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Models of the underwater acoustic soundscape are important for evaluating the effects of human generated sounds on marine life. The performance of models can be validated against measurements or verified against each other for consistency. A verification workshop was held to compare models that predict the soundscape from wind and vessels and estimate detection ranges for a submerged target. Eight modeling groups participated in the workshop which predicted sound levels with observation windows of 1 min and 1 km2. Substantial differences were found in how modelers computed the propagation losses for decidecade bands and estimated the source level of wind. Further investigations resulted in recommendations on best practices. Choices of temporal and spatial modeling resolution affected the estimates of metrics proportional to total sound energy more than distributions of sound pressure level. Deeper receivers were less sensitive to these parameters than shallow ones. A temporal resolution of 1 min and spatial resolution of 100 m is recommended. Models that follow the recommendations will yield similar results. The detection range of underwater targets is highly variable when the ambient noise depends on moving noise sources. Future work to verify models against data and understand model uncertainty is recommended., (© 2024 Author(s). All article content, except where otherwise noted, is licensed under a Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).)

Metrics to be used in noise impact assessment must integrate the physical acoustic characteristics of the sound field with relevant biology of animals. Several metrics have been established to determine and regulate underwater noise exposure to aquatic fauna. However, recent advances in understanding cause-effect relationships indicate that additional metrics are needed to fully describe and quantify the impact of sound fields on aquatic fauna. Existing regulations have primarily focused on marine mammals and are based on the dichotomy of sound types as being either impulsive or non-impulsive. This classification of sound types, however, is overly simplistic and insufficient for adequate impact assessments of sound on animals. It is recommended that the definition of impulsiveness be refined by incorporating kurtosis as an additional parameter and applying an appropriate conversion factor. Auditory frequency weighting functions, which scale the importance of particular sound frequencies to account for an animal's sensitivity to those frequencies, should be applied. Minimum phase filters are recommended for calculating weighted sound pressure. Temporal observation windows should be reported as signal duration influences its detectability by animals. Acknowledging that auditory integration time differs across species and is frequency dependent, standardized temporal integration windows are proposed for various signal types., (© 2024 Author(s). All article content, except where otherwise noted, is licensed under a Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).)

Objective: This cross-sectional study investigated the relationship between metacognition and mood symptoms four years post-stroke and examined fatigue as a potential moderator for this relationship., Methods: A number of 143 participants completed a survey that included the Hospital Anxiety and Depression Scale (HADS), the Metacognition Questionnaire-30 (MCQ-30), the Fatigue Severity Scale (FSS), and the modified Rankin Scale (mRS) (functional status) four years after stroke. Multiple regression analyses adjusting for demographic and stroke-specific covariates were performed with anxiety and depression as dependent variables and fatigue as a moderator., Results: The proportions of participants satisfying the caseness criteria for anxiety and depression were 20% and 19%, respectively, and 35% reported severe fatigue. Analysed separately, all MCQ-30 subscales contributed significantly to anxiety, whereas only three MCQ-30 subscales contributed significantly to depression. In the adjusted analyses, the MCQ-30 subscales 'positive beliefs' (p < 0.05) and 'uncontrollability and danger' (p < 0.001), as well as fatigue (p < 0.001) and functional status at four years (p < 0.05) were significantly associated with anxiety symptoms. Similarly, the MCQ-30 subscales 'cognitive confidence' (p < 0.05) and 'self-consciousness' (p < 0.05), as well as fatigue (p < 0.001), stroke severity at baseline (p < 0.01), and functional status at four years (p < 0.01) were significantly associated with depression symptoms. Fatigue did not significantly moderate the relationship between any MCQ-30 subscale and HADS scores., Conclusion: Maladaptive metacognitions were associated with the mood symptoms of anxiety and depression, independent of fatigue, even after controlling for demographic and stroke-specific factors. Future studies should implement longitudinal designs to determine whether metacognitions precede anxiety or depression after a stroke, and more strongly indicate the potential of metacognitive therapy for improving the mental health of individuals after a stroke., Competing Interests: The authors declared no competing interests with respect to the research, authorship and publication of this article, (Copyright: © 2024 Pedersen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

In recent years, there has been a proliferation of instruments for assessing mental health (MH) among autistic people. This study aimed to review the psychometric properties of broadband instruments used to assess MH problems among autistic people. In accordance with the PRISMA guidelines (PROSPERO: CRD42022316571) we searched the APA PsycINFO via Ovid, Ovid MEDLINE, Ovid Embase and the Web of Science via Clarivate databases from 1980 to March 2022, with an updated search in January 2024, to identify very recent empirical studies. Independent reviewers evaluated the titles and abstracts of the retrieved records (n = 11,577) and full-text articles (n = 1000). Data were extracted from eligible studies, and the quality of the included papers was appraised. In all, 164empirical articles reporting on 35 instruments were included. The review showed variable evidence of reliability and validity of the various instruments. Among the instruments reported in more than one study, the Aberrant Behavior Checklist had consistently good or excellent psychometric evidence. The reliability and validity of other instruments, including: the Developmental Behavior Checklist, Emotion Dysregulation Inventory, Eyberg Child Behavior Inventory, Autism Spectrum Disorder-Comorbid for Children Scale, and Psychopathology in Autism Checklist, were less documented. There is a need for a greater evidence-base for MH assessment tools for autistic people., (© 2024. The Author(s).)

Objective: To explore trajectories that describe change in post-stroke health-related quality of life with fatigue as outcome., Design: Observational and prospective study., Subjects: Stroke survivors (N = 144) with predominantly mild or moderate strokes., Methods: The multidimensional Stroke-Specific Quality of Life scale was used at 1 and 4 years, and the Fatigue Severity Scale at 4 years post-stroke. Latent class growth analyses were used as person-oriented analyses to identify meaningful trajectories. Socio-demographic and stroke-related covariables provided customary adjustment of the outcome, as well as prediction of class membership., Results: The latent class growth analysis models were estimated for "physical health", "visual-language", and "cognitive-social-mental" components of the Stroke-Specific Quality of Life scale, which extracted trajectories describing a variation in stable, deteriorating and improving functional patterns. The stable, well-functioning trajectory was most frequent across all components. More pronounced fatigue was associated with trajectories describing worse functioning, which was more prominent among females compared with males. Living alone implied more fatigue in the "cognitive-social-mental" component. Within the "visual-language" components' trajectories, younger and older participants reported more fatigue compared with middle-aged participants., Conclusion: Most participants belonged to the stable, well-functioning trajectories, which showed a consistently lower level of fatigue compared with the other trajectories.

