Obese patients with new onset atrial fibrillation/flutter have higher risk of hospitalization, cardioversions, and ablations.

Obesity significantly increases the risk of developing atrial fibrillation (AF) and atrial flutter (AFL) and evidence from randomized trials indicates that weight loss may reduce the burden of AF/AFL in obese patients; however, the relationship between obesity and healthcare resource utilization in AF/AFL patients is lacking. We sought to assess this relationship in patients with newly diagnosed AF/AFL in a nationally representative cohort of the United States by using the MarketScan® claims database. International Classification of Diseases, Tenth Revision [ICD 10] diagnosis codes were used to select individuals with a new diagnosis of AF/AFL in 2017 and 2018, adjudicate baseline variables and to classify them according to obesity status. Patients were followed for two years at which point all data was censored. The primary outcome of the study was hospitalizations due to AF/AFL. Cox proportional hazards regression models were used to assess the adjusted hazard ratio for obese versus non-obese patients. There were 55,271 patients with new onset AF/AFL, which included 43,314 (78.4 %) who were non-obese and 11,957 (21.6 %) who were obese. There were significantly more males than females among non-obese (65.3 % vs. 34.7 %) and obese individuals (62.3 % vs. 37.7 %). The average age (SD) was similar in the non-obese (54.5 (9.7)) and obese cohorts (54.7 (8.4)), respectively. The incidence of Emergency Department visits (4.0 % vs. 6.5 %), hospitalizations (5.5 % vs. 10.7 %), cardioversions (6.6 % vs. 12.7 %), and ablation procedures (5.3 % vs. 8.6 %) were significantly increased among obese patients.

Evaluating the Safety of an Educational Deprescribing Intervention: Lessons from the Optimize Trial.

BACKGROUND: Patients, family members, and clinicians express concerns about potential adverse drug withdrawal events (ADWEs) following medication discontinuation or fears of upsetting a stable medical equilibrium as key barriers to deprescribing. Currently, there are limited methods to pragmatically assess the safety of deprescribing and ascertain ADWEs. We report the methods and results of safety monitoring for the OPTIMIZE trial of deprescribing education for patients, family members, and clinicians. METHODS: This was a pragmatic cluster randomized trial with multivariable Poisson regression comparing outcome rates between study arms. We conducted clinical record review and adjudication of sampled records to assess potential causal relationships between medication discontinuation and outcomes. This study included adults aged 65+ with dementia or mild cognitive impairment, one or more additional chronic conditions, and prescribed 5+ chronic medications. The intervention included an educational brochure on deprescribing that was mailed to patients prior to primary care visits, a clinician notification about individual brochure mailings, and an educational tip sheets was provided monthly to primary care clinicians. The outcomes of the safety monitoring were rates of hospitalizations and mortality during the 4 months following brochure mailings and results of record review and adjudication. The adjudication process was conducted throughout the trial and included classifications: likely, possibly, and unlikely. RESULTS: There was a total of 3012 (1433 intervention and 1579 control) participants. There were 420 total hospitalizations involving 269 (18.8%) people in the intervention versus 517 total hospitalizations involving 317 (20.1%) people in the control groups. Adjusted risk ratios comparing intervention to control groups were 0.92 [95% confidence interval (CI) 0.72, 1.16] for hospitalization and 1.19 (95% CI 0.67, 2.11) for mortality. Both groups had zero deaths "likely" attributed to a medication change prior to the event. A total of 3 out of 30 (10%) intervention group hospitalizations and 7 out of 35 (20%) control group hospitalizations were considered "likely" due to a medication change. CONCLUSIONS: Population-based deprescribing education is safe in the older adult population with cognitive impairment in our study. Pragmatic methods for safety monitoring are needed to further inform deprescribing interventions. TRIAL REGISTRATION: NCT03984396. Registered on 13 June 2019.

Ethical Aspects of Physician Decision-Making for Deprescribing Among Older Adults With Dementia.

