Safety and Dose-Response of Vidofludimus Calcium in Relapsing Multiple Sclerosis: Extended Results of a Placebo-Controlled Phase 2 Trial.

BACKGROUND AND OBJECTIVES: Vidofludimus calcium suppressed MRI disease activity compared with placebo in patients with relapsing-remitting multiple sclerosis (RRMS) in the first cohort of the phase 2 EMPhASIS study. Because 30 mg and 45 mg showed comparable activity on multiple end points, the study enrolled an additional low-dose cohort to further investigate a dose-response relationship. METHODS: In a randomized, placebo-controlled, phase 2 trial, patients with RRMS, aged 18-55 years, and with ≥2 relapses in the last 2 years or ≥1 relapse in the last year, and ≥1 gadolinium-enhancing brain lesion in the last 6 months. Patients were randomly assigned (1:1:1) vidofludimus calcium (30 or 45 mg) or placebo in cohort 1 and vidofludimus calcium (10 mg) or placebo (4:1) in cohort 2 for 24 weeks. The primary end point was the cumulative number of combined unique active (CUA) lesions at week 24. Secondary end points were clinical outcomes and safety. RESULTS: Across cohorts 1 and 2, 268 patients were randomized to placebo (n = 81), 10 mg (n = 47) vidofludimus calcium, 30 mg (n = 71) vidofludimus calcium, or 45 mg (n = 69) vidofludimus calcium. The mean cumulative CUA lesions over 24 weeks was 5.8 (95% CI 4.1-8.2) for placebo, 5.9 (95% CI 3.9-9.0) for 10 mg treatment group, 1.4 (95% CI 0.9-2.1) for 30 mg treatment group, and 1.7 (95% CI 1.1-2.5) for 45 mg treatment group. Serum neurofilament light chain decreased in a dose-dependent manner. The number of patients with confirmed disability worsening after 24 weeks was 3 (3.7%) patients receiving placebo and 3 (1.6%) patients receiving any dose of vidofludimus calcium. Treatment-emergent adverse events occurred in 35 (43%) placebo patients compared with 11 (23%) and 71 (37%) patients in the 10 mg or any dose of vidofludimus calcium groups, respectively. The incidence of liver enzyme elevations and infections were similar between placebo and any dose of vidofludimus calcium. No new safety signals were observed. DISCUSSION: Compared with placebo, vidofludimus calcium suppressed the development of new brain lesions with daily doses of 30 mg and 45 mg, but not 10 mg, establishing the lowest efficacious dose is 30 mg. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that among adults with active RRMS and ≥1 Gd+ brain lesion in the past 6 months, the cumulative number of active lesions decreased with vidofludimus calcium. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov (NCT03846219) and EudraCT (2018-001896-19).

Temporal Relationship Between Serum Neurofilament Light Chain and Radiologic Disease Activity in Patients With Multiple Sclerosis.

BACKGROUND AND OBJECTIVES: Serum neurofilament light chain (sNfL) levels correlate with multiple sclerosis (MS) disease activity, but the dynamics of this correlation are unknown. We evaluated the relationship between sNfL levels and radiologic MS disease activity through monthly assessments during the 24-week natalizumab treatment interruption period in RESTORE (NCT01071083). METHODS: In the RESTORE trial, participants with relapsing forms of MS who had received natalizumab for ≥12 months were randomized to either continue or stop natalizumab and followed with MRI and blood draws every 4 weeks to week 28 and again at week 52 The sNfL was measured, and its dynamics were correlated with the development of gadolinium-enhancing (Gd+) lesions. Log-linear trend in sNfL levels were modeled longitudinally using generalized estimating equations with robust variance estimator from baseline to week 28. RESULTS: Of 175 patients enrolled in RESTORE, 166 had serum samples for analysis. Participants with Gd+ lesions were younger (37.7 vs 43.1, p = 0.001) and had lower Expanded Disability Status Scale scores at baseline (2.7 vs 3.4, p = 0.017) than participants without Gd+ lesions. sNfL levels increased in participants with Gd+ lesions (n = 65) compared with those without (n = 101, mean change from baseline to maximum sNfL value, 12.1 vs 3.2 pg/mL, respectively; p = 0.003). As the number of Gd+ lesions increased, peak median sNfL change also increased by 1.4, 3.0, 4.3, and 19.6 pg/mL in the Gd+ lesion groups of 1 (n = 12), 2-3 (n = 18), 4-9 (n = 21), and ≥10 (n = 14) lesions, respectively. However, 46 of 65 (71%) participants with Gd+ lesions did not increase above the 95th percentile threshold of the group without Gd+ lesions. The initial increase of sNfL typically trailed the first observation of Gd+ lesions, and the peak increase in sNfL was a median [interquartile range] of 8 [0, 12] weeks after the first appearance of the Gd+ lesion. DISCUSSION: Although sNfL correlated with the presence of Gd+ lesions, most participants with Gd+ lesions did not have elevations in sNfL levels. These observations have implications for the use and interpretation of sNfL as a biomarker for monitoring MS disease activity in controlled trials and clinical practice.

