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Background: Hereditary angioedema (HAE) is a rare genetic disorder characterized by painful, debilitating, and potentially fatal swelling attacks. Lanadelumab is approved as long-term prophylaxis (LTP) in patients with HAE. However, real-world data on LTP use in patients with HAE are limited. Objective: To describe clinical characteristics, attack history, and quality of life (QoL) of patients with HAE type I/II who were receiving lanadelumab or other LTPs. Methods: Data were drawn from the Adelphi HAE Disease Specific Program, a cross-sectional survey of HAE physicians conducted in the United States from July to November 2021. Physician-reported disease characteristics, HAE attack frequency, and QoL were compared among patients receiving lanadelumab or other LTPs for at least 12 months. Results: Physicians reported data for 144 patients, of whom 29 had received lanadelumab and 115 had received another prophylaxis for at least 12 months. The mean ± standard deviation number of attacks in the previous 12 months was lower among patients receiving lanadelumab than other LTPs (2.3 ± 3.1 versus 3.4 ± 2.8, respectively; p = 0.075). Although both groups had similar current disease activity and severity, more patients receiving lanadelumab versus other LTPs had high disease activity (51.7% versus 12.5%, respectively; p < 0.0001) and disease severity rated as severe (51.7% versus 16.1%, respectively; p = 0.0001) at diagnosis. Physicians reported that more patients who received lanadelumab had good or very good QoL (72.4%) than those receiving other LTPs (36.5%) (p = 0.003). Conclusion: Analysis of these findings suggests lower attack frequency, lower symptomatic impact, and better QoL in patients treated with lanadelumab than another prophylaxis in a real-world setting.

Background: Hereditary angioedema (HAE) is a rare genetic condition characterized by painful and often debilitating swelling attacks. Little is known about the differences in outcomes between patients with HAE types I or II (type I: HAE caused by C1 esterase inhibitor deficiency; type II: HAE caused by C1 esterase inhibitor dysfunction), with decreased or dysfunctional C1 esterase inhibitor (C1-INH), and those with normal C1-INH (nC1-INH-HAE). Objective: To compare physician- and patient-reported real-world outcomes in patients with HAE types I/II versus patients with nC1-INH-HAE. Methods: Data were drawn from the Adelphi HAE Disease Specific Programme TM a real-world, cross-sectional survey of HAE-treating physicians and their patients in the United States conducted between July and November 2021. Physicians reported patient disease activity and severity, and recent attack history. Patient-reported outcomes were collected. Bivariate tests used were either the Student's t -test, the Fisher exact test, or Mann-Whitney U test. Results: Physicians (N = 67) provided data on 368 patients (92.4% HAE types I/II and 7.6% nC1-INH-HAE). Physicians reported that a higher proportion of patients with nC1-INH-HAE had moderate or high disease activity and moderate or severe disease severity both at diagnosis and at data collection versus those with HAE types I/II. Patients with nC1-INH-HAE versus patients with HAE types I/II experienced increased attack severity (34.6% versus 4.4%) and hospitalization rate during the most recent attack (39.3% versus 6.6%), and reported lower health status and quality of life, via the European Quality of Life 5 Dimension 5 Level (US tariff) and Angioedema Quality of Life, respectively. On average, 25% of the patients with nC1-INH-HAE reported absenteeism and work or activity impairment due to HAE compared with 2.7% of patients with HAE types I/II. Both patient groups reported improvements in disease activity and severity from diagnosis to the time of data collection. Conclusion: These real-world findings suggest that patients with nC1-INH-HAE have increased disease activity and severity, and experience greater impairment to their quality of life, work, and daily functioning than patients with HAE types I/II. Powered statistical analyses are required to confirm these findings.

This study evaluated the cost-effectiveness of maribavir versus investigator-assigned therapy (IAT; valganciclovir/ganciclovir, foscarnet, or cidofovir) for post-transplant refractory cytomegalovirus (CMV) infection with or without resistance. A two-stage Markov model was designed using data from the SOLSTICE trial (NCT02931539), real-world multinational observational studies, and published literature. Stage 1 (0-78 weeks) comprised clinically significant CMV (csCMV), non-clinically significant CMV (n-csCMV), and dead states; stage 2 (78 weeks-lifetime) comprised alive and dead states. Total costs (2022 USD) and quality-adjusted life years (QALYs) were estimated for the maribavir and IAT cohorts. An incremental cost-effectiveness ratio was calculated to determine cost-effectiveness against a willingness-to-pay threshold of $100 000/QALY. Compared with IAT, maribavir had lower costs ($139 751 vs $147 949) and greater QALYs (6.04 vs 5.83), making it cost-saving and more cost-effective. Maribavir had higher acquisition costs compared with IAT ($80 531 vs $65 285), but lower costs associated with administration/monitoring ($16 493 vs $27 563), adverse events (AEs) ($11 055 vs $16 114), hospitalization ($27 157 vs $33 905), and graft loss ($4516 vs $5081), thus making treatment with maribavir cost-saving. Maribavir-treated patients spent more time without CMV compared with IAT-treated patients (0.85 years vs 0.68 years), leading to lower retreatment costs for maribavir (cost savings: -$42 970.80). Compared with IAT, maribavir was more cost-effective for transplant recipients with refractory CMV, owing to better clinical efficacy and avoidance of high costs associated with administration, monitoring, AEs, and hospitalizations. These results can inform healthcare decision-makers on the most effective use of their resources for post-transplant refractory CMV treatment., (© 2024 The Authors. Journal of Medical Virology published by Wiley Periodicals LLC.)