Background: Few studies have examined the psychometric properties of the Social Aptitudes Scale (SAS). The study aims of the current paper were to examine the internal consistency and the validity of the Norwegian SAS., Methods: Parents of children from a clinical neuropediatric sample (N = 257) and from a clinical sample from child and adolescent's mental health services (N = 804) filled in the SAS., Results: Internal consistency for the SAS were good in both samples and correlations between the SAS and different scales were in the expected directions. The results from the Confirmatory Factor Analyses indicated poor model fit., Conclusions: Future validity studies should investigate whether SAS is suitable as a screening instrument for detecting autism spectrum disorder., (© 2023. BioMed Central Ltd., part of Springer Nature.)

In impact assessments for underwater noise, the duration of a transient signal is often expressed by the 90%-energy signal duration τ90 %. Consequently, the rms sound pressure is computed over this duration. Using a large set of measurements on marine-seismic airgun signals, it is shown that τ90 % is often very close to the interval between the primary and secondary pulse (the bubble period) or a small integer multiple thereof. In this situation τ90 % is a measure of the duration of the relative silence between primary and secondary peaks, which is not the intended measure. Rarely, τ90 % quantifies the duration of the main peak, leading to a much lower value of τ90 %. Since the number of peaks included in τ90 % is sensitive to the nature of the signal, relatively small differences in the signal lead to large differences in τ90 %, causing instability in any metric based on τ90 %, e.g., the rms sound pressure. Alternative metrics are proposed that do not exhibit these weaknesses. The consequences for the interpretation of sound pressure level of a transient signal, and the benefits of using a more stable metric than τ90 % are demonstrated., (© 2023 Author(s). All article content, except where otherwise noted, is licensed under a Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).)

Objective: Post-stroke fatigue may be associated with functioning even in patients with mild stroke. In order to guide rehabilitation, the aim of this study was to investigate the independent contribution of 12 function-related domains to severe long-term fatigue., Design: Observational follow-up study., Subjects: A total of 144 stroke survivors (mean age 67.3, standard deviation (SD) 10.9 years) were included., Methods: Fatigue 3-4 years post-stroke was measured with the Fatigue Severity Scale (cut-off ≥5). Independent variables were the multidimensional Stroke-Specific Quality of Life scale with 12 domains, demographics, and baseline stroke characteristics., Results: Most of the participants had mild and moderate stroke. Thirty-five percent (n = 51) reported severe fatigue 3-4 years after stroke. Those living with a significant other, and working participants reported significantly less fatigue. All domains of the Stroke-specific Quality of Life scale were significantly associated with the Fatigue Severity Scale. Adjusted for age, sex, marital status, and work status, the domains "energy", "mood", and, unexpectedly, the domain "vision", were all variables independently associated with severe long-term fatigue., Conclusion: Stroke survivors with prominent self-reported visual problems were more likely to experience fatigue. This finding should be verified in further studies. Visual examination and visual rehabilitation may reduce fatigue in selected stroke survivors.

There is a need for more knowledge of valid and standardized measures of mental health problems among children and adolescents with intellectual disability (ID). In this study, we systematically reviewed and evaluated the psychometric properties of instruments used to assess general mental health problems in this population. Following PRISMA guidelines, we reviewed empirical research published from 1980 through February 2020 with an updated search in March 2021 in Medline, Embase, PsycINFO, Health and Psychological Instruments, CINAHL, ERIC, and Web of Science databases. Forty-nine empirical articles were included in this review. Overall, the review indicated consistently better documentation of the reliability and validity of instruments designed for the ID population compared to instruments developed for the general child population., (© 2022. The Author(s).)

Background: The Strengths and Difficulties Questionnaire (SDQ) is a frequently used behavioral screening instrument. However, its psychometric properties have been rarely examined among children with intellectual and developmental disabilities (IDD)., Aims: The main aims of this study were to examine the internal consistency (i.e., McDonald's Omega), the convergent validity (by correlating the Total difficulties score with the Aberrant Behavior Checklist [ABC]), the divergent validity (by correlating the Total difficulties score with the Vineland Adaptive Behavior Composite; VABS-II Total) and the factorial validity (by the means of confirmatory factor analyses [CFA]) of the SDQ self-report-, parent-, and teacher version in a sample of children with IDD., Method: Participants were 365 children and adolescents (males n = 238; 65 %) aged 4-18 years (M = 10.11, SD = 3.82) referred for a developmental/neurological assessment to the neuropediatric outpatient clinics in the specialist health services. The SDQ was filled inn by 115 children, 337 parents, and 248 teachers., Results: McDonald's Omega was overall lowest for the self-report version. Correlations of the SDQ Total difficulties score and the ABC subscales were strongest for the parent version. The results of the CFA indicated best model fit for the six-factor model that included a method factor for all three versions of the SDQ, however, model fit was overall not good., Conclusions: Further research that examines the psychometric properties of the SDQ among multiple informants in large samples of children with IDD is needed., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: This study investigated the completion rates, scores and factors associated with non-completion and low scores on physical capability tests in a health survey administered to adults with intellectual disabilities., Method: Assessment comprised body mass index (BMI), the Short Physical Performance Battery (SPPB), the timed up-and-go (TUG) test, the one-legged stance (OLS) test; and gross motor, communication and behavioural functioning tests., Results: The completion rates among 93 participants (aged 17-78) were 46% for the SPPB, 42% for the TUG, and 31% for the OLS. More severe intellectual disability (OR = 3.12, p < .001) and lower BMI (OR = 0.859, p = .001) were related to test non-completion. The SPPB scores were below the reference values from the general population. Lower scores were associated with older age, motor disabilities and intellectual disability severity., Conclusions: Including physical capability tests in health surveys among adults with intellectual disabilities is important to monitor functional status and guide prevention strategies., (© 2021 The Authors. Journal of Applied Research in Intellectual Disabilities published by John Wiley & Sons Ltd.)