Mental health in Ukraine in 2023.

BACKGROUND: Very little is known about the mental health of the adult population of Ukraine following Russia's full-scale invasion in February 2022. In this study, we estimated the prevalence of seven mental health disorders, the proportion of adults screening positive for any disorder, and the sociodemographic factors associated with meeting requirements for each and any disorder. METHODS: A non-probability quota sample (N = 2,050) of adults living in Ukraine in September 2023 was collected online. Participants completed self-report questionnaires of the seven mental health disorders. Logistic regression was used to determine the predictors of the different disorders. RESULTS: Prevalence estimates ranged from 1.5% (cannabis use disorder) to 15.2% (generalized anxiety disorder), and 36.3% screened positive for any of the seven disorders. Females were significantly more likely than males (39.0% vs. 33.8%) to screen positive for any disorder. Disruption to life due to Russia's 2014 invasion of Ukraine, greater financial worries, and having fewer positive childhood experiences were consistent risk factors for different mental health disorders and for any or multiple disorders. CONCLUSION: Our findings show that approximately one in three adults living in Ukraine report problems consistent with meeting diagnostic requirements for a mental health disorder 18 months after Russia's full-scale invasion. Ukraine's mental healthcare system has been severely compromised by the loss of infrastructure and human capital due to the war. These findings may help to identify those most vulnerable so that limited resources can be used most effectively.

Evaluating Speaker-Listener Cognitive Effort in Speech Communication Through Brain-to-Brain Synchrony: A Pilot Functional Near-Infrared Spectroscopy Investigation.

PURPOSE: We explore a new approach to the study of cognitive effort involved in listening to speech by measuring the brain activity in a listener in relation to the brain activity in a speaker. We hypothesize that the strength of this brain-to-brain synchrony (coupling) reflects the magnitude of cognitive effort involved in verbal communication and includes both listening effort and speaking effort. We investigate whether interbrain synchrony is greater in native-to-native versus native-to-nonnative communication using functional near-infrared spectroscopy (fNIRS). METHOD: Two speakers participated, a native speaker of American English and a native speaker of Korean who spoke English as a second language. Each speaker was fitted with the fNIRS cap and told short stories. The native English speaker provided the English narratives, and the Korean speaker provided both the nonnative (accented) English and Korean narratives. In separate sessions, fNIRS data were obtained from seven English monolingual participants ages 20-24 years who listened to each speaker's stories. After listening to each story in native and nonnative English, they retold the content, and their transcripts and audio recordings were analyzed for comprehension and discourse fluency, measured in the number of hesitations and articulation rate. No story retellings were obtained for narratives in Korean (an incomprehensible language for English listeners). Utilizing fNIRS technique termed sequential scanning, we quantified the brain-to-brain synchronization in each speaker-listener dyad. RESULTS: For native-to-native dyads, multiple brain regions associated with various linguistic and executive functions were activated. There was a weaker coupling for native-to-nonnative dyads, and only the brain regions associated with higher order cognitive processes and functions were synchronized. All listeners understood the content of all stories, but they hesitated significantly more when retelling stories told in accented English. The nonnative speaker hesitated significantly more often than the native speaker and had a significantly slower articulation rate. There was no brain-to-brain coupling during listening to Korean, indicating a break in communication when listeners failed to comprehend the speaker. CONCLUSIONS: We found that effortful speech processing decreased interbrain synchrony and delayed comprehension processes. The obtained brain-based and behavioral patterns are consistent with our proposal that cognitive effort in verbal communication pertains to both the listener and the speaker and that brain-to-brain synchrony can be an indicator of differences in their cumulative communicative effort. SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.25452142.