Background: Cytomegalovirus (CMV) infections among hematopoietic stem cell transplant (HSCT) and solid organ transplant (SOT) recipients impose a significant health care resource utilization (HCRU)-related economic burden. Maribavir (MBV), a novel anti-viral therapy (AVT), approved by the United States Food and Drug Administration for post-transplant CMV infections refractory (with/without resistance) to conventional AVTs has demonstrated lower hospital length of stay (LOS) versus investigator-assigned therapy (IAT; valgancilovir, ganciclovir, foscarnet, or cidofovir) in a phase 3 trial (SOLSTICE). This study estimated the HCRU costs of MBV versus IAT., Methods: An economic model was developed to estimate HCRU costs for patients treated with MBV or IAT. Mean per-patient-per-year (PPPY) HCRU costs were calculated using (i) annualized mean hospital LOS in SOLSTICE, and (ii) CMV-related direct costs from published literature. Probabilistic sensitivity analysis with Monte-Carlo simulations assessed model robustness., Results: Of 352 randomized patients receiving MBV (n = 235) or IAT (n = 117) for 8 weeks in SOLSTICE, 40% had HSCT and 60% had SOT. Mean overall PPPY HCRU costs of overall hospital-LOS were $67,205 (95% confidence interval [CI]: $33,767, $231,275) versus $145,501 (95% CI: $62,064, $589,505) for MBV and IAT groups, respectively. Mean PPPY ICU and non-ICU stay costs were: $32,231 (95% CI: $5,248, $184,524) versus $45,307 (95% CI: $3,957, $481,740) for MBV and IAT groups, and $82,237 (95% CI: $40,397, $156,945) MBV versus $228,329 (95% CI: $94,442, $517,476) for MBV and IAT groups, respectively. MBV demonstrated cost savings in over 99.99% of simulations., Conclusions: This analysis suggests that Mean PPPY HCRU costs were 29%-64% lower with MBV versus other-AVTs., (© 2024 Takeda Pharmaceuticals Inc, US and The Authors. Transplant Infectious Disease published by Wiley Periodicals LLC.)

Purpose: The human voice qualitatively changes across the lifespan. Although some of these vocal changes may be pathologic, other changes likely reflect natural physiological aging. Normative data for voice characteristics in healthy aging is limited and disparate studies have used a range of different acoustic features, some of which are implicated in pathologic voice changes. We examined the perceptual and acoustic features that predict healthy aging., Method: Participants (N = 150) aged between 50 and 92 years performed a sustained vowel task. Acoustic features were measured using the Multi-Dimensional Voice Program and the Analysis of Dysphonia in Speech and Voice. We used forward and backward variable elimination techniques based on the Bayesian information criterion and linear regression to assess which of these acoustic features predict age and perceptual features. Hearing thresholds were determined using pure-tone audiometry tests at frequencies 250 Hz, 500 Hz, 1000 Hz, 2000 Hz, and 4000 Hz. We further explored potential relationships between these acoustic features and clinical assessments of voice quality using the Consensus Auditory-Perceptual Evaluation of Voice., Results: Chronological age was significantly predicted by greater voice turbulence, variability of cepstral fundamental frequency, low relative to high spectral energy, and cepstral intensity. When controlling for hearing loss, age was significantly predicted by amplitude perturbations and cepstral intensity. Clinical assessments of voice indicated perceptual characteristics of speech were predicted by different acoustic features. For example, breathiness was predicted by the soft phonation index, mean cepstral peak prominence, mean low-high spectral ratio, and mean cepstral intensity., Conclusions: Findings suggest that acoustic features that predict healthy aging are different than those previously reported for the pathologic voice. We propose a model of healthy and pathologic voice development in which voice characteristics are mediated by the inability to monitor vocal productions associated with age-related hearing loss. This normative data of healthy vocal aging may assist in separating voice pathologies from healthy aging., (Copyright © 2021 The Voice Foundation. Published by Elsevier Inc. All rights reserved.)

The medial geniculate body (MGB) of the thalamus is an obligatory relay for auditory processing. A breakdown of adaptive filtering and sensory gating at this level may lead to multiple auditory dysfunctions, while high-frequency stimulation (HFS) of the MGB might mitigate aberrant sensory gating. To further investigate the sensory gating functions of the MGB, this study (i) recorded electrophysiological evoked potentials in response to continuous auditory stimulation, and (ii) assessed the effect of MGB HFS on these responses in noise-exposed and control animals. Pure-tone sequences were presented to assess differential sensory gating functions associated with stimulus pitch, grouping (pairing), and temporal regularity. Evoked potentials were recorded from the MGB and acquired before and after HFS (100 Hz). All animals (unexposed and noise-exposed, pre- and post-HFS) showed gating for pitch and grouping. Unexposed animals also showed gating for temporal regularity not found in noise-exposed animals. Moreover, only noise-exposed animals showed restoration comparable to the typical EP amplitude suppression following MGB HFS. The current findings confirm adaptive thalamic sensory gating based on different sound characteristics and provide evidence that temporal regularity affects MGB auditory signaling., Competing Interests: Declaration of Competing interest No conflicts of interest to report., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: This study retrospectively compared annualized billed bleed rates (ABR b ) in people with hemophilia A (PwHA) without inhibitors who switched from factor VIII (FVIII) prophylaxis to emicizumab., Research Design and Methods: A real-world comparison study was performed on the effect of switching from FVIII to emicizumab prophylaxis in male, non-inhibitor patients on ABR b using an all-payer claims database (APCD) dataset from 1 January 2014, to 31 March 2021. The identification period was from 1 November 2017, to 30 September 2020., Results: One hundred and thirty-one patients were included with a total of 82 and 45 bleeds in the pre- and post-switch periods, respectively. The average follow-up period pre-switch was 978.37 days (SD 555.03), whereas the average follow-up period post-switch was 522.26 days (SD 191.36). No significant differences in mean ABR b were observed pre-/post-switch (0.25 and 0.20, respectively; P  = 0.4456)., Conclusions: The results of this study demonstrate no significant reduction in ABR b , suggesting that switching from FVIII to emicizumab may not deliver incremental benefits to PwHA receiving prophylactic care.

Objective: To evaluate the financial impact of utilizing rpFVIII or rFVIIa during a hospital admission for the diagnosis of acquired hemophilia A (AHA) by reviewing the margin between the cost to the hospital for providing care and the amount the hospital is reimbursed by the Centers for Medicare & Medicaid Services (CMS) in the US., Methods: Data source was the Medicare Limited Data Set, which contains claims for hospitalizations, charges, and amounts reimbursed by CMS. Study patients were hospitalized with AHA and treated with rpFVIII and/or rFVIIa between 1/1/2015 and 12/31/2019. CMS Fiscal Year 2020 Impact Files, with hospital-level cost-to-charge ratios (CCRs), were used to estimate hospital costs. Sensitivity analyses were conducted to estimate margins at different CCRs., Results: Hospital margins were, on average, positive with use of either rpFVIII or rFVIIa (rpFVIII: $51,548.89; rFVIIa: $35,943.80). Sensitivity analysis results suggest that the use of rpFVIII is similiar, compared with rFVIIa for a large majority of hospitals., Conclusions: While there may be higher reimbursement for rpFVIII hospitalizations, this analysis suggests that the use of rpFVIII, compared to rFVIIa, may have no impact on hospital finances for the majority of hospitals, despite rpFVIII's higher per unit cost.