The acoustical output of marine-seismic airguns is determined from recordings of the sound pressure made on hydrophones suspended below a floating barge from which the airguns are also deployed. The signals from multiple types of airguns are considered and each type is operated over a range of deployment depths and chamber pressures. The acoustical output is characterized in terms of a "source waveform" with dimensions of the pressure-times-distance and in an infinite idealized medium, could be divided by the source-receiver distance to give the sound pressure at that receiver. In more realistic environments, the source waveform may be used to predict the pressure at any arbitrary receiver position simply by the application of a time-domain transfer function describing the propagation between the source and receiver. The sources are further characterized by metrics such as the peak source waveform and energy source level. These metrics are calculated in several frequency bands so that the resulting metrics can be used to characterize the acoustical output of the airguns in terms of their utility for seismic image-processing or possible effects on marine life. These characterizations provide reference data for the calibration of models that predict the airguns' acoustical output. They are validated via comparisons of the acoustic pressure measured on far-field hydrophones and predicted using the source waveforms. Comparisons are also made between empirically derived expressions relating the acoustic metrics to the chamber volume, chamber pressure, and deployment depth and similar expressions from the literature.

Background: Adults with intellectual disability (ID) have poorer physical and perceived health than the general population. Knowledge of perceived health predictors is both limited and important for guiding the development of preventive actions. The aims of this study were to investigate (1) the associations between perceived health and demographics, degree of ID, physical health conditions, and weight and physical activity level and (2) lifestyle factors and multimorbidity as predictors for perceived health adjusted for age, gender, and level of ID., Method: The North Health in Intellectual Disability study is a community based cross-sectional survey. The POMONA-15 health indicators were used. Univariate and multivariate logistic regression analyses with poor versus good health as the dependent variable were applied., Results: The sample included 214 adults with a mean age 36.1 (SD 13.8) years; 56% were men, and 27% reported perceiving their health as poor. In univariate analyses, there were significant associations between poor health ratings and female gender, lower motor function, number of physical health conditions and several indicators of levels of physical activity. In the final adjusted model, female gender [odds ratio (OR) 2.4, P < 0.05], level of ID (OR 0.65, P < 0.05), numbers of physical health conditions (OR 1.6, P < 0.001) and lower motor function (OR 1.5 P < 0.05) were significant explanatory variables for poor perceived health, with a tendency to independently impact failure to achieve 30 min of physical activity daily (OR 2.0, P = 0.07)., Conclusion: Adults with ID with female gender, reduced motor function and more physical health conditions are at increased risk of lower perceived health and should be given attention in health promoting interventions. A lack of physical activity tends to negatively influence perceived health., (© 2021 The Authors. Journal of Intellectual Disability Research published by MENCAP and International Association of the Scientific Study of Intellectual and Developmental Disibilities and John Wiley & Sons Ltd.)

Background: Many previous studies have highlighted distress in parents of children with neurodevelopmental disorders. Further knowledge about the relationship between parental mental health and children's characteristics could help neuropaediatric services improve treatment. The current study examined the applicability of the Everyday Feeling Questionnaire (EFQ) as a screening tool for parental mental health in a neuropaediatric sample., Methods: Children and adolescents (N = 299) referred to neurodevelopmental/neurological assessment at neuropaediatric outpatient clinics in Northern Norway were assessed for concurrent mental health problems; one of their parents completed the EFQ., Results: The EFQ items loaded highly on a general mental health factor. Parental mental health was more strongly associated with child functional impairment than child emotional/conduct difficulties; it was not associated with child neurodevelopmental disorders., Conclusions: The EFQ is a suitable screening tool for parental mental health in a neuropaediatric population. Child functional impairment seems an important predictor of parental mental health., (© 2020 John Wiley & Sons Ltd.)

Background: In addition to patient evaluations, caregiver evaluations and experiences are important indicators of the quality of health services. The aim of this study was to examine determinants of caregiver satisfaction with and perceived benefit of child neurodevelopmental assessment in neuropaediatric clinics., Methods: The study was conducted among caregivers of children and adolescents aged 4-18 years (N = 330) referred for neurodevelopmental assessment in two neuropaediatric clinics in the specialised health service in Northern Norway. The Generic Short Patient Experiences Questionnaire (GS-PEQ) for child psychiatric outpatient patients was distributed to caregivers immediately following the assessment, and two of its items were used as measurements of caregiver satisfaction with and perceived benefit of the assessment., Results: Caregiver satisfaction with the assessment was correlated with a better general level of function in the child, higher socioeconomic status, Norwegian mother tongue, referral from a specialist, and the respondent being a woman. Higher perceived benefit of the assessment was correlated with higher socioeconomic status, Norwegian mother tongue, and younger age of the child. Regression analysis revealed that caregivers' perception that the assessment was suited to their child's situation and that there was good cooperation with other public services (e.g., primary care and social/educational services) seemed more fundamental to caregiver satisfaction with neuropaediatric clinics' services than any background variable. Younger age of the child, in addition to caregivers' perception that the assessment was suited to their child and receiving sufficient information about the child's diagnosis/afflictions, were essential to the perceived benefit of the assessment., Conclusions: Caregiver satisfaction with child neurodevelopmental assessment in neuropaediatric clinics partly depends on variables not related to the assessment experience per se. An assessment that was suited to the child, good cooperation with other public services such as primary health care and social/educational services, and giving sufficient information about the child's diagnosis are essential to an overall positive caregiver evaluation of neurodevelopmental assessments.

Regulations for underwater anthropogenic noise are typically formulated in terms of peak sound pressure, root-mean-square sound pressure, and (weighted or unweighted) sound exposure. Sound effect studies on humans and other terrestrial mammals suggest that in addition to these metrics, the impulsiveness of sound (often quantified by its kurtosis β) is also related to the risk of hearing impairment. Kurtosis is often used to distinguish between ambient noise and transients, such as echolocation clicks and dolphin whistles. A lack of standardization of the integration interval leads to ambiguous kurtosis values, especially for transient signals. In the current research, kurtosis is applied to transient signals typical for high-power underwater noise. For integration time (t 2 -t 1 ), the quantity (t 2 -t 1 )/β is shown to be a robust measure of signal duration, closely related to the effective signal duration, τ eff for sounds from airguns, pile driving, and explosions. This research provides practical formulas for kurtosis of impulsive sounds and compares kurtosis between measurements of transient sounds from different sources.