Importance: Physicians endorse deprescribing of risky or unnecessary medications for older adults (aged ≥65 years) with dementia, but there is a lack of information on what influences decisions to deprescribe in this population. Objective: To understand how physicians make decisions to deprescribe for older adults with moderate dementia and ethical and pragmatic concerns influencing those decisions. Design, Setting, and Participants: A cross-sectional national mailed survey study of a random sample of 3000 primary care physicians from the American Medical Association Physician Masterfile who care for older adults was conducted from January 15 to December 31, 2021. Main Outcomes and Measures: The study randomized participants to consider 2 clinical scenarios in which a physician may decide to deprescribe a medication for older adults with moderate dementia: 1 in which the medication could cause an adverse drug event if continued and the other in which there is no evidence of benefit. Participants ranked 9 factors related to possible ethical and pragmatic concerns through best-worst scaling methods (from greatest barrier to smallest barrier to deprescribing). Conditional logit regression quantified the relative importance for each factor as a barrier to deprescribing. Results: A total of 890 physicians (35.0%) returned surveys; 511 (57.4%) were male, and the mean (SD) years since graduation was 26.0 (11.7). Most physicians had a primary specialty in family practice (50.4% [449 of 890]) and internal medicine (43.5% [387 of 890]). A total of 689 surveys were sufficiently complete to analyze. In both clinical scenarios, the 2 greatest barriers to deprescribing were (1) the patient or family reporting symptomatic benefit from the medication (beneficence and autonomy) and (2) the medication having been prescribed by another physician (autonomy and nonmaleficence). The least influential factor was ease of paying for the medication (justice). Conclusions and Relevance: Findings from this national survey study of primary care physicians suggests that understanding ethical aspects of physician decision-making can inform clinician education about medication management and deprescribing decisions for older adults with moderate dementia.

Defining Clinical Trial Estimands: A Practical Guide for Study Teams with Examples Based on a Psychiatric Disorder.

While the ICH E9(R1) Addendum on "Estimands and Sensitivity Analysis in Clinical Trials" was released in late 2019, the widespread implementation of defining and reporting estimands across clinical trials is still in progress and the engagement of non-statistical functions in this process is also in progress. Case studies are sought after, especially those with documented clinical and regulatory feedback. This paper describes an interdisciplinary process for implementing the estimand framework, devised by the Estimands and Missing Data Working Group (a group with clinical, statistical, and regulatory representation) of the International Society for CNS Clinical Trials and Methodology. This process is illustrated by specific examples using various types of hypothetical trials evaluating a treatment for major depressive disorder. Each of the estimand examples follows the same template and features all steps of the proposed process, including identifying the trial stakeholder(s), the decisions they need to make about the investigated treatment in their specific role and the questions that would support their decision making. Each of the five strategies for handling intercurrent events are addressed in at least one example; the featured endpoints are also diverse, including continuous, binary and time to event. Several examples are presented that include specifications for a potential trial design, key trial implementation elements needed to address the estimand, and main and sensitivity estimator specifications. Ultimately this paper highlights the need to incorporate multi-disciplinary collaborations into implementing the ICH E9(R1) framework.

Willingness of older people living with dementia and mild cognitive impairment and their caregivers to have medications deprescribed.

BACKGROUND: people living with cognitive impairment commonly take multiple medications including potentially inappropriate medications (PIMs), which puts them at risk of medication related harms. AIMS: to explore willingness to have a medication deprescribed of older people living with cognitive impairment (dementia or mild cognitive impairment) and multiple chronic conditions and assess the relationship between willingness, patient characteristics and belief about medications. METHODS: cross-sectional study using results from the revised Patients' Attitudes Towards Deprescribing questionnaire (rPATDcog) collected as baseline data in the OPTIMIZE study, a pragmatic, cluster-randomised trial educating patients and clinicians about deprescribing. Eligible participants were 65+, diagnosed with dementia or mild cognitive impairment, and prescribed at least five-long-term medications. RESULTS: the questionnaire was mailed to 1,409 intervention patients and 553 (39%) were returned and included in analysis. Participants had a mean age of 80.1 (SD 7.4) and 52.4% were female. About 78.5% (431/549) of participants said that they would be willing to have one of their medications stopped if their doctor said it was possible. Willingness to deprescribe was negatively associated with getting stressed when changes are made and with previously having a bad experience with stopping a medication (P < 0.001 for both). CONCLUSION: most older people living with cognitive impairment are willing to deprescribe. Addressing previous bad experiences with stopping a medication and stress when changes are made to medications may be key points to discuss during deprescribing conversations.

Intervention design in cognitively impaired populations-Lessons learned from the OPTIMIZE deprescribing pragmatic trial.