Immunologic basis for development of keratoconjunctivitis sicca in systemic autoimmune diseases: Role of innate immune sensors.

The literature is filled with citations reporting an increased incidence of chronic dry eye disease, also known as keratoconjunctivitis sicca, in patients with systemic autoimmune diseases such as rheumatoid arthritis, Sjögren's Syndrome, systemic sclerosis and lupus. As the most environmentally exposed mucosal surface of the body, the conjunctiva constantly responds to environmental challenges which are typically self limited, but when persistent and unresolved may provoke pathogenic innate and adaptive immune reactions. Our understanding of the pathophysiological mechanisms by which systemic autoimmune diseases cause dry eye inducing ocular surface inflammation continues to evolve. Conjunctival immune tone responds to self or foreign danger signals (including desiccating stress) on the ocular surface with an initial non-specific innate inflammatory response. If unchecked, this can lead to activation of dendritic cells that present antigen and prime T and B cells resulting in an adaptive immune reaction. These reactions generally resolve, but dysfunctional, hyper-responsive immune cells found in systemic autoimmune diseases that are recruited to the ocular surface can amplify inflammatory stress responses in the ocular surface and glandular tissues and result in autoimmune reactions that disrupt tear stability and lead to chronic dry eye disease. We here propose that unique features of the ocular surface immune system and the impact of systemic immune dysregulation in autoimmune diseases, can predispose to development of dry eye disease, and exacerbate severity of existing dry eye.

The Morphology of the Dorsal Part of the First Rib in Neurogenic Thoracic Outlet Syndrome Patients: A Retrospective Clinical Study.

BACKGROUND: The recurrence or persistence of symptoms after thoracic outlet decompression (TOD) in patients with neurogenic thoracic outlet syndrome (NTOS) is not uncommon. Some authors have shown significantly better clinical outcomes in patients who underwent TOD with exarticulation of the first rib compared to a group who underwent TOD with preservation of the dorsal portion of the first rib. Several other case series have shown significant improvement after redo surgery with removal of the dorsal first rib remnant. This indicates the importance of the dorsal part of the first rib in NTOS. However, radical exarticulation may not always be necessary. In this study, we tried to answer the question of whether there is a morphological difference in the dorsal part of the first rib in NTOS patients that might help in the diagnosis and treatment of NTOS. METHODS: We used the CT data of 21 NTOS patients who underwent TOD surgery and measured the dorsal part of the first rib, then compared them with a quota sample. RESULTS: We found no difference in the dorsal part of the first rib between NTOS patients and the quota sample in our data. CONCLUSIONS: As there was no detectable difference, we were not able to use these data to help decide whether exarticulation is necessary in achieving adequate symptom relief. Therefore, we advocate exarticulation of the first rib when TOD is indicated.

Rethinking Sjögren Beyond Inflammation: Considering the Role of Nerves in Driving Disease Manifestations.

ABSTRACT: Sjögren syndrome (SS) is a chronic inflammatory autoimmune disease characterized by destruction of mucosal glands resulting in dry eye and dry mouth. Ocular presentations can be heterogenous in SS with corneal nerves abnormalities that are structural, functional, or both. Some individuals present with corneal hyposensitivity, with a phenotype of decreased tear production and epithelial disruption. Others present with corneal hypersensitivity, with a phenotype of neuropathic pain including light sensitivity and pain out of proportion to signs of tear dysfunction. A similar correlate can be found outside the eye, with dry mouth predominating in some individuals while pain conditions predominate in others. Understanding how nerve status affects SS phenotype is an important first step to improving disease management by targeting nerve abnormalities, as well as inflammation.

Clinical trials for progressive multiple sclerosis: progress, new lessons learned, and remaining challenges.

Despite the success of disease-modifying treatments in relapsing multiple sclerosis, for many individuals living with multiple sclerosis, progressive disability continues to accrue. How to interrupt the complex pathological processes underlying progression remains a daunting and ongoing challenge. Since 2014, several immunomodulatory approaches that have modest but clinically meaningful effects have been approved for the management of progressive multiple sclerosis, primarily for people who have active inflammatory disease. The approval of these drugs required large phase 3 trials that were sufficiently powered to detect meaningful effects on disability. New classes of drug, such as Bruton tyrosine-kinase inhibitors, are coming to the end of their trial stages, several candidate neuroprotective compounds have been successful in phase 2 trials, and innovative approaches to remyelination are now also being explored in clinical trials. Work continues to define intermediate outcomes that can provide results in phase 2 trials more quickly than disability measures, and more efficient trial designs, such as multi-arm multi-stage and futility approaches, are increasingly being used. Collaborations between patient organisations, pharmaceutical companies, and academic researchers will be crucial to ensure that future trials maintain this momentum and generate results that are relevant for people living with progressive multiple sclerosis.

