNA adducts, which were also BaP concentration-dependent. In summary, our studies established that biotransformation of BaP contributes to cytotoxicity, proliferation of tumor cells, and alteration of gene expression by BaP. • Benzo(a)pyrene (BaP) is an environmental and dietary toxicant. • BaP causes cytotoxicity in cultured HT-29 colon cancer cells. • mRNA transcriptome analyses revealed that BaP impacts cell growth, cell cycle, biotransformation, and DNA damage.

Intra- and interhemispheric white matter tract associations with auditory spatial processing: Distinct normative and aging effects.

Declining auditory spatial processing is hypothesized to contribute to the difficulty older adults have detecting, locating, and selecting a talker from among others in noisy listening environments. Though auditory spatial processing has been associated with several cortical structures, little is known regarding the underlying white matter architecture or how age-related changes in white matter microstructure may affect it. The arcuate fasciculus is a target for understanding age-related differences in auditory spatial attention based on normative spatial attention findings in humans. Similarly, animal and human clinical studies suggest that the corpus callosum plays a role in the cross-hemispheric integration of auditory spatial information important for spatial localization and attention. The current investigation used diffusion imaging to examine the extent to which age-group differences in the identification of spatially cued speech were accounted for by individual differences in the white matter microstructure of the right arcuate fasciculus and the corpus callosum. Higher right arcuate and callosal fractional anisotropy (FA) predicted better segregation and identification of spatially cued speech across younger and older listeners. Further, individual differences in callosal microstructure mediated age-group differences in auditory spatial processing. Follow-up analyses suggested that callosal tracts connecting left and right pre-frontal and posterior parietal cortex are particularly important for auditory spatial processing. The results are consistent with previous work in animals and clinical human samples and provide a cortical mechanism to account for age-related deficits in auditory spatial processing. Further, the results suggest that both intrahemispheric and interhemispheric mechanisms are involved in auditory spatial processing.

Cingulo-opercular adaptive control for younger and older adults during a challenging gap detection task.

Cingulo-opercular activity is hypothesized to reflect an adaptive control function that optimizes task performance through adjustments in attention and behavior, and outcome monitoring. While auditory perceptual task performance appears to benefit from elevated activity in cingulo-opercular regions of frontal cortex before stimuli are presented, this association appears reduced for older adults compared to younger adults. However, adaptive control function may be limited by difficult task conditions for older adults. An fMRI study was used to characterize adaptive control differences while 15 younger (average age = 24 years) and 15 older adults (average age = 68 years) performed a gap detection in noise task designed to limit age-related differences. During the fMRI study, participants listened to a noise recording and indicated with a button-press whether it contained a gap. Stimuli were presented between sparse fMRI scans (TR = 8.6 s) and BOLD measurements were collected during separate listening and behavioral response intervals. Age-related performance differences were limited by presenting gaps in noise with durations calibrated at or above each participant's detection threshold. Cingulo-opercular BOLD increased significantly throughout listening and behavioral response intervals, relative to a resting baseline. Correct behavioral responses were significantly more likely on trials with elevated pre-stimulus cingulo-opercular BOLD, consistent with an adaptive control framework. Cingulo-opercular adaptive control estimates appeared higher for participants with better gap sensitivity and lower response bias, irrespective of age, which suggests that this mechanism can benefit performance across the lifespan under conditions that limit age-related performance differences.

Urinary Continence Outcomes in Classic Bladder Exstrophy: A Long-Term Perspective.

PURPOSE: We investigated surgical approaches to urinary incontinence and long-term continence outcomes after successful bladder reconstruction in a heterogeneous patient population with classic bladder exstrophy. We hypothesized that while most patients will achieve urinary continence after surgery, only a select group will void volitionally per urethra. MATERIALS AND METHODS: An institutional database of 1,323 patients with exstrophy-epispadias complex was reviewed for patients with classic bladder exstrophy who underwent successful bladder closure and a subsequent continence procedure between 1975 and 2017. Procedures included bladder neck reconstruction, bladder neck reconstruction with augmentation cystoplasty or continent catheterizable stoma, and bladder neck closure with continent catheterizable stoma. Cloacal exstrophy, epispadias and variant exstrophy cases were excluded from analysis. Continence at last followup was defined as a dry interval of 3 or more hours without nighttime leakage. Those patients with more than 3 months of followup were assessed. RESULTS: Overall 432 patients underwent successful bladder closure (primary 71.5%, repeat 28.5%) and a urinary continence procedure. At last followup 162 (37%) underwent bladder neck reconstruction, 76 (18%) underwent bladder neck reconstruction with augmentation cystoplasty or continent catheterizable stoma, 173 (40%) underwent bladder neck closure with continent catheterizable stoma and 18 underwent other procedures. Median followup from the first continence procedure was 7.2 years (IQR 2.3-13.7). Continence was assessed in 350 patients. After isolated bladder neck reconstruction 91 of 142 patients were continent (64%, 95% CI 56-72). After bladder neck closure with continent catheterizable stoma 124 of 133 patients evaluated were continent (93%, 95% CI 87-97). CONCLUSIONS: Most patients with classic bladder exstrophy require multiple reconstructive procedures to achieve continence. Only about 25% of patients are expected to void normally per urethra without reliance on catheterization or urinary diversion.

