Hell's Itch: A Unique Reaction to UV Exposure.

We present a survey-based exploration of Hell's Itch, a severe dermatologic reaction often mistaken for sunburn, that reveals distinct symptoms including intense pain, unrelenting itching, paresthesia, and even suicidal ideation, differentiating it from a typical sunburn.

The effects of intervention with intravenous edaravone in Study 19 on hospitalization, tracheostomy, ventilation, and death in patients with amyotrophic lateral sclerosis.

INTRODUCTION/AIMS: Intravenous (IV) edaravone is a US Food and Drug Administration-approved treatment for amyotrophic lateral sclerosis (ALS), shown in clinical trials to slow physical functional decline. In this study we compared the effect of IV edaravone (edaravone-first group) versus placebo followed by IV edaravone (placebo-first group) on survival and additional milestone events. METHODS: This work is a post hoc analysis of Study 19/MCI186-19, which was a randomized, placebo-controlled, phase 3 study investigating IV edaravone versus placebo. Study 19 and its 24-week extension have been described previously (NCT01492686). Edaravone-first versus placebo-first group time to events for specific milestone(s) were analyzed post hoc. Time-to-event composite endpoints were time to death; time to death, tracheostomy, or permanent assisted ventilation (PAV); and time to death, tracheostomy, PAV, or hospitalization. RESULTS: The risk for death, tracheostomy, PAV, or hospitalization was 53% lower among patients in the edaravone-first vs placebo-first groups (hazard ratio = 0.47 [95% confidence interval 0.25 to 0.88], P = .02). The overall effect of IV edaravone on ALS progression could be seen in the significant separation of time-to-event curves for time to death, tracheostomy, PAV, or hospitalization. ALS survival composite endpoint analyses (ALS/SURV) suggested a treatment benefit (least-squares mean difference) for the edaravone-first versus the placebo-first group at week 24 (0.15 ± 0.05 [95% confidence interval 0.06 to 0.25], P < .01) and week 48 (0.11 ± 0.05 [95% confidence interval 0.02 to 0.21], P = .02). DISCUSSION: These analyses illustrate the value of timely and continued IV edaravone treatment, as earlier initiation was associated with a lower risk of death, tracheostomy, PAV, or hospitalization in patients with ALS.

The Correlation of Sleep Disturbance and Location of Glioma Tumors: A Narrative Review.

Sleep disturbance can occur when sleep centers of the brain, regions that are responsible for coordinating and generating healthy amounts of sleep, are disrupted by glioma growth or surgical resection. Several disorders cause disruptions to the average duration, quality, or patterns of sleep, resulting in sleep disturbance. It is unknown whether specific sleep disorders can be reliably correlated with glioma growth, but there are sufficient numbers of case reports to suggest that a connection is possible. In this manuscript, these case reports and retrospective chart reviews are considered in the context of the current primary literature on sleep disturbance and glioma diagnosis to identify a new and useful connection which warrants further systematic and scientific examination in preclinical animal models. Confirmation of the relationship between disruption of the sleep centers in the brain and glioma location could have significant implications for diagnostics, treatment, monitoring of metastasis/recurrence, and end-of-life considerations.

Rapid shallow megathrust afterslip from the 2021 M8.2 Chignik, Alaska earthquake revealed by seafloor geodesy.

The shallower portions of subduction zone megathrust faults host Earth's most hazardous tsunamigenic earthquakes, yet understanding how and when they slip remains elusive because of challenges making seafloor observations. We performed Global Navigation Satellite System Acoustic seafloor geodetic surveys before and ~2.5 months after the 29 July 2021 Mw (moment magnitude) 8.2 Chignik, Alaska, earthquake and determine ~1.4 meters cumulative co- and post-seismic horizontal displacement ~60 kilometers from the megathrust front. Only for the 2011 Mw 9 Tohoku event have closer subduction zone earthquake displacements been observed. We estimate ~2 to 3 meters of megathrust afterslip shallower than 20 kilometers, a portion of the megathrust on which both inter- and co-seismic slip likely had occurred previously. Our analysis demonstrates that by 2.5 months, shallower and deeper moment had effectively equilibrated on the megathrust, suggesting that its tsunamigenic potential remains no more elevated than before the earthquake.