Environmental risk assessment for impact pile driving requires characterization of the radiated sound field. Damped cylindrical spreading (DCS) describes propagation of the acoustic Mach cone generated by striking a pile and predicts sound exposure level (L E ) versus range. For known water depth and sediment properties, DCS permits extrapolation from a measurement at a known range. Impact assessment criteria typically involve zero-to-peak sound pressure level (L p,pk ), root-mean-square sound pressure level (L p,rms ), and cumulative sound exposure level (L E,cum ). To facilitate predictions using DCS, L p,pk and L p,rms were estimated from L E using empirical regressions. Using a wind farm construction scenario in the North Sea, DCS was applied to estimate ranges to recommended thresholds in fishes. For 3500 hammer strikes, the estimated L E,cum impact ranges for mortal and recoverable injury were up to 1.8 and 3.1 km, respectively. Applying a 10 dB noise abatement measure, these distances reduced to 0.29 km for mortal injury and 0.65 km for recoverable injury. An underlying detail that produces unstable results is the averaging time for calculating L p,rms , which by convention is equal to the 90%-energy signal duration. A stable alternative is proposed for this quantity based on the effective signal duration.

Previous studies exploring injury response to pile driving in fishes presented exposure paradigms (>900 strikes) that emulated circumstances where fish would not leave an area being ensonified. Those studies did not, however, address the question of how many strikes are needed before injuries appear. Thus, the number of strikes paired with a constant single strike sound exposure level (SEL ss ) that can cause injuries is not yet clear. In order to examine this question, hybrid striped bass (white bass Morone chrysops × striped bass Morone saxatilis) were exposed to 8-384 strikes in three different SEL ss treatments that generated different cumulative sound exposure level values. The treatment with the highest SEL ss values caused swim bladder injuries in fish exposed to as few as eight pile strikes. These results have important implications for pile driving operations where SEL ss values meet or exceed the exposure levels used in this study.

Objective: The aim of this study was to evaluate long-term safety, efficacy, and quality of life (QOL) of ≤400-mg/day USL255, Qudexy® XR (topiramate) extended-release capsules, as adjunctive therapy for partial-onset seizures (POS) in adults., Methods: Patients who completed the 11-week double-blind treatment phase of the phase 3 PREVAIL study were eligible to enroll in this 1-year open-label extension (OLE) study (PREVAIL OLE). The primary objective was to evaluate the safety and tolerability of USL255 (including treatment-emergent adverse events [TEAEs]). The secondary objective was to assess seizure frequency in patients (e.g., median percent reduction from baseline in weekly POS frequency, responder rate [proportion of patients with ≥25%, ≥50%, ≥75%, or 100% reduction from baseline in POS frequency], and seizure-free intervals [proportion of patients who were seizure-free for 4, 12, 24, 36, or 48weeks]). Exploratory clinical-status endpoints included the Global Impression of Change (CGI-C) and Quality of Life in Epilepsy-Problems (QOLIE-31-P) questionnaires. Post hoc analyses evaluated neurocognitive TEAE incidences during the first 11 and entire 55weeks of treatment and efficacy by patient age and drug-resistant status., Results: Of the 217 patients who completed PREVAIL (USL255, n=103; placebo, n=114), 210 (97%) enrolled in PREVAIL OLE and were included in the ITT population. Across the entire 55-week treatment period, USL255 was generally safe and well tolerated, with low individual neurocognitive TEAE incidences. Seizure reduction was sustained across the year-long study and observed in patient subgroups, including those with highly drug-resistant seizures and those ≥50years of age. Improvements in CGI-C and QOLIE-31-P were also observed., Significance: The results of PREVAIL OLE are consistent with those from PREVAIL and demonstrate that adjunctive treatment with up to 400mg/day of USL255 may be a safe and effective treatment option for a variety of adult patients with refractory POS., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Six species of fishes were tested under aquatic far-field, plane-wave acoustic conditions to answer several key questions regarding the effects of exposure to impulsive pile driving. The issues addressed included which sound levels lead to the onset of barotrauma injuries, how these levels differ between fishes with different types of swim bladders, the recovery from barotrauma injuries, and the potential effects exposure might have on the auditory system. The results demonstrate that the current interim criteria for pile-driving sound exposures are 20 dB or more below the actual sound levels that result in the onset of physiological effects on fishes.

Objective: To compare the pharmacokinetics, pharmacodynamics, and tolerability of USL261, a midazolam formulation optimized for intranasal delivery, versus midazolam intravenous (IV) solution administered intranasally (MDZ-inj IN) or intravenously (MDZ-inj IV) in healthy adults., Methods: In this phase 1, five-way crossover, open-label study, 25 healthy adults (aged 18-42 years) were randomly assigned to receive 2.5, 5.0, and 7.5 mg USL261; 2.5 mg MDZ-inj IV; and 5.0 mg MDZ-inj IN. Blood samples were collected for 12 h post dose to determine pharmacokinetic profiles. Pharmacodynamic assessments of sedation and psychomotor impairment also were conducted. Adverse events, oxygen saturation, and vital signs were recorded., Results: Increasing USL261 dose corresponded with increases in midazolam area under the concentration time curve (AUC) and maximum observed plasma concentration (Cmax ), with all doses demonstrating rapid median time to Cmax (Tmax ; 10-12 min). USL261 also demonstrated increased absorption, with a 134% relative bioavailability, compared with the same MDZ-inj IN dose. USL261 was associated with dose-dependent increases in sedation and psychomotor impairment (p < 0.05); however, these effects lasted <4 h and generally did not differ from MDZ-inj IN or MDZ-inj IV at comparable doses. No serious adverse events (SAEs) or deaths were reported, and no treatment-emergent adverse events (TEAEs) led to study discontinuation., Significance: Compared with intranasal delivery of a midazolam formulation intended for IV delivery, USL261, optimized for intranasal administration demonstrated improved bioavailability with similar pharmacodynamic effects. Therefore, USL261 may be a preferable alternative to the currently approved rectal diazepam treatment for intermittent bouts of increased seizure activity., (Wiley Periodicals, Inc. © 2015 International League Against Epilepsy.)