Design of a high-temperature cell for cobalt-60 irradiations of aqueous solutions with in situ UV-visible spectroscopy.

To understand the speciation of solutes in aqueous solutions in high temperature radiation environments, we report the design and fabrication of a custom-built, high temperature (≤300 °C) titanium irradiation cell with in situ optical spectroscopy capabilities, as afforded by coupled fiber optic cables. The wetted surfaces of the 8-inch tall cylindrical cell with 3.5 in. diameter are entirely made of titanium, sapphire, and gold, which are chemically and radiolytically inert. The initial benchmarking results are reported, including the baseline spectrum of deionized water as a function of temperature, the stability of a spectrum over 4 h at 100 °C, and an irradiated Fricke dosimetry solution under ambient irradiator temperature conditions (27.0 ± 0.5 °C). The average gamma radiation dose rate in the cell in its current configuration is 26.1 ± 1.3 Gy min-1. This cell has application in studying several processes throughout the nuclear fuel cycle, including the reactor coolant behavior.

Ibudilast reduces slowly enlarging lesions in progressive multiple sclerosis.

BACKGROUND: Ibudilast has shown beneficial effects on several imaging outcomes in progressive multiple sclerosis (MS). Slowly enlarging lesions are a proposed imaging biomarker of compartmentalized inflammation within chronic active lesions. OBJECTIVE: To assess the treatment effect of ibudilast on slowly enlarging lesion volumes over 96 weeks from a phase II clinical trial of ibudilast (Secondary and Primary Progressive Ibudilast NeuroNEXT Trial in Multiple Sclerosis [SPRINT-MS]). METHODS: In total, 255 participants with progressive MS from 28 sites were randomized to oral ibudilast or placebo. Participants with at least four analyzable magnetic resonance imaging (MRI) were included. Slowly enlarging lesions were quantified using Jacobian determinant maps. A linear model was used to assess the effect of ibudilast. Magnetization transfer ratio within slowly enlarging lesions was assessed to determine the effect of ibudilast on tissue integrity. RESULTS: In total, 195 participants were included in this analysis. Ibudilast significantly decreased slowly enlarging lesion volume (23%, p = 0.003). Ibudilast also reduced magnetization transfer ratio change in slowly enlarging lesions: 0.22%/year, p = 0.04. CONCLUSION: Ibudilast showed a significant effect on baseline volume of lesions that were slowly enlarging and magnetization transfer ratio in slowly enlarging lesions. The results support the use of slowly enlarging lesions for assessment of compartmentalized inflammation represented by chronic active lesions and provide further support for the neuroprotective effects of ibudilast in progressive MS.

Is Dissociation a Fundamental Component of ICD-11 Complex Posttraumatic Stress Disorder?

ICD-11 Complex Posttraumatic Stress Disorder (CPTSD) is a disorder of six symptom clusters including reexperiencing, avoidance, sense of threat, affective dysregulation, negative self-concept, and disturbed relationships. Unlike earlier descriptions of complex PTSD, ICD-11 CPTSD does not list dissociation as a unique symptom cluster. We tested whether the ICD-11 CPTSD symptoms can exist independently of dissociation in a nationally representative sample of adults (N = 1,020) who completed self-report measures. Latent class analysis was used to identify unique subsets of people with distinctive symptom profiles. The best fitting model contained four classes including a "low symptoms" class (48.9%), a "PTSD" class (14.7%), a "CPTSD" class (26.5%), and a "CPTSD + Dissociation" class (10.0%). These classes were related to specific adverse childhood experiences, notably experiences of emotional and physical neglect. The "PTSD," "CPTSD," and "CPTSD + Dissociation" classes were associated with a host of poor health outcomes, however, the "CPTSD + Dissociation" class had the poorest mental health and highest levels of functional impairment. Findings suggest that ICD-11 CPTSD symptoms can occur without corresponding dissociative experiences, however, when CPTSD symptoms and dissociative experiences occur together, health outcomes appear to be more severe.

Serum macrophage migration inhibitory factor levels predict brain atrophy in people with primary progressive multiple sclerosis.