2019 M7.1 Ridgecrest earthquake slip distribution controlled by fault geometry inherited from Independence dike swarm.

Faults often form through reactivation of pre-existing structures, developing geometries and mechanical properties specific to the system's geologic inheritance. Competition between fault geometry and other factors (e.g., lithology) to control slip at Earth's surface is an open question that is central to our knowledge of fault processes and seismic hazards. Here we use remote sensing data and field observations to investigate the origin of the 2019 M7.1 Ridgecrest, California, earthquake rupture geometry and test its impact on the slip distribution observed at Earth's surface. Common geometries suggest the fault system evolved through reactivation of structures within the surrounding Independence dike swarm (IDS). Mechanical models testing a range of fault geometries and stress fields indicate that the inherited rupture geometry strongly controlled the M7.1 earthquake slip distribution. These results motivate revisiting the development of other large-magnitude earthquake ruptures (1992 M7.3 Landers, 1999 M7.1 Hector Mine) and tectonic provinces within the IDS.

Qualitative identification of volatile compounds in foods and flowers using passive headspace extraction with activated charcoal fabric.

This study investigates the application of passive headspace analysis to several different foods and flowers and compares these results to other published studies. The method demonstrates the applicability of passive headspace analysis for extraction and qualitative analysis of volatile flavor components of citrus fruits and flower blossoms. The method is simple, inexpensive, fast, and provides an alternative to analysis of volatile flavor and fragrance compounds using solid phase microextraction techniques and other extraction techniques.

A revision to the United States national ALS registry's algorithm to improve Case-Ascertainment.

OBJECTIVE: To evaluate the impact of 1) updating the existing algorithm to improve case-finding sensitivity and 2) reclassifying the Registry's diagnostic status nomenclature into four new categories ("confirmed ALS," "likely ALS," "undetermined ALS," or "not ALS") versus the current three ("definite ALS," "possible ALS," or "not ALS") to be more inclusive and descriptive of cases and individuals. METHODS: A retrospective analysis of Registry data from 2011-2017 was conducted to follow "possible ALS" individuals over time to determine what qualifier caused them to convert, if at all and when, to Registry-eligible cases (i.e. "confirmed ALS" or "likely ALS"). RESULTS: In 2011, 720 individuals were classified by the Registry algorithm as having "possible ALS". By 2017, 42% of these had converted to Registry-eligible ALS cases. Approximately 14% of those who were identified solely based on an ALS prescription drug never converted to Registry-eligible cases. This analysis indicates that "possible ALS" individuals with a single prescription for an ALS drug should be converted to Registry-eligible cases which would add between 300-500 cases per year on average. CONCLUSIONS: The Registry's existing algorithm likely results in the under-ascertainment of ALS cases. However, updating the algorithm with the inclusion of patients having been prescribed ALS-specific drugs, even with a single prescription, leads to improved epidemiologic estimates of ALS in the US. This and future algorithmic updates will help the Registry more accurately depict the true disease burden of ALS in the US.

Seizures, deep vein thrombosis, and pulmonary emboli in a severe case of May-Thurner syndrome: a case report.