Results from a previously conducted global phase III study (PREVAIL; NCT01142193) demonstrate the safety and efficacy of once-daily USL255, Qudexy™ XR (topiramate) extended-release capsules, as adjunctive treatment of drug-resistant partial-onset seizures (POSs). In this study, we report a post hoc analysis of PREVAIL data according to patient level of treatment resistance (based upon the number of concomitant antiepileptic drugs [AEDs] and lifetime AEDs) at baseline, with patients defined as either having "highly" drug-resistant seizures (≥ 2 concurrent AEDs and ≥ 4 lifetime AEDs) or having "less" drug-resistant seizures (1 concurrent AED or <4 lifetime AEDs) at baseline. For each subgroup, median percent reduction in POS frequency (primary endpoint), responder rate, Clinical Global Impression of Change (CGI-C), and Quality of Life in Epilepsy--Problems (QOLIE-31-P) survey were assessed. Of 249 PREVAIL patients, 115 were classified as having highly drug-resistant seizures (USL255: n = 52, placebo: n = 63), and 134 were classified as having less drug-resistant seizures (USL255: n = 72, placebo: n = 62) at baseline. For the primary endpoint, USL255 resulted in significantly better seizure outcomes compared with placebo regardless of drug-resistant status (P = .004 and P = .040 for "highly" and "less", respectively). Responder rate was also significantly improved in patients with highly drug-resistant group (P = .023). The CGI-C scores indicated significant improvement in both subgroups (P = .003 and P = .013 for "highly" and "less", respectively). On the QOLIE-31-P, a significant improvement on the seizure worry subscale for the group with less drug-resistant seizures was noted in USL255-treated patients compared with placebo-treated patients (P = .003); the overall score and all other subscales were not significantly different for both subgroups. We conclude that USL255 led to significant improvements across multiple outcomes compared with placebo, including in those classified as having highly drug-resistant seizures to prior treatment, making it a valuable treatment option for patients with epilepsy., (Copyright © 2014. Published by Elsevier Inc.)

Objective: Evaluate the pharmacokinetics (PK), safety, and tolerability of single doses of once-daily USL255, Qudexy XR (topiramate) extended-release capsules, over a wide dosing range., Methods: Two single-dose, phase I studies in healthy adults were used to evaluate the PK profile and maximum tolerated dose (MTD) of USL255 from 25-1,400 mg. Standard PK parameters assessed included area under the plasma concentration-time curve (AUC) and maximum plasma concentration (Cmax ). Dose proportionality, linearity, and intersubject and intrasubject variability (coefficient of variation [%CV]) of AUC and Cmax were evaluated. Investigator-reported adverse events (AEs) were obtained throughout the studies., Results: After the initial increase in plasma concentration levels immediately following administration of USL255 25-1,400 mg, plasma topiramate concentration-time profiles were flat up to 24 h after dosing. AUC was dose proportional from 25-1,400 mg, and Cmax was dose proportional from 50-1,400 mg; both AUC and Cmax were linear across the entire dose range. Low intersubject and intrasubject %CV values were observed for AUC0-t , AUC0-∞ , and Cmax (intersubject %CV: 20.2, 19.6, and 22.4%, respectively; intrasubject %CV of dose-normalized mean values: 10.8, 8.2, and 13.2%, respectively). USL255 was generally safe and well tolerated with MTD established at 1,200 mg., Significance: These results demonstrate that USL255 provides consistent plasma topiramate exposure across an extended-dosing interval and predictable plasma topiramate concentrations over a wide dosing range. Overall, the favorable safety profile and consistency of exposure suggest once-daily USL255 can be a useful treatment option for patients with epilepsy., (© 2014 The Authors. Epilepsia published by Wiley Periodicals, Inc. on behalf of International League Against Epilepsy.)

Objective: To evaluate the efficacy and safety of USL255, Qudexy(™) XR (topiramate) extended-release capsules, as an adjunctive treatment for refractory partial-onset seizures (POS) in adults taking one to three concomitant antiepileptic drugs., Methods: In this global phase III study (PREVAIL; NCT01142193), 249 adults with POS were randomized 1:1 to once-daily USL255 (200 mg/day) or placebo. The primary and key secondary efficacy endpoints were median percent reduction in weekly POS frequency and responder rate (proportion of patients with ≥ 50% reduction in seizure frequency). Seizure freedom was also assessed. Safety (adverse events, clinical and laboratory findings), as well as treatment effects on quality of life (QOLIE-31-P) and clinical global impression of change (CGI-C), were evaluated., Results: Across the entire 11-week treatment phase, USL255 significantly reduced the median percent seizure frequency and significantly improved responder rate compared with placebo. Efficacy over placebo was observed early in treatment, in patients with highly refractory POS, and in those with the most debilitating seizure types (i.e., complex partial, partial secondarily generalized). USL255 was safe and generally well tolerated with a low incidence of neurocognitive adverse events. USL255 was associated with significant clinical improvement without adversely affecting quality of life., Significance: The PREVAIL phase III clinical study demonstrated that once-daily USL255 (200 mg/day) significantly improved seizure control and was safe and generally well tolerated with few neurocognitive side effects., (© 2014 The Authors. Epilepsia published by Wiley Periodicals, Inc. on behalf of International League Against Epilepsy.)

Impulsive pile driving sound can cause injury to fishes, but no studies to date have examined whether such injuries include damage to sensory hair cells in the ear. Possible effects on hair cells were tested using a specially designed wave tube to expose two species, hybrid striped bass (white bass Morone chrysops × striped bass Morone saxatilis) and Mozambique tilapia (Oreochromis mossambicus), to pile driving sounds. Fish were exposed to 960 pile driving strikes at one of three treatment levels: 216, 213, or 210dB re 1 μPa(2)·s cumulative Sound Exposure Level. Both hybrid striped bass and tilapia exhibited barotraumas such as swim bladder ruptures, herniations, and hematomas to several organs. Hybrid striped bass exposed to the highest sound level had significant numbers of damaged hair cells, while no damage was found when fish were exposed at lower sound levels. Considerable hair cell damage was found in only one out of 11 tilapia specimens exposed at the highest sound level. Results suggest that impulsive sounds such as from pile driving may have a more significant effect on the swim bladders and surrounding organs than on the inner ears of fishes, at least at the sound exposure levels used in this study., (© 2013.)