BACKGROUND: Macrophage migration inhibitory factor (MIF) is a cytokine linked to multiple sclerosis (MS) progression that is thought to be inhibited by ibudilast. SPRINT-MS was a phase 2 placebo-controlled trial of ibudilast in progressive multiple sclerosis (PMS). OBJECTIVE: To determine whether baseline MIF levels predict imaging outcomes and assess the effects of ibudilast on serum and cerebrospinal fluid (CSF) MIF levels in people with PMS treated with ibudilast. METHODS: Participants in the SPRINT-MS trial were treated with either ibudilast or placebo and underwent brain magnetic resonance imaging (MRI) every 24 weeks over a duration of 96 weeks. MIF was measured in serum and CSF. RESULTS: MIF levels were compared with imaging outcomes in 223 participants from the SPRINT-MS study. In the primary progressive multiple sclerosis (PPMS) cohort, males had higher serum (p < 0.001) and CSF (p = 0.01) MIF levels, as compared with females. Higher baseline serum MIF levels in PPMS were associated with faster brain atrophy (beta = -0.113%, 95% confidence interval (CI): -0.204% to -0.021%; p = 0.016). These findings were not observed in secondary progressive multiple sclerosis (SPMS). Ibudilast did not affect either serum or CSF MIF levels. CONCLUSIONS: Serum MIF levels were associated with male sex and predicted brain atrophy in PPMS, but not SPMS. Ibudilast did not demonstrate an effect on MIF levels, as compared with placebo, although we cannot exclude a functional effect.

Introduction to the special issue on perception and production of sounds in the high-frequency range of human speecha).

The frequency range audible to humans can extend from 20 Hz to 20 kHz, but only a portion of this range-the lower end up to 8 kHz-has been systematically explored because extended high-frequency (EHF) information above this low range has been considered unnecessary for speech comprehension. This special issue presents a collection of research studies exploring the presence of EHF information in the acoustic signal and its perceptual utility. The papers address the role of EHF hearing in auditory perception, the impact of EHF hearing loss on speech perception in specific populations and occupational settings, the importance of EHF in speech recognition and in providing speaker-related information, the utility of acoustic EHF energy in fricative sounds, and ultrasonic vocalizations in mice in relation to human hearing. Collectively, the research findings offer new insights and converge in showing that not only is EHF energy present in the speech spectrum, but listeners can utilize EHF cues in speech processing and recognition, and EHF hearing loss has detrimental effects on perception of speech and non-speech sounds. Together, this collection challenges the conventional notion that EHF information has minimal functional significance.

High temperature gamma radiation-induced chromium redox chemistry via in situ spectroscopic measurements.

Chromium ions can make their way into the primary coolant of nuclear power reactors from the corrosion of stainless-steel reactor components, decreasing the material's corrosion resistance and resulting in increased transport of further corrosion products. Despite these potential effects, the radiation-induced redox speciation of chromium ions in aqueous solution is not well understood, especially at the elevated temperatures experienced by reactor coolants. In the present work, we report new experimental results demonstrating that in aerated aqueous solution, the radiolytic oxidation of Cr(III) to Cr(VI) occurs at pH 4, while the reduction of Cr(VI) to Cr(III) occurs at pH 2. The oxidation of Cr(III) is primarily attributed to the reaction of the hydroxyl radical (˙OH) with the Cr(OH)2+ species, while the reduction of Cr(VI) is attributed to reactions involving the hydrated electron (eaq-) and hydrogen atom (H˙). Additionally, the steady-state equilibrium yield of Cr(VI) from the gamma irradiation of pH 4 Cr(III) solutions decreased with increasing temperature (over a range of 37-195 °C). This observation indicates that the activation energy of the Cr(VI) reduction reactions is higher than that for the Cr(III) oxidation reactions, such that it becomes relatively more favorable at higher temperatures. Overall, these data are important for the development of complementary multiscale models for the prediction of metal ion speciation in high temperature radiation environments.

Overcoming barriers to informed consent in neurological research: Perspectives from a national survey.