BACKGROUND: Polypharmacy is common in older adults with cognitive impairment and multiple chronic conditions, increasing risks of adverse drug events, hospitalization, and death. Deprescribing, the process of reducing or stopping potentially inappropriate medications, may improve outcomes. The OPTIMIZE pragmatic trial examined whether educating and activating patients, family members and clinicians about deprescribing reduces number of chronic medications and potentially inappropriate medications. Acceptability and challenges of intervention delivery in cognitively impaired older adults are not well understood. METHODS: We explored mechanisms of intervention implementation through post hoc qualitative interviews and surveys with stakeholder groups of 15 patients, 7 caregivers, and 28 clinicians. We assessed the context in which the intervention was delivered, its implementation, and mechanisms of impact. RESULTS: Acceptance of the intervention was affected by contextual factors including cognition, prior knowledge of deprescribing, communication, and time constraints. All stakeholder groups endorsed the acceptability, importance, and delivery of the intervention. Positive mechanisms of impact included patients scheduling specific appointments to discuss deprescribing and providers being prompted to consider deprescribing. Recollection of intervention materials was inconsistent but most likely shortly after intervention delivery. Short visit times remained the largest provider barrier to deprescribing. CONCLUSIONS: Our work identifies key learnings in intervention delivery that can guide future scaling of deprescribing interventions in this population. We highlight the critical roles of timing and repetition in intervention delivery to cognitively impaired populations and the barrier posed by short consultation times. The acceptability of the intervention to patients and family members highlights the potential to incorporate deprescribing education into routine clinical practice and expand proven interventions to other vulnerable populations.

Comparison of the effect of sedation and general anesthesia on pattern and flash visual evoked potentials in normal dogs.

BACKGROUND: Visual evoked potentials (VEPs) can provide objective functional assessment of the post-retinal visual pathway. This study compared the effects of sedation (butorphanol and dexmedetomidine) and general anesthesia (propofol and sevoflurane) on pattern and flash VEPs. Dogs (n = 13) underwent sedation or anesthesia and VEPs were obtained from 3 subcutaneous recording electrodes placed on the head (O1, Oz, O2). RESULTS: Pattern VEPs could only be recorded under sedation and a maximum of 3 peaks were identified (N75, P100, N135). Flash VEPs could be recorded under both sedation and anesthesia and a maximum of 5 peaks were identified (N1, P1, N2, P2, N3). The latency of the N1 peak and the baseline-N1 amplitude were significantly longer under general anesthesia. CONCLUSION: Visual evoked potentials should be preferentially recorded in dogs sedated with dexmedetomidine and butorphanol, regardless of the stimulus.

Deprescribing Education vs Usual Care for Patients With Cognitive Impairment and Primary Care Clinicians: The OPTIMIZE Pragmatic Cluster Randomized Trial.

Background: Individuals with dementia or mild cognitive impairment frequently have multiple chronic conditions (defined as ≥2 chronic medical conditions) and take multiple medications, increasing their risk for adverse outcomes. Deprescribing (reducing or stopping medications for which potential harms outweigh potential benefits) may decrease their risk of adverse outcomes. Objective: To examine the effectiveness of increasing patient and clinician awareness about the potential to deprescribe unnecessary or risky medications among patients with dementia or mild cognitive impairment. Design, Setting, and Participants: This pragmatic, patient-centered, 12-month cluster randomized clinical trial was conducted from April 1, 2019, to March 31, 2020, at 18 primary care clinics in a not-for-profit integrated health care delivery system. The study included 3012 adults aged 65 years or older with dementia or mild cognitive impairment who had 1 or more additional chronic medical conditions and were taking 5 or more long-term medications. Interventions: An educational brochure and a questionnaire on attitudes toward deprescribing were mailed to patients prior to a primary care visit, clinicians were notified about the mailing, and deprescribing tip sheets were distributed to clinicians at monthly clinic meetings. Main Outcomes and Measures: The number of prescribed long-term medications and the percentage of individuals prescribed 1 or more potentially inappropriate medications (PIMs). Analysis was performed on an intention-to-treat basis. Results: This study comprised 1433 individuals (806 women [56.2%]; mean [SD] age, 80.1 [7.2] years) in 9 intervention clinics and 1579 individuals (874 women [55.4%]; mean [SD] age, 79.9 [7.5] years) in 9 control clinics who met the eligibility criteria. At baseline, both groups were prescribed a similar mean (SD) number of long-term medications (7.0 [2.1] in the intervention group and 7.0 [2.2] in the control group), and a similar proportion of individuals in both groups were taking 1 or more PIMs (437 of 1433 individuals [30.5%] in the intervention group and 467 of 1579 individuals [29.6%] in the control group). At 6 months, the adjusted mean number of long-term medications was similar in the intervention and control groups (6.4 [95% CI, 6.3-6.5] vs 6.5 [95% CI, 6.4-6.6]; P = .14). The estimated percentages of patients in the intervention and control groups taking 1 or more PIMs were similar (17.8% [95% CI, 15.4%-20.5%] vs 20.9% [95% CI, 18.4%-23.6%]; P = .08). In preplanned subgroup analyses, adjusted differences between the intervention and control groups were -0.16 (95% CI, -0.34 to 0.01) for individuals prescribed 7 or more long-term medications at baseline (n = 1434) and -0.03 (95% CI, -0.20 to 0.13) for those prescribed 5 to 6 medications (n = 1578) (P = .28 for interaction; P = .19 for subgroup interaction for PIMs). Conclusions and Relevance: This large-scale educational deprescribing intervention for older adults with cognitive impairment taking 5 or more long-term medications and their primary care clinicians demonstrated small effect sizes and did not significantly reduce the number of long-term medications and PIMs. Such interventions should target older adults taking relatively more medications. Trial Registration: ClinicalTrials.gov Identifier: NCT03984396.