The effects of loud sounds on fishes, such as those produced during impulsive pile driving, are an increasing concern in the management of aquatic ecosystems. However, very little is known about such effects. Accordingly, a High Intensity Controlled Impedance Fluid Filled wave Tube (HICI-FT) was used to investigate the effects of sounds produced by impulsive pile driving on two size groups of hybrid striped bass (white bass Moronechrysops x striped bass Moronesaxatilis). The larger striped bass (mean size 17.2 g) had more severe injuries, as well as more total injuries, than the smaller fish (mean size 1.3 g). However, fish in each size group recovered from most injuries within 10 days of exposure. A comparison with different species from previously published studies show that current results support the observation that fishes with physoclistous swim bladders are more susceptible to injury from impulsive pile driving than are fishes with physostomous swim bladders.

Purpose: Compare the pharmacokinetic (PK) profiles of immediate- and extended-release formulations of topiramate (TPM) in healthy subjects following multiple dosing, and evaluate maintenance of topiramate exposures after switching formulations., Methods: A randomized, open-label, single-center, two-way crossover, multiple-dose study comparing the steady-state PK profile of once-daily extended-release topiramate (USL255) to immediate-release topiramate (TPM-IR) administered twice-daily. The TPM PK profile was evaluated using standard PK parameters (e.g., AUC0-24 , Cmax , Cmin ) as well as less common PK criteria such as fluctuation index (FI), peak occupancy time (POT), and percent coefficient of variation (%CV). In addition, partial AUC (AUCp ) analyses provided comparisons of the AUC profiles over predetermined time intervals between TPM-IR and USL255. Pharmacokinetic equivalence between formulations was defined as containment of the 90% confidence intervals (CIs) of the USL255/TPM-IR geometric least-squares mean (GLSM) ratio within the equivalence limits of 80-125%. The effect of switching between treatments was assessed by evaluating equivalence of PK parameters between the day prior to formulation switch and the day immediately following formulation switch. Maintenance of steady state after switching formulations was also evaluated by comparing the slope between Cmin values at formulation switch and 24 h postswitch. Tolerability was evaluated through adverse event monitoring, vital sign measurements, and clinical laboratory evaluations., Key Findings: USL255 was well tolerated and provided TPM plasma exposure equivalent to TPM-IR at various time intervals. USL255 also demonstrated a significantly lower Cmax (p < 0.001) and higher Cmin (p < 0.001), longer tmax , lower %CV, and 26% decreased FI, as compared with TPM-IR. Further, switching between TPM-IR and USL255 did not affect TPM concentrations, including Cmin , immediately after transitioning and at steady state., Significance: As compared with TPM-IR, USL255 provided equivalent plasma exposure with an extended absorption profile. Therefore, USL255 offers a once-daily alternative to twice-daily TPM-IR, with reduced TPM fluctuations., (Wiley Periodicals, Inc. © 2013 International League Against Epilepsy.)

To address growing concern over the impact of anthropogenic sound on fishes, a series of experiments was conducted that exposed several fish species to high-intensity low-frequency naval sonar. This study extends auditory findings by adding largemouth bass, yellow perch, and channel catfish. No effects on hearing were found in largemouth bass and yellow perch and only small effects in channel catfish (a fish with morphological adaptations for enhanced pressure reception). Together with prior findings, these results suggest limited impact on hearing from high-intensity sonar. Susceptibility may be due to genetic stock, developmental conditions, seasonal variation, and/or buoyancy during exposure.

Pile-driving and other impulsive sound sources have the potential to injure or kill fishes. One mechanism that produces injuries is the rapid motion of the walls of the swim bladder as it repeatedly contacts nearby tissues. To further understand the involvement of the swim bladder in tissue damage, a specially designed wave tube was used to expose three species to pile-driving sounds. Species included lake sturgeon (Acipenser fulvescens)--with an open (physostomous) swim bladder, Nile tilapia (Oreochromis niloticus)--with a closed (physoclistous) swim bladder and the hogchoker (Trinectes maculatus)--a flatfish without a swim bladder. There were no visible injuries in any of the exposed hogchokers, whereas a variety of injuries were observed in the lake sturgeon and Nile tilapia. At the loudest cumulative and single-strike sound exposure levels (SEL(cum) and SEL(ss) respectively), the Nile tilapia had the highest total injuries and the most severe injuries per fish. As exposure levels decreased, the number and severity of injuries were more similar between the two species. These results suggest that the presence and type of swim bladder correlated with injury at higher sound levels, while the extent of injury at lower sound levels was similar for both kinds of swim bladders.

Juvenile Chinook salmon, Oncorhynchus tshawytscha, were exposed to simulated high intensity pile driving signals to evaluate their ability to recover from barotrauma injuries. Fish were exposed to one of two cumulative sound exposure levels for 960 pile strikes (217 or 210 dB re 1 µPa(2)·s SEL(cum); single strike sound exposure levels of 187 or 180 dB re 1 µPa(2)⋅s SEL(ss) respectively). This was followed by an immediate assessment of injuries, or assessment 2, 5, or 10 days post-exposure. There were no observed mortalities from the pile driving sound exposure. Fish exposed to 217 dB re 1 µPa(2)·s SEL(cum) displayed evidence of healing from injuries as post-exposure time increased. Fish exposed to 210 dB re 1 µPa(2)·s SEL(cum) sustained minimal injuries that were not significantly different from control fish at days 0, 2, and 10. The exposure to 210 dB re 1 µPa(2)·s SEL(cum) replicated the findings in a previous study that defined this level as the threshold for onset of injury. Furthermore, these data support the hypothesis that one or two Mild injuries resulting from pile driving exposure are unlikely to affect the survival of the exposed animals, at least in a laboratory environment.

Elasmobranch fishes have been around for hundreds of millions of years with very little evolutionary changes, yet our understanding of their hearing abilities is limited to only a few of the hundreds of extant species. Our general understanding suggests a relatively narrow hearing range with relatively poor sensitivity, particularly compared with many teleosts. This lack of knowledge makes it difficult to evaluate the potential effects that could be associated with exposure to anthropogenic noise. However, given the combination of the worldwide increase in anthropogenic aquatic noise as well as the drastic population decline in many species of elasmobranch fishes, it is imperative that noise-exposure studies be conducted to determine whether these fishes are being further threatened by our noise pollution.