The ethical recruitment of participants with neurological disorders in clinical research requires obtaining initial and ongoing informed consent. The purpose of this study is to characterize barriers faced by research personnel in obtaining informed consent from research participants with neurological disorders and to identify strategies applied by researchers to overcome those barriers. This study was designed as a web-based survey of US researchers with an optional follow-up interview. A subset of participants who completed the survey were selected using a stratified purposeful sampling strategy and invited to participate in an in-depth qualitative interview by phone or video conference. Data were analyzed using a mixed methods approach, including content analysis of survey responses and thematic analysis of interview responses. Over 1 year, 113 survey responses were received from US research personnel directly involved in obtaining informed consent from participants in neurological research. Frequently identified barriers to informed consent included: cognitive and communication impairments (e.g. aphasia), unrealistic expectations of research participants, mistrust of medical research, time constraints, literacy barriers, lack of available social support, and practical or resource-related constraints. Strategies to enhance informed consent included: involving close others to support participant understanding of study-related information, collaborating with more experienced research personnel to facilitate training in obtaining informed consent, encouraging participants to review consent forms in advance of consent discussions, and using printed materials and visual references. Beyond conveying study-related information, researchers included in this study endorsed ethical responsibilities to support deliberation necessary to informed consent in the context of misconceptions about research, unrealistic expectations, limited understanding, mistrust, and/or pressure from close others. Findings highlight the importance of training researchers involved in obtaining informed consent in neurological research to address disease-specific challenges and to support the decision-making processes of potential research participants and their close others.

The Role of Instructions in Motor Learning of Oral Versus Nasalized Speech Targets.

PURPOSE: The purpose of this study was to investigate how general, implicit instructions with auditory-perceptual emphasis; specific, explicit instructions with biomechanical focus; or both affect learning of oral-nasal balance control in speech. METHOD: Thirty healthy, vocally untrained participants were assigned to one of three instructional groups (i.e., implicit, explicit, and integrated) and learned to produce oral versus nasalized vowel-, syllable-, and phrase-level targets during once-weekly sessions over 4 weeks. Learning gains and performance variability were analyzed using nasometry. RESULTS: We observed a significant main effect of instruction type on learning gains at phrase level (p = .016). Specifically, the integrated group (M = 59.8%) significantly outperformed the explicit group (M = 37.9%) and numerically outperformed the implicit group (M = 45.1%). For nasalized phrase targets, results revealed a significant main effect of instruction type on performance variability (p = .042), but pairwise comparisons between instruction groups were not significant. CONCLUSIONS: The integration of implicit processes via auditory-perceptual modeling and explicit processes via relevant biomechanical directives resulted in larger motor learning gains, especially at higher levels of task complexity (i.e., phrase) compared to providing implicit or explicit instruction alone. The higher performance variability (i.e., less stable productions) that was sometimes induced by explicit instruction did not negatively impact learning when integrated with implicit instruction. Clinical implications for speech/voice therapy models are discussed.

Ghrelin receptor antagonist JMV2959 blunts cocaine and oxycodone drug-seeking, but not self-administration, in male rats.

The drug overdose crisis has spawned serious health consequences, including the increased incidence of substance use disorders (SUDs), conditions manifested by escalating medical and psychological impairments. While medication management is a key adjunct in SUD treatment, this crisis has crystallized the need to develop additional therapeutics to facilitate extended recovery from SUDs. The "hunger hormone" ghrelin acts by binding to the growth hormone secretagogue receptor 1α (GHS1αR) to control homeostatic and hedonic aspects of food intake and has been implicated in the mechanisms underlying SUDs. Preclinical studies indicate that GHS1αR antagonists and inverse agonists suppress reward-related signaling associated with cocaine and opioids. In the present study, we found that the GHS1αR antagonist JMV2959 was efficacious to suppress both cue-reinforced cocaine and oxycodone drug-seeking, but not cocaine or oxycodone self-administration in male Sprague-Dawley rats. These data suggest a role of the ghrelin-GHS1αR axis in mediating overlapping reward-related aspects of cocaine and oxycodone and premises the possibility that a GHS1αR antagonist may be a valuable therapeutic strategy for relapse vulnerability in SUDs.

Dialect and gender perception in relation to the intelligibility of low-pass and high-pass filtered spontaneous speecha).