Background: Inflammatory bowel disease poses significant social and economic burdens. We assessed the budget impact of including the recently approved subcutaneous (SC) formulation of vedolizumab as maintenance therapy (MT) in patients with ulcerative colitis (UC) in France., Methods: A decision-analytic model was developed from a French payer's perspective over 5 years to assess budget impact of including vedolizumab SC as MT for UC following induction therapy with vedolizumab intravenous (IV), by subtracting outcomes of a 'world without vedolizumab SC' from a 'world with vedolizumab SC.' Comparators included approved therapies: infliximab (branded/biosimilar), adalimumab (branded/biosimilar), golimumab, ustekinumab, and vedolizumab IV. The model predicts drug, medical, and total costs, including indirect costs in a scenario analysis. A one-way sensitivity analysis explored the impact of varying individual parameters., Results: Including vedolizumab SC as MT following vedolizumab IV induction yielded total cost savings of €59,176,842 (biologic-naïve) and €22,004,135 (biologic-experienced) versus a world without vedolizumab SC. Including indirect costs yielded cost savings in biologic-naïve (€62,600,716) and biologic-experienced (€24,314,915) populations in a world with vedolizumab SC., Conclusions: Introducing vedolizumab SC as MT after IV induction is expected to have substantial cost savings to a health plan from a French payer's perspective versus a world without vedolizumab SC.

Aims: To compare healthcare costs in patients with non-inhibitor hemophilia A treated with Rurioctocog Alfa Pegol (FVIII-PEG) versus Antihemophilic Factor (Recombinant), FC Fusion Protein (rFVIIIFc)., Materials and Methods: Administrative claims data from the Merative MarketScan Commercial (Commerical) and Medicaid (Medicaid) databases were used for these analyses. Males with non-inhibitor hemophilia A treated with FVIII-PEG or rFVIIIFc from 1 January 2016 to 31 March 2021 were identified (earliest treatment = index). Patients were required to have continuous database enrollment for six months before and after the index date. Follow-up was variable in length until disenrollment or study end. All-cause and hemophilia-related healthcare costs were reported per-patient per month [PPPM] and the average weekly dose during follow-up was compared between treatment groups. Generalized linear regressions were used to estimate multivariable-adjusted differences in total costs and weekly dosage in the two treatment groups., Results: A total of 131 FVIII-PEG (66 Commercial; 65 Medicaid) and 204 rFVIIIFc (111 Commercial; 93 Medicaid) patients were eligible. Mean age was 20.5 and 24.4 for FVIII-PEG and rFVIIIFc in Commercial and 14.9 and 17.5 for FVIII-PEG and rFVIIIFc in Medicaid. PPPM mean (standard deviations [SD]) total healthcare costs in Commercially insured patients were $35,868 [$21,717] for FVIII-PEG vs $40,424 [$25,882] for rFVIIIFc. Costs in Medicaid were $27,495 [$23,243] for FVIII-PEG vs $30,237 [$28,430] for rFVIIIFc. After adjusting for baseline characteristics, the costs for rFVIIIFc (vs FVIII-PEG) were higher by $5,215 in Commercial and $3,895 in Medicaid, but the differences were not statistically significant ( p  > 0.05). Similar findings were observed for hemophilia-specific healthcare costs. The adjusted mean weekly dose was 6,047 vs 4,892 IU, p  = 0.21 for FVIII-PEG vs rFVIIIFc in Commercial and 5,549 vs 7,228 IU, p  = 0.07 for FVIII-PEG vs rFVIIIFc in Medicaid., Conclusions: Healthcare costs and treatment dosing were similar ( p  > 0.05) for non-inhibitor hemophilia A patients treated with FVIII-PEG and rFVIIIFc.

Aims: Investigate trends in paid lanadelumab costs over time in a population of patients persistent for 18 months, and to understand overall hereditary angioedema (HAE) treatment cost trends, including costs of acute medication/short-term prophylaxis and supportive care. Lastly, we sought to describe the proportion of lanadelumab patients with evidence of down titration via changes in total paid amounts for lanadelumab in a fixed time period., Methods: Patients were identified in the Merative MarketScan Databases who had ≥1 claim for lanadelumab during 1/1/2018-6/30/2022 (index), a  ≤ 60-d gap in days of supply over 18 months, and were enrolled for ≥6 months pre-index and 18 months post-index. Lanadelumab and HAE-specific costs were assessed during follow-up months 0-6, 7-12, and 13-18. Down titration was defined as a  ≥ 25% decrease in lanadelumab costs from months 0-6 to months 7-12 or 13-18. Outcomes were compared between time periods using paired t -tests and McNemar's test., Results: Fifty-four lanadelumab users were included; 25 (46%) had evidence of down titration. Lanadelumab costs decreased from $316,724 to $269,861 to $246,919 in months 0-6, 7-12, and 13-18, respectively ( p  < .01); total HAE treatment costs decreased from $377,076 to $329,855 to $286,074 in months 0-6, 7-12, and 13-18, respectively ( p  < .01)., Limitations: Persistence was determined via days of supply on medication claims; use of the medication was not confirmed. Down titration was based on costs; the lanadelumab regimen could not be assessed. Results may not be generalizable to uninsured patients or those without commercial or Medicare insurance., Conclusions: Patients on long-term prophylaxis with lanadelumab experienced a significant reduction (24%) in HAE treatment costs over 18 months, driven by lower costs of acute medications and lanadelumab down titration. Down titration among appropriate patients with controlled HAE may lead to substantial savings in healthcare costs.

Background: Factor VIII (FVIII) replacement and emicizumab are effective at preventing bleeds in patients with hemophilia A (HA). Though benefits of emicizumab among inhibitor patients with HA (PwHA) are well established, more real-world evidence among non-inhibitor patients is needed., Methods: Using a United States healthcare claims database, we compared billed annualized bleed rates (ABR b ) and the total cost of care (TCC) before and after switching from FVIII prophylaxis to emicizumab among non-inhibitor male PwHA. Bayesian inferences were used to assess the difference in ABR b and TCC per patient per year (PPPY) pre- versus post-prophylaxis switch., Results: We included 101 non-inhibitor male PwHA aged between 3 and 63 years old who switched from FVIII prophylaxis to emicizumab prophylaxis in 2018 or 2019. The ABR b increased from 0.52 to 0.62 ( p  = 0.83) after switch. The posterior probability of the mean ABR b increasing after the switch was 75.54%. The TCC PPPY increased from $517,143 to $627,005 ( p  < 0.0001) after switch and the posterior probability of mean costs increasing after the switch was 99.80%., Conclusions: Personalization of care through the identification of the most appropriate therapy for each patient can optimize clinical and economic outcomes. Future real-world evidence research could help establish the value of prophylactic options in targeted populations such as the non-inhibitor male PwHA.