BACKGROUND: May-Thurner syndrome is a vascular disorder caused by the right common iliac artery compressing the left common iliac vein against the lumbar spine, causing distal venous stasis and potentially leading to fibrous change in the venous wall structure. Although May-Thurner syndrome is most commonly discovered in females upon investigation of new-onset deep vein thrombosis, we present the case of an otherwise healthy 29-year-old male with severe May-Thurner syndrome who presented with seizures, bilateral deep vein thrombosis, and diffuse pulmonary emboli. Seizures constituted the earliest presenting symptoms for the patient. Although it is difficult to prove that the patient's seizures were related to the May-Thurner syndrome, this possible association renders this case extraordinary. CASE PRESENTATION: This report describes the case of a 29-year-old previously healthy white male with a severe case of left-sided May-Thurner syndrome that required extensive medical and interventional treatment. The patient experienced two seizures, one month apart, both of which occurred while residing at high altitude. The patient had no prior history of seizures, and epilepsy was ruled out. Three weeks after the second seizure, he presented to the emergency room with hemoptysis, dyspnea, and severe leg pain. Sites of thrombus were confirmed in both legs and diffusely in the lungs. Etiological work-up after treatment with intravenous tissue plasminogen activator revealed May-Thurner syndrome. Hematology workup including genetic testing showed no evidence of coagulopathy. Bilateral common iliac venous stents were placed to attempt definitive treatment. Despite stenting, the patient had another thrombotic event with associated sequelae after discontinuation of anticoagulation. The patient has not had another seizure since the stents were placed. Despite the negative testing, the patient remains on lifelong chemoprophylaxis in the event of an undiscovered hypercoagulopathy. CONCLUSIONS: The care team theorizes that the seizures resulted from hypoxia due to May-Thurner syndrome-induced hemostasis and associated thrombotic events, the high-altitude location of his residence at the time he experienced the seizures, and shallow breathing during sleep. For patients with lower limb venous thrombosis, May-Thurner syndrome should be considered in the differential diagnosis. Endovascular treatment followed by extended prophylactic anticoagulation therapy until the patient is determined to be no longer at risk for thrombosis is recommended. Post-venoplasty thrombosis is a common complication of endovascular treatment of May-Thurner syndrome and should be carefully monitored.

Intravenous edaravone treatment in ALS and survival: An exploratory, retrospective, administrative claims analysis.

Background: We aimed to evaluate overall survival in US patients with amyotrophic lateral sclerosis (ALS) treated with intravenous (IV) edaravone compared with those not treated with IV edaravone in a real-world setting. Methods: This exploratory retrospective comparative effectiveness observational analysis included patients with ALS who were enrolled in an administrative claims database from 8 August 2017 to 31 March 2020. Propensity score matching identified IV edaravone-treated patients (cases) and non-edaravone-treated patients (controls) matched for covariates: age, race, geographic region, sex, pre-index disease duration, insurance, history of cardiovascular disease, riluzole prescription, gastrostomy tube placement, artificial nutrition, noninvasive ventilation, and all-cause hospitalisation. For cases, the index date was the date of the first claim for IV edaravone. For controls, it was the date IV edaravone was available (8 August 2017). The effect of IV edaravone on all-cause mortality was estimated with shared frailty Cox regression analysis. Findings: 318 cases were matched to 318 controls. In both groups, 208 patients (65.4%) had a history of riluzole prescription. As of 31 March 2021, there were 155 deaths (48.7%) among the cases and 196 among the controls (61.6%). Median overall survival time was 29.5 months with edaravone and 23.5 months without, respectively, and the risk of death was 27% lower in cases than in controls (HR, 0.73; 95% CI, 0.59-0.91; p=0.005). Interpretation: In this real-world analysis, IV edaravone treatment in a large predominantly riluzole-treated US cohort was associated with prolonged overall survival compared with not using IV edaravone. Data from adequately powered RCTs are needed to support this finding. Funding: Funded by Mitsubishi Tanabe Pharma America.

Assessment of management approaches for hyperemesis gravidarum and nausea and vomiting of pregnancy: a retrospective questionnaire analysis.