Skilled home healthcare clinicians' experiences in communicating with physicians: A national survey.

BACKGROUND: Effective communication between skilled home healthcare (SHHC) clinicians and physicians is critical to care coordination. No studies have examined this from the point of view of SHHC clinicians at the national level. The objective is to determine in national sample issues related to how SHHC agency clinicians communicate with physicians. DESIGN: Mailed survey. METHODS: Mailed survey to a national representative random sample of SHHC agencies. The survey measured the experiences of SHHC clinicians in communicating with physicians. Multilevel logistic regression models examining odds of adverse patient outcomes associated with communication failures. RESULTS: A total of 265 surveys from 168 SHHC agencies were returned for a response rate of 13.3% at the individual respondent level and 16.8% at the SHHC agency level. Agency-level characteristics were similar between responding and nonresponding agencies. The most common method of contacting physicians during routine SHHC visits was telephone; communication via the electronic health record was uncommon. Nearly 40% of SHHC clinicians report never or rarely being able to reach a physician. SHHC clinicians rate the Center for Medicare and Medicaid Services Home Health Certification and Plan of Care (CMS-485) as a useful means of communication 6.3 (SD, 2.5) scale of 1 (least useful) to 10 (most useful); only 14% could have SHHC orders signed electronically. In multilevel logistic models, compared to SHHC clinicians who could reach a physician nearly every time or always, the odds of an SHHC clinician sending someone to the emergency department were 3.66 (95% confidence interval 1.16-11.5) for SHHC clinicians who were sometimes or often able to reach a physician and 5.43 (95% CI 1.56-18.9) for those who never or rarely reached a physician. CONCLUSIONS: In this exploratory study, SHHC clinicians experience significant communication barriers with physicians who order SHHC services. Strategies to enhance meaningful communication between SHHC clinicians and physicians must be developed.

A performance comparison of the most commonly used minimally invasive monitors of cardiac output.