Neurodegenerative disease often affects speech. Speech acoustics can be used as objective clinical markers of pathology. Previous investigations of pathological speech have primarily compared controls with one specific condition and excluded comorbidities. We broaden the utility of speech markers by examining how multiple acoustic features can delineate diseases. We used supervised machine learning with gradient boosting (CatBoost) to delineate healthy speech from speech of people with multiple sclerosis or Friedreich ataxia. Participants performed a diadochokinetic task where they repeated alternating syllables. We subjected 74 spectral and temporal prosodic features from the speech recordings to machine learning. Results showed that Friedreich ataxia, multiple sclerosis and healthy controls were all identified with high accuracy (over 82%). Twenty-one acoustic features were strong markers of neurodegenerative diseases, falling under the categories of spectral qualia, spectral power, and speech rate. We demonstrated that speech markers can delineate neurodegenerative diseases and distinguish healthy speech from pathological speech with high accuracy. Findings emphasize the importance of examining speech outcomes when assessing indicators of neurodegenerative disease. We propose large-scale initiatives to broaden the scope for differentiating other neurological diseases and affective disorders.

Background: Determining the relative cost-effectiveness between advanced therapeutic options for ulcerative colitis (UC) may optimize resource utilization. We evaluated total cost per response, cost per remission, and cost of safety events for patients with moderately-to-severely active UC after 52 weeks of treatment with advanced therapies at standard dosing., Methods: An analytic model was developed to estimate costs from the US healthcare system perspective associated with achieving efficacy outcomes and managing safety outcomes for advanced therapies approved for the treatment of UC. Numbers needed to treat (NNT) for response and remission, and numbers needed to harm (NNH) for serious adverse events (SAEs) and serious infections (SIs) were derived from a network meta-analysis of pivotal trials. NNT for induction and maintenance were combined with drug regimen costs to calculate cost per clinical remission. Cost of managing AEs was calculated using NNH for safety outcomes and published costs of treating respective AEs., Results: Costs per remission were $205,240, $249,417, $267,463, $365,050, $579,622, $750,200, and $787,998 for tofacitinib 10 mg, tofacitinib 5 mg, infliximab, vedolizumab, golimumab, adalimumab, and ustekinumab, respectively. Incremental costs of SAEs and SIs collectively were $136,390, $90,333, $31,888, $31,061, $20,049, $12,059, and $0 for tofacitinib 5 mg, golimumab, adalimumab, tofacitinib 10 mg, infliximab, ustekinumab, and vedolizumab (reference), respectively., Conclusions: Tofacitinib was associated with the lowest cost per response and cost per remission, while vedolizumab had the lowest costs related to SAEs and SIs. Balancing efficacy versus safety is important when evaluating the costs associated with treatment of moderate-to-severe UC., (© 2022. The Author(s).)

Providing natural opportunities that scaffold interpersonal engagement is important for supporting social interactions for young children with Autism spectrum disorder (ASD). Musical activities are often motivating, familiar, and predictable, and may support both children and their interaction partners by providing opportunities for shared social engagement. We assessed multiple facets of nonverbal social engagement - child and caregiver visual attention and interpersonal movement coordination - during musical (song) and non-musical (picture) book-sharing contexts in caregiver-child dyads of preschoolers with ( n = 13) and without ( n = 16) ASD. Overall, children with ASD demonstrated reduced visual attention during the book sharing activity, as well as reduced movement coordination with their caregivers, compared to children with typical development. Children in both diagnostic groups, as well as caregivers, demonstrated greater visual attention (gaze toward the activity and/or social partner) during song books compared to picture books. Visual attention behavior was correlated between children and caregivers in the ASD group but only in the song book condition. Findings highlight the importance of considering how musical contexts impact the behavior of both partners in the interaction. Musical activities may support social engagement by modulating the behavior of both children and caregivers., Competing Interests: Declaration of Conflicting Interests The authors have no conflicts of interest to disclose. We have no known conflicts of interest to disclose.

Objective: Factor VIII (FVIII) replacement and emicizumab have demonstrated efficacy for prevention of bleeds among patients with hemophilia A (PwHA) compared to on-demand (OD) use. Evidence investigating clinical outcomes and healthcare costs of non-inhibitor PwHA switching from prophylaxis with FVIII concentrates to emicizumab has not been well-established within large real-world datasets. This study aimed to investigate billed annualized bleed rates (ABR b ) and total cost of care (TCC) among non-inhibitor PwHA switching from FVIII-prophylaxis to emicizumab-prophylaxis., Methods: This retrospective, observational study was conducted using IQVIA PharMetrics Plus, a US administrative claims database. The date of first claim for emicizumab was defined as the index date. OD patients and inhibitor patients were excluded. Bleeds were identified using a list of 535 diagnosis codes. Bayesian models were developed to estimate the probability ABR b worsens and TCC increases after switching to emicizumab. Wilcoxon rank-sum tests were used to test statistical significance of changes in ABR b and TCC after switch., Results: Among the 121 identified patients, the difference in mean ABR b between FVIII-prophylaxis (0.68 [SD = 1.28]) and emicizumab (0.55 [SD = 1.48]) was insignificant ( p  = .142). The mean annual TCC significantly increased for patients switching from FVIII-prophylaxis ($518,151 [SD = $289,934]) to emicizumab ($652,679 [SD = $340,126]; p  < .0001). The Bayesian models estimated a 21.0% probability of the ABR b worsening and a 99.9% probability of increasing TCC after switch., Conclusions: This study found that in male non-inhibitor PwHA, switching from FVIII prophylaxis to emicizumab incurs substantial cost increase with no significant benefit in ABR b . This evidence may help guide providers, payers, and patients in shared decision-making conversations around best treatment options.