BACKGROUND: Hyperemesis gravidarum is the most severe form of nausea and vomiting of pregnancy, or morning sickness. 2% of pregnancies in the United States are affected by hyperemesis gravidarum. The condition is characterized by severe vomiting in pregnant people, especially during the first trimester, often leading to hypovolemia and weight loss. The standard of care for hyperemesis and nausea and vomiting of pregnancy is commonly ineffective. We hypothesize that based on patient experience; the current treatment guidelines for hyperemesis are not clinically effective. Our objective was to identify the efficacy of the various management approaches that are currently in place for hyperemesis and nausea and vomiting of pregnancy. METHODS: A questionnaire was designed based on diagnostic criteria, standard demographic identifiers, and common medications for the treatment of hyperemesis gravidarum. This questionnaire was distributed online to through hyperemesis and nausea and vomiting of pregnancy support groups, personal social media, and institutional email. RESULTS: In our study, most participants diagnosed with hyperemesis gravidarum trialed at least three medications, most of which were ineffective and/or had severe side effects. The most used medication for treatment of hyperemesis gravidarum is ondansetron, a standard antiemetic, with fatigue and constipation being the most reported side effects. All data in the dataset was coded as categorical and analyzed using contingency tables using Mantel-Haenszel Chi square tests. CONCLUSIONS: The data presented in this research provides insight into the suffering that patients with these diagnoses face day-to-day due to the lack of efficacious, well-tolerated treatment options. Establishing this gap in treatment can facilitate the development of effective treatments that will provide relief for thousands of patients.

Edaravone efficacy in amyotrophic lateral sclerosis with reduced forced vital capacity: Post-hoc analysis of Study 19 (MCI186-19) [clinical trial NCT01492686].

BACKGROUND: Edaravone slowed the rate of functional decline in subjects with amyotrophic lateral sclerosis (ALS) in phase 3 study MCI186-19 (Study 19). One of the Study 19 inclusion criteria was forced vital capacity (FVC) ≥80% of predicted (≥80%p). Therefore, the study provided no information on edaravone efficacy in subjects with FVC <80%p. In Study 19, 24-week, double-blind treatment was followed by open-label treatment where all subjects received edaravone. At 24 weeks, some subjects had FVC <80%p (FVC24 <80%p). This allowed for post-hoc assessment of the effects of edaravone in subgroups of subjects with FVC24 ≥80%p vs <80%p. OBJECTIVE: To address the question of the efficacy of edaravone in ALS patients with FVC <80%p. METHODS: Post-hoc analysis of Study 19 comparing edaravone efficacy at week 48 in subjects with FVC24 ≥80%p vs <80%p. RESULTS: With edaravone treatment, subjects in both the FVC24 ≥80%p and the FVC24 <80%p subgroups experienced a reduction in ALS Functional Rating Scale-Revised (ALSFRS-R) score loss vs placebo subjects through week 48. For the FVC24 ≥80%p subgroup, the changes in ALSFRS-R scores from baseline to week 48 were -7.63 for edaravone-edaravone vs -9.69 for placebo-edaravone, a difference of 2.05 (P = .034; 95% CI: 0.16, 3.94). For the FVC24 <80%p subgroup, the changes in ALSFRS-R scores from baseline to week 48 were -10.26 for edaravone-edaravone vs -15.20 for placebo-edaravone, a difference of 4.94 (P = .0038; 95% CI: 1.64, 8.25). Linear regression analysis indicated that, in the FVC24 <80%p subgroup, there was a notable change in the slope of the ALSFRS-R score-vs-time graph after the start of edaravone treatment. CONCLUSION: ALS subjects in the Study 19 placebo arm had a slowing in disease progression, even when edaravone was added with an FVC of <80%p prior to starting edaravone. A randomized, placebo-controlled study is needed to validate these post-hoc findings.

Advanced Telemedicine Training and Clinical Outcomes in Type II Diabetes: A Pilot Study.