Caged fish were exposed to sound from mid-frequency active (MFA) transducers in a 5 × 5 planar array which simulated MFA sounds at received sound pressure levels of 210 dB SPL(re 1 μPa). The exposure sound consisted of a 2 s frequency sweep from 2.8 to 3.8 kHz followed by a 1 s tone at 3.3 kHz. The sound sequence was repeated every 25 s for five repetitions resulting in a cumulative sound exposure level (SEL(cum)) of 220 dB re 1 μPa(2) s. The cumulative exposure level did not affect the hearing sensitivity of rainbow trout, a species whose hearing range is lower than the frequencies in the presented MFA sound. In contrast, one cohort of channel catfish showed a statistically significant temporary threshold shift of 4-6 dB at 2300 Hz, but not at lower tested frequencies, whereas a second cohort showed no change. It is likely that this threshold shift resulted from the frequency spectrum of the MFA sound overlapping with the upper end of the hearing frequency range of the channel catfish. The observed threshold shifts in channel catfish recovered within 24 h. There was no mortality associated with the MFA sound exposure used in this test., (© 2012 Acoustical Society of America.)

Fishes and marine mammals may suffer a range of potential effects from exposure to intense underwater sound generated by anthropogenic activities such as pile driving, shipping, sonars, and underwater blasting. Several underwater sound recording (USR) devices have been built to acquire samples of the underwater sound generated by anthropogenic activities. Software becomes indispensable for processing and analyzing the audio files recorded by these USRs. In this paper, we provide a detailed description of a new software package, the Aquatic Acoustic Metrics Interface (AAMI), specifically designed for analysis of underwater sound recordings to provide data in metrics that facilitate evaluation of the potential impacts of the sound on aquatic animals. In addition to the basic functions, such as loading and editing audio files recorded by USRs and batch processing of sound files, the software utilizes recording system calibration data to compute important parameters in physical units. The software also facilitates comparison of the noise sound sample metrics with biological measures such as audiograms of the sensitivity of aquatic animals to the sound, integrating various components into a single analytical frame. The features of the AAMI software are discussed, and several case studies are presented to illustrate its functionality.

The risk of effects to fishes and other aquatic life from impulsive sound produced by activities such as pile driving and seismic exploration is increasing throughout the world, particularly with the increased exploitation of oceans for energy production. At the same time, there are few data that provide insight into the effects of these sounds on fishes. The goal of this study was to provide quantitative data to define the levels of impulsive sound that could result in the onset of barotrauma to fish. A High Intensity Controlled Impedance Fluid filled wave Tube was developed that enabled laboratory simulation of high-energy impulsive sound that were characteristic of aquatic far-field, plane-wave acoustic conditions. The sounds used were based upon the impulsive sounds generated by an impact hammer striking a steel shell pile. Neutrally buoyant juvenile Chinook salmon (Oncorhynchus tshawytscha) were exposed to impulsive sounds and subsequently evaluated for barotrauma injuries. Observed injuries ranged from mild hematomas at the lowest sound exposure levels to organ hemorrhage at the highest sound exposure levels. Frequency of observed injuries were used to compute a biological response weighted index (RWI) to evaluate the physiological impact of injuries at the different exposure levels. As single strike and cumulative sound exposure levels (SEL(ss), SEL(cum) respectively) increased, RWI values increased. Based on the results, tissue damage associated with adverse physiological costs occurred when the RWI was greater than 2. In terms of sound exposure levels a RWI of 2 was achieved for 1920 strikes by 177 dB re 1 µPa(2)⋅s SEL(ss) yielding a SEL(cum) of 210 dB re 1 µPa(2)⋅s, and for 960 strikes by 180 dB re 1 µPa(2)⋅s SEL(ss) yielding a SEL(cum) of 210 dB re 1 µPa(2)⋅s. These metrics define thresholds for onset of injury in juvenile Chinook salmon.

Purpose: To compare the pharmacokinetics of USL255, a once-daily extended-release (ER) formulation of topiramate (TPM), with Topamax (immediate-release TPM) in healthy subjects after oral dosing and evaluate the effect of food on USL255 bioavailability and pharmacokinetics., Methods: This randomized, single-center, open-label, cross-over design study had three dosing periods separated by 21 days of washout between treatments. Thirty-six volunteers received single doses of USL255 (200 mg) in fasted and fed conditions and two doses of Topamax (100 mg) administered 12 h apart. TPM plasma samples were analyzed by liquid chromatography-mass spectroscopy. Pharmacokinetic parameters were calculated by noncompartmental methods., Key Findings: USL255 fasted pharmacokinetic parameters [point estimate (90% confidence interval, CI) compared to Topamax] were: relative bioavailability (F) 91.2% (84-99%), peak plasma concentration (C(max)) USL255/Topamax-ratio 59% (53-65%), time to reach C(max) (t(max)) 19.5 ± 7.2 h, accumulation ratio (R(ac)) 3.9 ± 1.2, effective half-life (t(1/2,eff)) 55.7 ± 19.9 h, terminal half-life (t(1/2,z)) 80.2 ± 14.2 h, and peak-occupancy-time (POT) 12.1 ± 4.0 h. Although the F and C(max) were unaffected by food, R(ac) and t(1/2,eff) increased to 4.9 ± 0.9, and 72.5 ± 15.4 h, respectively. In contrast to t(1/2,z,) t(1/2,eff) reflects absorption rate; therefore, USL255's t(1/2,eff) was significantly longer than Topamax's t(1/2,eff) (37.1 ± 6.5 h)., Significance: Although bioequivalent to Topamax in extent of absorption, USL255 had a slower absorption rate as reflected in its lower C(max) and longer t(max), larger POT and longer t(1/2,eff), and similar R(ac) values to that of Topamax (q12 h). This relative flat plasma profile allows for once-daily dosing with diminished fluctuations in TPM plasma levels. In addition, neither USL255's peak nor extent of plasma exposure of TPM was affected by food., (Wiley Periodicals, Inc. © 2011 International League Against Epilepsy.)