Purpose: The human voice changes with the progression of neurological disease and the onset of diseases that affect articulators, often decreasing the effectiveness of communication. These changes can be objectively measured using signal processing techniques that extract acoustic features. When measuring acoustic features, there are often several steps and assumptions that might be known to experts in acoustics and phonetics, but are less transparent for other disciplines (e.g., clinical medicine, speech pathology, engineering, and data science). This tutorial describes these signal processing techniques, explicitly outlines the underlying steps for accurate measurement, and discusses the implications of clinical acoustic markers., Conclusions: We establish a vocabulary using straightforward terms, provide visualizations to achieve common ground, and guide understanding for those outside the domains of acoustics and auditory signal processing. Where possible, we highlight the best practices for measuring clinical acoustic markers and suggest resources for obtaining and further understanding these measures.

During multisensory speech perception, slow δ oscillations (∼1-3 Hz) in the listener's brain synchronize with the speech signal, likely engaging in speech signal decomposition. Notable fluctuations in the speech amplitude envelope, resounding speaker prosody, temporally align with articulatory and body gestures and both provide complementary sensations that temporally structure speech. Further, δ oscillations in the left motor cortex seem to align with speech and musical beats, suggesting their possible role in the temporal structuring of (quasi)-rhythmic stimulation. We extended the role of δ oscillations to audiovisual asynchrony detection as a test case of the temporal analysis of multisensory prosody fluctuations in speech. We recorded Electroencephalograph (EEG) responses in an audiovisual asynchrony detection task while participants watched videos of a speaker. We filtered the speech signal to remove verbal content and examined how visual and auditory prosodic features temporally (mis-)align. Results confirm (1) that participants accurately detected audiovisual asynchrony, and (2) increased δ power in the left motor cortex in response to audiovisual asynchrony. The difference of δ power between asynchronous and synchronous conditions predicted behavioral performance, and (3) decreased δ-β coupling in the left motor cortex when listeners could not accurately map visual and auditory prosodies. Finally, both behavioral and neurophysiological evidence was altered when a speaker's face was degraded by a visual mask. Together, these findings suggest that motor δ oscillations support asynchrony detection of multisensory prosodic fluctuation in speech. SIGNIFICANCE STATEMENT Speech perception is facilitated by regular prosodic fluctuations that temporally structure the auditory signal. Auditory speech processing involves the left motor cortex and associated δ oscillations. However, visual prosody (i.e., a speaker's body movements) complements auditory prosody, and it is unclear how the brain temporally analyses different prosodic features in multisensory speech perception. We combined an audiovisual asynchrony detection task with electroencephalographic (EEG) recordings to investigate how δ oscillations support the temporal analysis of multisensory speech. Results confirmed that asynchrony detection of visual and auditory prosodies leads to increased δ power in left motor cortex and correlates with performance. We conclude that δ oscillations are invoked in an effort to resolve denoted temporal asynchrony in multisensory speech perception., (Copyright © 2022 the authors.)

BACKGROUND: The efficacy of intravenous (IV) vedolizumab vs subcutaneous (SC) adalimumab for the treatment of moderately to severely active ulcerative colitis (UC) was assessed in the VARSITY clinical trial, which demonstrated for the first time in a head-to-head clinical trial setting the superiority of IV vedolizumab with respect to clinical remission and endoscopic improvement. Both therapies offer better clinical outcomes compared with immunomodulators and corticosteroids but are often more expensive than other pharmacologic treatment options. Thus, payers and decision makers face the task of leveraging finite resources for optimal health benefits, which can be aided by the use of cost-effectiveness models. OBJECTIVE: To assess the cost-effectiveness of IV vedolizumab vs SC adalimumab from a US payer perspective using head-to-head data from the VARSITY trial. METHODS: A cohort decision tree was developed to estimate the costs and clinical outcomes associated with IV vedolizumab vs SC adalimumab to treat adults with moderately to severely active UC. Simulated cohorts began the model at treatment induction and continued to maintenance treatment with vedolizumab or adalimumab unless experiencing nonresponse or serious adverse drug reaction (ADR), in which case those patients transitioned to second-line treatment with tofacitinib, infliximab, or golimumab, where they could achieve response and/or remission or not. Those who still did not achieve response or remission or who had a serious ADR transitioned to a state of nonresponse for the remainder of the model or received surgery. The process was modeled for patients who were treatment naive and treatment experienced at baseline separately. Efficacy and safety inputs for vedolizumab and adalimumab were taken from the VARSITY trial, and corresponding inputs for other biologics were derived from a network meta-analysis. All clinical inputs were extrapolated over 2 years. Direct medical costs (expressed in 2019 US dollars) included those related to drug acquisition and administration, ADRs, routine monitoring, and additional treatment procedures. Outcomes were not discounted given the short time horizon. Univariate sensitivity and scenario analysis were applied to evaluate the robustness of the model to underlying parameter and structural uncertainty. RESULTS: Initial treatment with vedolizumab was associated with a higher remission rate at 2 years (73.5% vs 71.5%) and higher persistence (22.0% vs 14.4%) compared with adalimumab. Total direct medical costs were lower for the vedolizumab cohort ($100,022 vs $151,133), primarily driven by the lower annual drug acquisition cost of vedolizumab ($85,953 vs $137,492). When endoscopic improvement was used as the outcome measure, IV vedolizumab was also associated with higher endoscopic remission and lower overall costs. CONCLUSIONS: With better clinical outcomes and lower direct medical costs over a 2-year model horizon, vedolizumab IV was the dominant treatment strategy vs adalimumab SC in adults with moderately to severely active UC. Outcomes were driven primarily by the probability of major ADRs and induction response. DISCLOSURES: This study was supported by Takeda Pharmaceuticals U.S.A., Inc. (Lexington, MA). Schultz and Turpin are employees of Takeda Pharmaceuticals U.S.A., Inc. Turpin has stock or stock options in Takeda Pharmaceuticals. Diakite, Carter, and Snedecor are employees of OPEN Health (Bethesda, MD), which received payment from Takeda for the design and execution of this study. This study was presented at the European Crohn's and Colitis Organisation (ECCO) 2020 Congress and Digestive Disease Week (DDW), 2020 Virtual Congress.