Background: COVID-19 caused a dramatic increase in the scope and utilization of telemedicine. However, the sustainability of the permanent integration of telemedicine in the management of chronic disease beyond the pandemic is still enigmatic. The purpose of this retrospective chart review was to analyze the effect of advanced training in telemedicine on clinical outcomes in type II diabetes mellitus (T2DM) in the United States. Methods: A retrospective chart review was conducted in 104 deidentified patients with diabetes from 28 specialized telemedicine agency physicians who had received specialized telemedicine training. After establishing exclusion criteria, the charts of 59 T2DM patients were evaluated. Glycated hemoglobin (HbA1c) percentage and body mass index (BMI) were used as quantitative endpoints. Visit consistency, mediation data, and compliance data were also studied. Results: The mean change in HbA1c for the 42 patients who met the inclusion criteria for evaluating HbA1c (n = 42) was -0.429%. The largest decrease in HbA1c was 5.4%, and the most significant increase was 3.9%. The mean change in BMI for the 16 patients who met the inclusion criteria for evaluating BMI (n = 16) was -2.175 kg/m2. The largest decrease in BMI was 9.5 kg/m2 and the largest increase was +0.7 kg/m2. The average number of visits for patients with a decrease in HbA1c was 3.45. The average number of visits for patients with an increase in HbA1c was 2.62. Conclusions: Outcomes of telemedicine providers with training are comparable with the standard of care. Advanced telemedicine training and its effect on clinical outcomes in the management of chronic disease warrant further investigation. For telemedicine to become a mainstay in U.S. medicine, a standard of best practices should be evaluated and available for providers who wish to continue telehealth care delivery.

Analysis of the US Safety Data for Edaravone (Radicava®) From the Third Year After Launch.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neuromuscular disease with no curative therapies. Edaravone (Radicava®) (Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan), approved in the United States (US) for ALS in adults in 2017, was shown in a clinical trial to slow the rate of physical functional decline in ALS and is administered intravenously. The aim of this paper is to summarize the observed safety profile from real-world patient use during the first 3 years of edaravone availability in the US. METHODS: Edaravone usage data were collected, and adverse events (AEs) were identified from a postmarketing safety database from August 8, 2017 through August 7, 2020 (cutoff date). RESULTS: As of October 3, 2020, 5207 ALS patients had been treated with edaravone. As of August 7, 2020, the most commonly reported AEs included death (not specified), drug ineffective, disease progression, therapeutic response unexpected, fall, asthenia, fatigue, muscular weakness, gait disturbance, and dyspnea. The most commonly reported serious AEs (SAEs) included death (not specified), pneumonia, disease progression, ALS, fall, dyspnea, respiratory failure, device-related infection, hospitalization, and injection-site infection. There were 687 deaths, with 494 reported as death without specifying the cause. Deaths were most commonly attributed to ALS, disease progression, respiratory failure, or pneumonia. Review for administration-site reactions revealed 95 AEs, including 34 site infections, with 22 SAEs (all non-fatal). Five non-fatal SAEs of anaphylaxis were reported. CONCLUSION: In the postmarketing reporting to date, no new safety signals were identified beyond those already known from the edaravone clinical trial program.

Moving beyond Titers.

Vaccination to prevent and even eliminate disease is amongst the greatest achievements of modern medicine. Opportunities remain in vaccine development to improve protection across the whole population. A next step in vaccine development is the detailed molecular characterization of individual humoral immune responses against a pathogen, especially the rapidly evolving pathogens. New technologies such as sequencing the immune repertoire in response to disease, immunogenomics/vaccinomics, particularly the individual HLA variants, and high-throughput epitope characterization offer new insights into disease protection. Here, we highlight the emerging technologies that could be used to identify variation within the human population, facilitate vaccine discovery, improve vaccine safety and efficacy, and identify mechanisms of generating immunological memory. In today's vaccine-hesitant climate, these techniques used individually or especially together have the potential to improve vaccine effectiveness and safety and thus vaccine uptake rates. We highlight the importance of using these techniques in combination to understand the humoral immune response as a whole after vaccination to move beyond neutralizing titers as the standard for immunogenicity and vaccine efficacy, especially in clinical trials.

Slowing the loss of physical function in amyotrophic lateral sclerosis with edaravone: Post hoc analysis of ALSFRS-R item scores in pivotal study MCI186-19.