This study investigated immediate effects of intense sound exposure associated with low-frequency (170-320 Hz) or with mid-frequency (2.8-3.8 kHz) sonars on caged rainbow trout Oncorhynchus mykiss, channel catfish Ictalurus punctatus and hybrid sunfish Lepomis sp. in Seneca Lake, New York, U.S.A. This study focused on potential effects on inner ear tissues using scanning electron microscopy and on non-auditory tissues using gross and histopathology. Fishes were exposed to low-frequency sounds for 324 or 628 s with a received peak signal level of 193 dB re 1 microPa (root mean square, rms) or to mid-frequency sounds for 15 s with a received peak signal level of 210 dB re 1 microPa (rms). Although a variety of clinical observations from various tissues and organ systems were described, no exposure-related pathologies were observed. This study represents the first investigation of the effects of high-intensity sonar on fish tissues in vivo. Data from this study indicate that exposure to low and midfrequency sonars, as described in this report, might not have acute effects on fish tissues.

This study investigated the effects on rainbow trout (Oncorhynchus mykiss) of exposure to high-intensity, low-frequency sonar using an element of the standard Surveillance Towed Array Sensor System Low Frequency Active (LFA) sonar source array. Effects of the LFA sonar on hearing were tested using auditory brainstem responses. Effects were also examined on inner ear morphology using scanning electron microscopy and on nonauditory tissues using general pathology and histopathology. Animals were exposed to a maximum received rms sound pressure level of 193 dB re 1 microPa(2) for 324 or 648 s, an exposure that is far in excess of any exposure a fish would normally encounter in the wild. The most significant effect was a 20-dB auditory threshold shift at 400 Hz. However, the results varied with different groups of trout, suggesting developmental and/or genetic impacts on how sound exposure affects hearing. There was no fish mortality during or after exposure. Sensory tissue of the inner ears did not show morphological damage even several days post-sound exposure. Similarly, gross- and histopathology observations demonstrated no effects on nonauditory tissues.

Many species of odontocete cetaceans (toothed whales) use high-frequency clicks (60-170 kHz) to identify objects in their environment, including potential prey. Behavioral studies have shown that American shad, Alosa sapidissima, can detect ultrasonic signals similar to those of odontocetes that are potentially their predators. American shad also show strong escape behavior in response to ultrasonic pulses between 70 and 110 kHz and can determine the location of the sound source at least in the horizontal plane. The present study examines physiological aspects of ultrasound detection by American shad and provides the first insights into the neural encoding of ultrasound signals in any nonmammalian vertebrate. The recordings were obtained by penetration through the cerebellar surface. All but two units responded exclusively to ultrasound. Ultrasound-sensitive units did not phase-couple to any stimulus frequency. Some units resembled the response of constant latency neurons found in the ventral nucleus of the lateral lemniscus of bats. We suggest that ultrasonic and sonic signals are processed along different pathways in Alosa. The ultrasonic pathway in Alosa appears to be a feature detector that is likely to be adapted (e.g., frequency, intensity) to odontocete echolocation signals.

Cockroaches ( Periplaneta americana) orient their antennae toward moving objects based on visual cues. Presumably, this allows exploration of novel objects by the antennal flagellum. We used videographic and electrophysiological methods to determine if receptors on the flagellum are essential for triggering escape, or if they enable cockroaches to discriminate threatening from non-threatening objects that are encountered. When a flagellum was removed, and replaced with a plastic fiber, deflection of a "prosthetic flagellum" still activated the descending mechanosensory interneurons associated with escape and produced typical escape responses. However, escape was essentially eliminated by constraining the movement of the scape and pedicel at the antennal base. When cockroaches approached and briefly explored the surface of a spider or another cockroach with the flagellum, they produced escape significantly more often in response to subsequent controlled contact from a spider than from a cockroach. This discrimination did not depend on visual or wind-sensory input, but required flagellar palpation of the surface. The crucial sensory cues appear to involve texture rather than surface chemicals. These results indicate that cockroaches acquire basic information on stimulus identity during exploration of surfaces with flagellar receptors, but that basal receptors are triggers for escape behavior.

The response latencies of sensory neurons typically shorten with increases in stimulus intensity. In the central auditory system this phenomenon should have a significant impact on a number of auditory functions that depend critically on an integration of precisely timed neural inputs. Evidence from previous studies suggests that the auditory system not only copes with the potential problems associated with intensity-dependent latency change, but that it also modifies latency change to shape the response properties of many cells for specific functions. This observation suggests that intensity-dependent latency change may undergo functional transformations along the auditory neuraxis. The goal of our study was to explore these transformations by making a direct, quantitative comparison of intensity-dependent latency change among a number of auditory centers from the lower brainstem to the thalamus. We found two main ways in which intensity-dependent latency change transformed along the neuraxis: (1) the range of latency change increased substantially and (2) one particular type of latency change, which has been suggested to be associated with sensitivity to temporally segregated stimulus components, occurred only at the highest centers tested, the midbrain and thalamus. Additional testing in the midbrain (inferior colliculus) indicated that inhibitory inputs are involved in shaping latency change. Our findings demonstrate that the central auditory system modifies intensity-dependent latency changes. We suggest that these changes may be functionally incorporated, actively enhanced, or modified to suit specific functions of the auditory system.

Nausea and vomiting are common complaints in the postoperative period and contribute to patient distress and delay of discharge for outpatient surgical procedures. Laparoscopic procedures are associated with a high incidence of postoperative nausea and vomiting (PONV) episodes. Parenteral use of metoclopramide prevents and treats PONV. The intranasal route provides rapid and complete absorption of metoclopramide without many of the adverse effects observed with parenteral administration of the drug. We performed a prospective, double-blinded, randomized, placebo-controlled study to evaluate the safety and efficacy of metoclopramide 20 mg administered intranasally for emetic prophylaxis in laparoscopic surgery patients. The results from 109 patients enrolled in the study showed that this intranasal dose of metoclopramide may be ineffective in preventing the occurrence of PONV. The poor performance of the intranasal metoclopramide formulation in this study cannot be attributed to patient-specific and perioperative factors. It may be due to an inadequate dose or slow absorption of the drug. The small sample size, however, may also have been a factor.

The disposition of encainide and metabolites O-desmethylencainide (ODE) and 3-methyl-ODE (MODE) was evaluated in a 31-year-old hemodialysis patient following a 25 mg oral dose during an interdialytic period and a second 25 mg oral dose 48 h later, 2 h before a hemodialysis procedure. The inter- and intradialytic elimination half-lives were not different for encainide and its metabolites ODE and MODE. The hemodialysis clearance of encainide, MODE, and ODE are all less than 10% of the creatinine clearance of the dialyzer. Thus, hemodialysis does not result in clinically significant removal of encainide or its metabolites.