Most cues to speech intelligibility are within a narrow frequency range, with its upper limit not exceeding 4 kHz. It is still unclear whether speaker-related (indexical) information is available past this limit or how speaker characteristics are distributed at frequencies within and outside the intelligibility range. Using low-pass and high-pass filtering, we examined the perceptual salience of dialect and gender cues in both intelligible and unintelligible speech. Setting the upper frequency limit at 11 kHz, spontaneously produced unique utterances (n = 400) from 40 speakers were high-pass filtered with frequency cutoffs from 0.7 to 5.56 kHz and presented to listeners for dialect and gender identification and intelligibility evaluation. The same material and experimental procedures were used to probe perception of low-pass filtered and unmodified speech with cutoffs from 0.5 to 1.1 kHz. Applying statistical signal detection theory analyses, we found that cues to gender were well preserved at low and high frequencies and did not depend on intelligibility, and the redundancy of gender cues at higher frequencies reduced response bias. Cues to dialect were relatively strong at low and high frequencies; however, most were in intelligible speech, modulated by a differential intelligibility advantage of male and female speakers at low and high frequencies.

Remote patient monitoring for COVID-19 patients: comparisons and framework for reporting.

BACKGROUND: COVID-19 has challenged health services throughout the world in terms of hospital capacity and put staff and vulnerable populations at risk of infection. In the face of these challenges, many health providers have implemented remote patient monitoring (RPM) of COVID-19 patients in their own homes. However systematic reviews of the literature on these implementations have revealed wide variations in how RPM is implemented; along with variations in particulars of RPM reported on, making comparison and evaluation difficult. A review of reported items is warranted to develop a framework of key items to enhance reporting consistency. The aims of this review of remote monitoring for COVID-19 patients are twofold: (1) to facilitate comparison between RPM implementations by tabulating information and values under common domains. (2) to develop a reporting framework to enhance reporting consistency. METHOD: A review of the literature for RPM for COVID-19 patients was conducted following PRISMA guidelines. The Medline database was searched for articles published between 2020 to February 2023 and studies reporting on items with sufficient detail to compare one with another were included. Relevant data was extracted and synthesized by the lead author. Quality appraisal was not conducted as the the articles considered were evaluated as informational reports of clinical implementations rather than as studies designed to answer a research question. RESULTS: From 305 studies retrieved, 23 studies were included in the review: fourteen from the US, two from the UK and one each from Africa, Ireland, China, the Netherlands, Belgium, Australia and Italy. Sixteen generally reported items were identified, shown with the percentage of studies reporting in brackets: Reporting Period (82%), Rationale (100%), Patients (100%), Medical Team (91%) Provider / Infrastructure (91%), Communications Platform (100%), Patient Equipment (100%), Training (48%), Markers (96%), Frequency of prompt / Input (96%),Thresholds (82%), Discharge (61%), Enrolled (96%), Alerts/Escalated (78%), Patient acceptance (43%), and Patient Adherence (52%). Whilst some studies reported on patient training and acceptance, just one reported on staff training and none on staff acceptance. CONCLUSIONS: Variations in reported items were found. Pending the establishment of a robust set of reporting guidelines, we propose a reporting framework consisting of eighteen reporting items under the following four domains: Context, Technology, Process and Metrics.

Effect of ibudilast on thalamic magnetization transfer ratio and volume in progressive multiple sclerosis.

BACKGROUND: Thalamic volume (TV) is a sensitive biomarker of disease burden of injury in multiple sclerosis (MS) and appears to reflect overall lesion loads. Ibudilast showed significant treatment effect on brain atrophy and magnetization transfer ratio (MTR) of normal-appearing brain tissue but not in new/enlarging T2 lesion in the SPRINT-MS randomized clinical trial. OBJECTIVE: To evaluate the effect of ibudilast on thalamic tissue integrity and volume in the SPRINT-MS. METHODS: A total of 255 participants with progressive MS were randomized to oral ibudilast or placebo, and thalamic MTR and normalized TV over 96 weeks were quantified. Mixed-effect modeling assessed treatment effects on the thalamic MTR and TV, separately. Similarly, the measures were compared between the participants with confirmed disability progression (CDP). RESULTS: Ibudilast's treatment effect was observed compared to placebo for thalamic MTR (p = 0.03) but not for TV (p = 0.68) while TV correlated with T2 lesion volume (p < 0.001). CDP associated with thalamic MTR (p = 0.04) but not with TV (p = 0.7). CONCLUSION: Ibudilast showed an effect on thalamic MTR, which was associated with CDP, suggesting a clinically relevant effect on thalamic tissue integrity. However, the treatment effect was not observed in TV, suggesting that thalamic atrophy is more closely associated with global inflammatory activity than local tissue integrity. CLINICALTRIALS.GOV: NCT01982942.