INTRODUCTION: Phase 3 study MCI186-19 demonstrated less loss of physical function with edaravone versus placebo, as measured by the revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) total score. A 1-point drop in an individual ALSFRS-R item may be clinically meaningful. We assessed ALSFRS-R item score changes to identify clinical features protected by edaravone treatment. METHODS: Time-to-event analysis was used to assess the cumulative probabilities of reductions in ALSFRS-R item scores and Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-40) subdomain scores. RESULTS: Edaravone use was accompanied by: (1) delayed drop of ≥1 point in ALSFRS-R item score for four items: salivation, walking, climbing stairs, orthopnea (unadjusted), or for two items: walking, climbing stairs (after Bonferroni correction for multiple comparisons); (2) delayed score transition from 4 or 3 at baseline to ≤2 for five items: swallowing, eating motion, walking, climbing stairs, orthopnea (unadjusted), or for one item: climbing stairs (after Bonferroni correction for multiple comparisons); and (3) delayed worsening of ALSAQ-40 domain scores representing daily living/independence, eating and drinking (unadjusted). DISCUSSION: These post-hoc analyses identified the ALSFRS-R item scores and ALSAQ-40 domain scores that were associated with preserved gross motor function and health-related quality of life, respectively, after edaravone treatment. Limitations of post-hoc analyses should be considered when interpreting these results. We recommend that clinical trials employing the ALSFRS-R include this type of analysis as a pre-specified secondary outcome measure.

Evidence for generalizability of edaravone efficacy using a novel machine learning risk-based subgroup analysis tool.

Introduction: The edaravone development program for amyotrophic lateral sclerosis (ALS) included trials MCI186-16 (Study 16) and MCI186-19 (Study 19). A cohort enrichment strategy was based on a Study 16 post hoc analysis and applied to Study 19 to elucidate a treatment effect in that study. To determine whether the Study 19 results could be generalized to a broader ALS population, we used a machine learning (ML) model to create a novel risk-based subgroup analysis tool. Methods: A validated ML model was used to rank order all Study 16 participants by predicted time to 50% expected vital capacity. Subjects were stratified into nearest-neighbor risk-based subgroups that were systematically expanded to include the entire Study 16 population. For each subgroup, a statistical analysis generated heat maps that revealed statistically significant effect sizes. Results: A broad region of the Study 16 heat map with significant effect sizes was identified, including up to 70% of the trial population. Incorporating participants identified in the cohort enrichment strategy yielded a broad group comprising 76% of the original participants with a statistically significant treatment effect. This broad group spanned the full range of the functional score progression observed in Study 16. Conclusions: This analysis, applying predictions derived using an ML model to a novel methodology for subgroup identification, ascertained a statistically significant edaravone treatment effect in a cohort of participants with broader disease characteristics than the Study 19 inclusion criteria. This novel methodology may assist clinical interpretation of study results and potentially inform efficient future clinical trial design strategies.

Potential Therapeutic Targets for Combination Antibody Therapy against Pseudomonas aeruginosa Infections.

Despite advances in antimicrobial therapy and even the advent of some effective vaccines, Pseudomonas aeruginosa (P. aeruginosa) remains a significant cause of infectious disease, primarily due to antibiotic resistance. Although P. aeruginosa is commonly treatable with readily available therapeutics, these therapies are not always efficacious, particularly for certain classes of patients (e.g., cystic fibrosis (CF)) and for drug-resistant strains. Multi-drug resistant P. aeruginosa infections are listed on both the CDC's and WHO's list of serious worldwide threats. This increasing emergence of drug resistance and prevalence of P. aeruginosa highlights the need to identify new therapeutic strategies. Combinations of monoclonal antibodies against different targets and epitopes have demonstrated synergistic efficacy with each other as well as in combination with antimicrobial agents typically used to treat these infections. Such a strategy has reduced the ability of infectious agents to develop resistance. This manuscript details the development of potential therapeutic targets for polyclonal antibody therapies to combat the emergence of multidrug-resistant P. aeruginosa infections. In particular, potential drug targets for combinational immunotherapy against P. aeruginosa are identified to combat current and future drug resistance.