Objectives: Uncontrolled hypertension is a common cause of cardiovascular disease, which is the deadliest and costliest chronic disease in the United States. Pharmacists are an accessible community healthcare resource and are equipped with clinical skills to improve the management of hypertension through medication therapy management (MTM). Nevertheless, current reimbursement models do not incentivize pharmacists to provide clinical services. We aim to investigate the cost-effectiveness of a pharmacist-led comprehensive MTM clinic compared with no clinic for 10-year primary prevention of stroke and cardiovascular disease events in patients with hypertension., Methods: We built a semi-Markov model to evaluate the clinical and economic consequences of an MTM clinic compared with no MTM clinic, from the payer perspective. The model was populated with data from a recently published controlled observational study investigating the effectiveness of an MTM clinic. Methodology was guided using recommendations from the Second Panel on Cost-Effectiveness in Health and Medicine, including appropriate sensitivity analyses., Results: Compared with no MTM clinic, the MTM clinic was cost-effective with an incremental cost-effectiveness ratio of $38 798 per quality-adjusted life year (QALY) gained. The incremental net monetary benefit was $993 294 considering a willingness-to-pay threshold of $100 000 per QALY. Health-benefit benchmarks at $100 000 per QALY and $150 000 per QALY translate to a 95% and 170% increase from current reimbursement rates for MTM services., Conclusions: Our model shows current reimbursement rates for pharmacist-led MTM services may undervalue the benefit realized by US payers. New reimbursement models are needed to allow pharmacists to offer cost-effective clinical services., (Copyright © 2020 ISPOR–The Professional Society for Health Economics and Outcomes Research. Published by Elsevier Inc. All rights reserved.)

Audio-motor integration is currently viewed as a predictive process in which the brain simulates upcoming sounds based on voluntary actions. This perspective does not consider how our auditory environment may trigger involuntary action in the absence of prediction. We address this issue by examining the relationship between acoustic salience and involuntary motor responses. We investigate how acoustic features in music contribute to the perception of salience, and whether those features trigger involuntary peripheral motor responses. Participants with little-to-no musical training listened to musical excerpts once while remaining still during the recording of their muscle activity with surface electromyography (sEMG), and again while they continuously rated perceived salience within the music using a slider. We show cross-correlations between 1) salience ratings and acoustic features, 2) acoustic features and spontaneous muscle activity, and 3) salience ratings and spontaneous muscle activity. Amplitude, intensity, and spectral centroid were perceived as the most salient features in music, and fluctuations in these features evoked involuntary peripheral muscle responses. Our results suggest an involuntary mechanism for audio-motor integration, which may rely on brainstem-spinal or brainstem-cerebellar-spinal pathways. Based on these results, we argue that a new framework is needed to explain the full range of human sensorimotor capabilities. This goal can be achieved by considering how predictive and reactive audio-motor integration mechanisms could operate independently or interactively to optimize human behavior., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Wearing face masks (alongside physical distancing) provides some protection against infection from COVID-19. Face masks can also change how people communicate and subsequently affect speech signal quality. This study investigated how three common face mask types (N95, surgical, and cloth) affected acoustic analysis of speech and perceived intelligibility in healthy subjects. Acoustic measures of timing, frequency, perturbation, and power spectral density were measured. Speech intelligibility and word and sentence accuracy were also examined using the Assessment of Intelligibility of Dysarthric Speech. Mask type impacted the power distribution in frequencies above 3 kHz for the N95 mask, and above 5 kHz in surgical and cloth masks. Measures of timing and spectral tilt mainly differed with N95 mask use. Cepstral and harmonics to noise ratios remained unchanged across mask type. No differences were observed across conditions for word or sentence intelligibility measures; however, accuracy of word and sentence translations were affected by all masks. Data presented in this study show that face masks change the speech signal, but some specific acoustic features remain largely unaffected (e.g., measures of voice quality) irrespective of mask type. Outcomes have bearing on how future speech studies are run when personal protective equipment is worn.

Background: Researchers rely on the specified capabilities of their hardware and software even though, in reality, these capabilities are often not achieved. Considering that the number of experiments examining neural oscillations has increased steadily, easy-to-implement tools for testing the capabilities of hardware and software are necessary., New Method: We present an open-source MATLAB toolbox, the Schultz Cigarette Burn Toolbox (SCiBuT) that allows users to benchmark the capabilities of their visual display devices and align neural and behavioral responses with veridical timing of visual stimuli. Specifically, the toolbox marks the corners of the display with black or white squares to indicate the timing of the onset of static images and the timing of frame changes within videos. Using basic hardware (i.e., a photodiode, an Arduino microcontroller, and an analogue input box), the light changes in the corner of the screen can be captured and synchronized with EEG recordings and/or behavioral responses., Results: We demonstrate that the SCiBuT is sensitive to framerate inconsistencies and provide examples of hardware setups that are suboptimal for measuring fine timing. Finally, we show that inconsistencies in framerate during video presentation can affect EEG oscillations., Conclusions: The SCiBuT provides tools to benchmark framerates and frame changes and to synchronize frame changes with neural and behavioral signals. This is the first open-source toolbox that can perform these functions. The SCiBuT can be freely downloaded (www.band-lab.com/scibut) and be used during experimental trials to improve the accuracy and precision of timestamps to ensure videos are presented at the intended framerate., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.)

Most human communication is carried by modulations of the voice. However, a wide range of cultures has developed alternative forms of communication that make use of a whistled sound source. For example, whistling is used as a highly salient signal for capturing attention, and can have iconic cultural meanings such as the catcall, enact a formal code as in boatswain's calls or stand as a proxy for speech in whistled languages. We used real-time magnetic resonance imaging to examine the muscular control of whistling to describe a strong association between the shape of the tongue and the whistled frequency. This bioacoustic profile parallels the use of the tongue in vowel production. This is consistent with the role of whistled languages as proxies for spoken languages, in which one of the acoustical features of speech sounds is substituted with a frequency-modulated whistle. Furthermore, previous evidence that non-human apes may be capable of learning to whistle from humans suggests that these animals may have similar sensorimotor abilities to those that are used to support speech in humans.