Sustained envelope periodicity representations are associated with speech-in-noise performance in difficult listening conditions for younger and older adults.

Temporal modulations are an important part of speech signals. An accurate perception of these time-varying qualities of sound is necessary for successful communication. The current study investigates the relationship between sustained envelope encoding and speech-in-noise perception in a cohort of normal-hearing younger (ages 18-30 yr, n = 22) and older adults (ages 55-90+ yr, n = 35) using the subcortical auditory steady-state response (ASSR). ASSRs were measured in response to the envelope of 400-ms amplitude-modulated (AM) tones with 3,000-Hz carrier frequencies and 80-Hz modulation frequencies. AM tones had modulation depths of 0, -4, and -8 dB relative to m = 1 (m = 1, 0.631, and 0.398, respectively). The robustness, strength at modulation frequency, and synchrony of subcortical envelope encoding were quantified via time-domain correlations, spectral amplitude, and phase-locking value, respectively. Speech-in-noise ability was quantified via the QuickSIN test in the 0- and 5-dB signal-to-noise (SNR) conditions. All ASSR metrics increased with increasing modulation depth and there were no effects of age group. ASSR metrics in response to shallow modulation depths predicted 0-dB speech scores. Results demonstrate that sustained amplitude envelope processing in the brainstem relates to speech-in-noise abilities, but primarily in difficult listening conditions at low SNRs. These findings furthermore highlight the utility of shallow modulation depths for studying temporal processing. The absence of age effects in these data demonstrate that individual differences in the robustness, strength, and specificity of subcortical envelope processing, and not age, predict speech-in-noise performance in the most difficult listening conditions.NEW & NOTEWORTHY Failure to correctly understand speech in the presence of background noise is a significant problem for many normal-hearing adults and may impede healthy communication. The relationship between sustained envelope encoding in the brainstem and speech-in-noise perception remains to be clarified. The present study demonstrates that the strength, specificity, and robustness of the brainstem's representations of sustained stimulus periodicity relates to speech-in-noise perception in older and younger normal-hearing adults, but only in highly challenging listening environments.

Complementary metrics of human auditory nerve function derived from compound action potentials.

Declines in auditory nerve (AN) function contribute to suprathreshold auditory processing and communication deficits in individuals with normal hearing, hearing loss, hyperacusis, and tinnitus. Procedures to characterize AN loss or dysfunction in humans are limited. We report several novel complementary metrics using the compound action potential (CAP), a direct measure of summated AN activity. Together, these metrics may be used to characterize AN function noninvasively in humans. We examined how these metrics change with stimulus intensity and interpreted these changes within a framework of known physiological properties of the basilar membrane and AN. Our results reveal how neural synchrony and the recruitment of AN fibers with longer first-spike latencies likely contribute to the CAP, affect auditory processing, and differ with noise exposure history in younger adults with normal pure-tone thresholds. Moving forward, this new battery of metrics provides a crucial step toward new diagnostics of AN function in humans. NEW & NOTEWORTHY Loss or inactivity of auditory nerve (AN) fibers is thought to contribute to suprathreshold auditory processing deficits, but evidence-based methods to assess these effects are not available. We describe several novel metrics that together may be used to quantify neural synchrony and characterize AN function in humans.

Adherence to National Comprehensive Cancer Network® Guidelines for Testicular Cancer.

PURPOSE: Testicular cancer is the most common malignancy among young men and well established treatment guidelines exist to optimize outcomes. We characterized errors in the management of testicular cancer observed among patients seen at 3 referral centers in the United States. MATERIALS AND METHODS: We retrospectively reviewed data from 593 patients presenting with testicular cancer to 3 academic medical centers from 2007 to 2016. Nonguideline directed care was defined as management differing from National Comprehensive Care Network guideline recommendations. Cases of nonguideline directed care were systematically described. Patient and tumor characteristics were compared between guideline directed care and nonguideline directed care. Multivariable logistic regression was used to identify predictors of nonguideline directed care, and Cox regression modeling was used to assess the association between nonguideline directed care and relapse-free survival. RESULTS: Nonguideline directed care was identified in 177 of 593 (30%) patients. Inappropriate imaging (44%) and overtreatment (40%) were the most common classifications. Misdiagnosis (24%) and under treatment (16%) occurred relatively frequently, while inappropriate treatment (6%) was rare. Multivariable Cox regression modeling controlling for race, tumor stage and tumor histology identified nonguideline directed care as a significant predictor of relapse (HR 2.49, 95% CI 1.61-3.85, p <0.01). CONCLUSIONS: Nonguideline directed care of patients with testicular cancer is common, most frequently in the form of inappropriate imaging and overtreatment. Nonguideline directed care leads to delayed definitive therapy, unnecessary morbidity and higher rates of relapse.