MN-166 (ibudilast) in amyotrophic lateral sclerosis in a Phase IIb/III study: COMBAT-ALS study design.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with motor neuron loss as a defining feature. Despite significant effort, therapeutic breakthroughs have been modest. MN-166 (ibudilast) has demonstrated neuroprotective action by various mechanisms: inhibition of proinflammatory cytokines and macrophage migration inhibitory factor, phosphodiesterase inhibition, and attenuation of glial cell activation in models of ALS. Early-phase studies suggest that MN-166 may improve survival outcomes and slow disease progression in patients with ALS. This article describes the rationale and design of COMBAT-ALS, an ongoing randomized, double-blind, placebo-controlled, multicenter Phase IIb/III study in ALS. This study is designed to evaluate the pharmacokinetics, safety and tolerability and assess the efficacy of MN-166 on function, muscle strength, quality of life and survival in ALS.

Lay abstract Amyotrophic lateral sclerosis (ALS) is a neurological disease defined by the loss of the nerve cells going to the muscles. Despite significant effort, we still do not have good treatments for ALS. MN-166 (ibudilast) can protect nerve cells by calming inflammation in several ways in models of ALS. Early human studies suggest that MN-166 may extend life and slow disease progression in ALS patients. This article describes the rationale and design of COMBAT-ALS, an ongoing randomized, double-blind, placebo-controlled, multicenter Phase IIb/III study. This study will show the drug's safety and tolerability and its effects on physical function, muscle strength, quality of life and survival in people living with ALS. Trial registration number: NCT04057898 (ClinicalTrial.gov).

Psychometric Properties of Rapid Word-Based Rate Measures in the Assessment of Bulbar Amyotrophic Lateral Sclerosis: Comparisons With Syllable-Based Rate Tasks.

Purpose Rapid maximum performance repetition tasks have increasingly demonstrated their utility as clinimetric markers supporting diagnosis and monitoring of bulbar disease in amyotrophic lateral sclerosis (ALS). A recently developed protocol uses novel real-word repetitions instead of traditional nonword/syllable sequences in hopes of improving sensitivity to motor speech impairments by adding a phonological target constraint that would activate a greater expanse of the motor speech neuroanatomy. This study established the psychometric properties of this novel clinimetric protocol in its assessment of bulbar ALS and compared performance to traditional syllable sequence dysdiadochokinetic (DDK) tasks. Specific objectives were to (a) compare rates between controls and speakers with symptomatic versus presymptomatic bulbar disease, (b) characterize their discriminatory ability in detecting presymptomatic bulbar disease compared to healthy speech, (c) determine their articulatory movement underpinnings, and (d) establish within-individual longitudinal changes. Method DDK and novel tongue ("ticker"-TAR) and labial ("pepper"-LAR) articulatory rates were compared between n = 18 speakers with presymptomatic bulbar disease, n = 10 speakers with symptomatic bulbar disease, and n = 13 healthy controls. Bulbar disease groups were determined by a previously validated speaking rate cutoff. Discriminatory ability was determined using receiver operating characteristic analysis. Within-individual change over time was characterized in a subset of 16 participants with available longitudinal data using linear mixed-effects models. Real-time articulatory movements of the tongue front, tongue dorsum, jaw, and lips were captured using 3-D electromagnetic articulography; effects of movement displacement and speed on clinimetric rates were determined using stepwise linear regressions. Results All clinimetric rates (traditional DDK tasks and novel tasks) were reduced in speakers with symptomatic bulbar disease; only TAR was reduced in speakers with presymptomatic bulbar disease and was able to detect this group with an excellent discrimination ability (area under the curve = 0.83). Kinematic analyses revealed associations with expected articulators, greater motor complexity, and differential articulatory patterns for the novel real-word repetitions than their DDK counterparts. Only LAR significantly declined longitudinally over the disease course. Conclusion Novel real-word clinimetric rate tasks evaluating tongue and labial articulatory dysfunction are valid and effective markers for early detection and tracking of bulbar disease in ALS.