Forming temporal expectancies plays a crucial role in our survival as it allows us to identify the occurrence of temporal deviants that might signal potential dangers. The dynamic attending theory suggests that temporal expectancies are formed more readily for rhythms that imply a beat (i.e., metrical rhythms) compared to those that do not (i.e., nonmetrical rhythms). Moreover, metrical frameworks can be used to detect temporal deviants. Although several studies have demonstrated that congenital or early blindness correlates with modality-specific neural changes that reflect compensatory mechanisms, few have examined whether blind individuals show a learning advantage for auditory rhythms and whether learning can occur unintentionally and without awareness, that is, implicitly. We compared blind to sighted controls in their ability to implicitly learn metrical and nonmetrical auditory rhythms. We reasoned that the loss of sight in blindness might lead to improved sensitivity to rhythms and predicted that the blind learn rhythms more readily than the sighted. We further hypothesized that metrical rhythms are learned more readily than nonmetrical rhythms. Results partially confirmed our predictions; the blind group learned nonmetrical rhythms more readily than the sighted group but the blind group learned metrical rhythms less readily than the sighted group. Only the sighted group learned metrical rhythms more readily than nonmetrical rhythms. The blind group demonstrated awareness of the nonmetrical rhythms while learning was implicit for all other conditions. Findings suggest that improved deviant-sensitivity might have provided the blind group a learning advantage for nonmetrical rhythms. Future research could explore the plastic changes that affect deviance-detection and stimulus-specific adaptation in blindness.

Auditory feedback of actions provides additional information about the timing of one's own actions and those of others. However, little is known about how musicians and nonmusicians integrate auditory feedback from multiple sources to regulate their own timing or to (intentionally or unintentionally) coordinate with a partner. We examined how musical expertise modulates the role of auditory feedback in a two-person synchronization-continuation tapping task. Pairs of individuals were instructed to tap at a rate indicated by an initial metronome cue in all four auditory feedback conditions: no feedback, self-feedback (cannot hear their partner), other feedback (cannot hear themselves), or full feedback (both self and other). Participants within a pair were either both musically trained (musicians), both untrained (nonmusicians), or one musically trained and one untrained (mixed). Results demonstrated that all three pair types spontaneously synchronized with their partner when receiving other or full feedback. Moreover, all pair types were better at maintaining the metronome rate with self-feedback than with no feedback. Musician pairs better maintained the metronome rate when receiving other feedback than when receiving no feedback; in contrast, nonmusician pairs were worse when receiving other or full feedback compared to no feedback. Both members of mixed pairs maintained the metronome rate better in the other and full feedback conditions than in the no feedback condition, similar to musician pairs. Overall, nonmusicians benefited from musicians' expertise without negatively influencing musicians' ability to maintain the tapping rate. One implication is that nonmusicians may improve their beat-keeping abilities by performing tasks with musically skilled individuals.

The Musical Instrument Digital Interface (MIDI) was readily adopted for auditory sensorimotor synchronization experiments. These experiments typically use MIDI percussion pads to collect responses, a MIDI-USB converter (or MIDI-PCI interface) to record responses on a PC and manipulate feedback, and an external MIDI sound module to generate auditory feedback. Previous studies have suggested that auditory feedback latencies can be introduced by these devices. The Schultz MIDI Benchmarking Toolbox (SMIDIBT) is an open-source, Arduino-based package designed to measure the point-to-point latencies incurred by several devices used in the generation of response-triggered auditory feedback. Experiment 1 showed that MIDI messages are sent and received within 1 ms (on average) in the absence of any external MIDI device. Latencies decreased when the baud rate increased above the MIDI protocol default (31,250 bps). Experiment 2 benchmarked the latencies introduced by different MIDI-USB and MIDI-PCI interfaces. MIDI-PCI was superior to MIDI-USB, primarily because MIDI-USB is subject to USB polling. Experiment 3 tested three MIDI percussion pads. Both the audio and MIDI message latencies were significantly greater than 1 ms for all devices, and there were significant differences between percussion pads and instrument patches. Experiment 4 benchmarked four MIDI sound modules. Audio latencies were significantly greater than 1 ms, and there were significant differences between sound modules and instrument patches. These experiments suggest that millisecond accuracy might not be achievable with MIDI devices. The SMIDIBT can be used to benchmark a range of MIDI devices, thus allowing researchers to make informed decisions when choosing testing materials and to arrive at an acceptable latency at their discretion.

Chronic inflammatory diseases are complex to treat and have an impact on a large number of patients. Due to the difficulty of treating these diseases and the great impact on quality of life, patients often seek off-label, complimentary, or alternative medicines to gain relief from symptoms. Low-dose naltrexone has been used off-label for treatment of pain and inflammation in multiple sclerosis, Crohn's disease, fibromyalgia, and other diseases. Naltrexone is a mu-opioid receptor antagonist indicated by the U.S. Food and Drug Administration for opioid and alcohol dependence. It is hypothesized that lower than standard doses of naltrexone inhibit cellular proliferation of T and B cells and block Toll-like receptor 4, resulting in an analgesic and antiinflammatory effect. It is the purpose of this review to examine the evidence of the safety, tolerability, and efficacy of low-dose naltrexone for use in chronic pain and inflammatory conditions. Currently, evidence supports the safety and tolerability of low-dose naltrexone in multiple sclerosis, fibromyalgia, and Crohn's disease. Fewer studies support the efficacy of low-dose naltrexone, with most of these focusing on subjective measures such as quality of life or self-reported pain. These studies do demonstrate that low-dose naltrexone has subjective benefits over placebo, but evidence for more objective measures is limited. However, further randomized controlled trials are needed to determine the efficacy of low-dose naltrexone due to insufficient evidence supporting its use in these disease states. This review provides practitioners with the extent of low-dose naltrexone evidence so that they can be cognizant of situations where it may not be the most appropriate therapy., (© 2018 Pharmacotherapy Publications, Inc.)

Nearly 30% of adults 40 years and older in the United States are on a statin. Their widespread use heightens the importance of careful consideration of their varied effects on the body. Although randomized controlled trials have not confirmed cognitive impairing effects with statins, continuing evidence suggests statins have the ability to cause reversible cognitive impairment in some patients. Paradoxically, statins have also been shown to decrease the risk of dementia, Alzheimer's disease, and improve cognitive impairment in some cases. However, randomized controlled trials have similarly failed to find the beneficial effect. Supporting evidence for both claims is compelling whereas known limitations of the clinical trials may explain the lack of findings. This narrative review aims to explain why there is still controversy and how both effects can, and may, be possible. The mechanisms that have been hypothesized for each effect are seemingly independent from one another and may explain the contradicting results. Being mindful of the complex effects of statins, health care providers need to be able to identify patients who are at risk for or already experiencing cognitive impairment from statin use while also identifying those who could potentially decrease their risk of dementia with statins., Competing Interests: Not Applicable.All authors consent to publication of all individual data included within the manuscript.The authors declare they have no competing interests.

Timing abilities are often measured by having participants tap their finger along with a metronome and presenting tap-triggered auditory feedback. These experiments predominantly use electronic percussion pads combined with software (e.g., FTAP or Max/MSP) that records responses and delivers auditory feedback. However, these setups involve unknown latencies between tap onset and auditory feedback and can sometimes miss responses or record multiple, superfluous responses for a single tap. These issues may distort measurements of tapping performance or affect the performance of the individual. We present an alternative setup using an Arduino microcontroller that addresses these issues and delivers low-latency auditory feedback. We validated our setup by having participants (N = 6) tap on a force-sensitive resistor pad connected to the Arduino and on an electronic percussion pad with various levels of force and tempi. The Arduino delivered auditory feedback through a pulse-width modulation (PWM) pin connected to a headphone jack or a wave shield component. The Arduino's PWM (M = 0.6 ms, SD = 0.3) and wave shield (M = 2.6 ms, SD = 0.3) demonstrated significantly lower auditory feedback latencies than the percussion pad (M = 9.1 ms, SD = 2.0), FTAP (M = 14.6 ms, SD = 2.8), and Max/MSP (M = 15.8 ms, SD = 3.4). The PWM and wave shield latencies were also significantly less variable than those from FTAP and Max/MSP. The Arduino missed significantly fewer taps, and recorded fewer superfluous responses, than the percussion pad. The Arduino captured all responses, whereas at lower tapping forces, the percussion pad missed more taps. Regardless of tapping force, the Arduino outperformed the percussion pad. Overall, the Arduino is a high-precision, low-latency, portable, and affordable tool for auditory experiments.

Philosophers have proposed that when people coordinate their actions with others they may experience a sense of joint agency, or shared control over actions and their effects. However, little empirical work has investigated the sense of joint agency. In the current study, pairs coordinated their actions to produce tone sequences and then rated their sense of joint agency on a scale ranging from shared to independent control. People felt more shared than independent control overall, confirming that people experience joint agency during joint action. Furthermore, people felt stronger joint agency when they (a) produced sequences that required mutual coordination compared to sequences in which only one partner had to coordinate with the other, (b) held the role of follower compared to leader, and (c) were better coordinated with their partner. Thus, the strength of joint agency is influenced by the degree to which people mutually coordinate with each other's actions., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Ecstasy use has been associated with short-term and long-term memory deficits on a standard Word Learning Task (WLT). The clinical relevance of this has been debated and is currently unknown. The present study aimed at evaluating the clinical relevance of verbal memory impairment in Ecstasy users. To that end, clinical memory impairment was defined as decrement in memory performance that exceeded the cut-off value of 1.5 times the standard deviation of the average score in the healthy control sample. The primary question was whether being an Ecstasy user (E-user) was predictive of having clinically deficient memory performance compared to a healthy control group., Methods: WLT data were pooled from four experimental MDMA studies that compared memory performance during placebo and MDMA intoxication. Control data were taken from healthy volunteers with no drug use history who completed the WLT as part of a placebo-controlled clinical trial. This resulted in a sample size of 65 E-users and 65 age- and gender-matched healthy drug-naïve controls. All participants were recruited by similar means and were tested at the same testing facilities using identical standard operating procedures. Data were analyzed using linear mixed-effects models, Bayes factor, and logistic regressions., Results: Findings were that verbal memory performance of placebo-treated E-users did not differ from that of controls, and there was substantial evidence in favor of the null hypothesis. History of use was not predictive of memory impairment. During MDMA intoxication of E-users, verbal memory was impaired., Conclusion: The combination of the acute and long-term findings demonstrates that, while clinically relevant memory impairment is present during intoxication, it is absent during abstinence. This suggests that use of Ecstasy/MDMA does not lead to clinically deficient memory performance in the long term. Additionally, it has to be investigated whether the current findings apply to more complex cognitive measures in diverse 'user categories' using a combination of genetics, imaging techniques and neuropsychological assessments.

Implicit learning (IL) occurs unconsciously and without intention. Perceptual fluency is the ease of processing elicited by previous exposure to a stimulus. It has been assumed that perceptual fluency is associated with IL. However, the role of perceptual fluency following IL has not been investigated in temporal pattern learning. Two experiments by Schultz, Stevens, Keller, and Tillmann demonstrated the IL of auditory temporal patterns using a serial reaction-time task and a generation task based on the process dissociation procedure. The generation task demonstrated that learning was implicit in both experiments via motor fluency, that is, the inability to suppress learned information. With the aim to disentangle conscious and unconscious processes, we analyze unreported recognition data associated with the Schultz et al. experiments using the sequence identification measurement model. The model assumes that perceptual fluency reflects unconscious processes and IL. For Experiment 1, the model indicated that conscious and unconscious processes contributed to recognition of temporal patterns, but that unconscious processes had a greater influence on recognition than conscious processes. In the model implementation of Experiment 2, there was equal contribution of conscious and unconscious processes in the recognition of temporal patterns. As Schultz et al. demonstrated IL in both experiments using a generation task, and the conditions reported here in Experiments 1 and 2 were identical, two explanations are offered for the discrepancy in model and behavioral results based on the two tasks: 1) perceptual fluency may not be necessary to infer IL, or 2) conscious control over implicitly learned information may vary as a function of perceptual fluency and motor fluency.

Implicit learning (IL) occurs unintentionally. IL of temporal patterns has received minimal attention, and results are mixed regarding whether IL of temporal patterns occurs in the absence of a concurrent ordinal pattern. Two experiments examined the IL of temporal patterns and the conditions under which IL is exhibited. Experiment 1 examined whether uncertainty of the upcoming stimulus identity obscures learning. Based on probabilistic uncertainty, it was hypothesized that stimulus-detection tasks are more sensitive to temporal learning than multiple-alternative forced-choice tasks because of response uncertainty in the latter. Results demonstrated IL of metrical patterns in the stimulus-detection but not the multiple-alternative task. Experiment 2 investigated whether properties of rhythm (i.e., meter) benefit IL using the stimulus-detection task. The metric binding hypothesis states that metrical frameworks guide attention to periodic points in time. Based on the metric binding hypothesis, it was hypothesized that metrical patterns are learned faster than nonmetrical patterns. Results demonstrated learning of metrical and nonmetrical patterns but metrical patterns were not learned more readily than nonmetrical patterns. However, abstraction of a metrical framework was still evident in the metrical condition. The present study shows IL of auditory temporal patterns in the absence of an ordinal pattern.