BACKGROUND: Shock is common in critically ill and injured patients. Survival during shock is highly dependent on rapid restoration of tissue oxygenation with therapeutic goals based on cardiac output (CO) optimization. Despite the clinical availability of numerous minimally invasive monitors of CO, limited supporting performance data are available. METHODS: Following approval of the University of Saskatchewan Animal Research Ethics Board, we assessed the performance and trending ability of PiCCOplus™, FloTrac™, and CardioQ-ODM™ across a range of CO states in pigs. In addition, we assessed the ability of invasive mean arterial blood pressure (iMAP) to follow changes in CO using a periaortic transit-time flow probe as the reference method. Statistical analysis was performed with function-fail, bias and precision, percent error, and linear regression at all flow, low-flow (> 1 standard deviation [SD] below the mean), and high-flow (> 1 SD above the mean) CO conditions. RESULTS: We made a total of 116,957 paired CO measurements. The non-invasive CO monitors often failed to provide a CO value (CardioQ-ODM: 40.6% failed measurements; 99% confidence interval [CI], 38.5 to 42.6; FloTrac: 9.6% failed measurements; 99% CI, 8.7 to 10.5; PiCCOplus: 4.7% failed measurements; 99% CI, 4.5 to 4.9; all comparisons, P < 0.001). The invasive mean arterial pressure provided zero failures, failing less often than any of the tested CO monitors (all comparisons, P < 0.001). The PiCCOplus was most interchangeable with the flow probe at all flow states: PiCCOplus (20% error; 99% CI, 19 to 22), CardioQ-ODM (25% error; 99% CI, 23 to 27), FloTrac (34% error; 99% CI, 32 to 38) (all comparisons, P < 0.001). At low-flow states, CardioQ-ODM (43% error; 99% CI, 32 to 63) and Flotrac (45% error; 99% CI, 33 to 70) had similar interchangeability (P = 0.07), both superior to PiCCOplus (48% error; 99% CI, 42 to 60) (P < 0.001). Regarding CO trending, the CardioQ-ODM (correlation coefficient, 0.82; 99% CI, 0.81 to 0.83) was statistically superior to other monitors including iMAP, but at low flows iMAP (correlation coefficient, 0.58; 99% CI, 0.58 to 0.60) was superior to all minimally invasive CO monitors (all comparisons P < 0.001). CONCLUSIONS: None of the minimally invasive monitors of CO performed well at all tested flows. Invasive mean arterial blood pressure most closely tracked CO change at critical flow states.

RéSUMé: CONTEXTE: L'état de choc est fréquent chez les patients blessés et en urgence absolue. La survie pendant le choc dépend fortement de la restauration rapide de l'oxygénation tissulaire avec des objectifs thérapeutiques basés sur l'optimisation du débit cardiaque (DC). Malgré la disponibilité clinique de nombreux moniteurs minimalement invasifs du DC, il n'existe que des données limitées sur leur performance pour appuyer leur utilisation. MéTHODE: À la suite de l'approbation du comité d'éthique de la recherche animale de l'Université de la Saskatchewan, nous avons évalué la performance et la capacité de suivi des tendances des appareils PiCCOplus™, FloTrac™ et CardioQ-ODM™ sur une vaste gamme d'état de DC chez des cochons. Nous avons également évalué la capacité de la tension artérielle moyenne invasive (iMAP) à suivre les changements de DC en utilisant une sonde périaortique de débit basée sur le temps de transit comme méthode de référence. L'analyse statistique a été réalisée avec fonction-échec, biais et précision, pourcentage d'erreur et régression linéaire à des conditions de DC de tous les débits, de faible débit (> 1 écart-type [ET] au-dessous de la moyenne) et de débit élevé (> 1 ET au-dessus de la moyenne). RéSULTATS: Nous avons effectué un total de 116 957 mesures de DC appariées. Les moniteurs non invasifs de la DC n'ont souvent pas réussi à fournir une valeur de DC (CardioQ-ODM : 40,6% de mesures échouées; intervalle de confiance [IC] de 99 %, 38,5 à 42,6; FloTrac : 9,6 % de mesures échouées; IC 99 %, 8,7 à 10,5; PiCCOplus : 4,7 % de mesures échouées; IC 99 %, 4,5 à 4,9; toutes les comparaisons, P < 0,001). La tension artérielle moyenne invasive n'a fourni aucun échec plus souvent que n'importe lequel des moniteurs de DC testés (toutes les comparaisons, P < 0,001). Le PiCCOplus était le plus interchangeable avec la sonde de débit à tous les états de débit : PiCCOplus (erreur de 20 %; IC 99 %, 19 à 22), CardioQ-ODM (erreur de 25 %; IC 99 %, 23 à 27), FloTrac (erreur de 34 %; IC 99 %, 32 à 38) (toutes les comparaisons, P < 0,001). Aux états de débit faible, les moniteurs CardioQ-ODM (erreur de 43 %; IC 99 %, 32 à 63) et FloTrac (erreur de 45 %; IC 99 %, 33 à 70) présentaient une interchangeabilité similaire (P = 0,07), tous deux supérieurs au PiCCOplus (erreur de 48 %; IC 99 %, 42 à 60) (P < 0,001). En ce qui concerne le suivi des tendances de DC, le CardioQ-ODM (coefficient de corrélation, 0,82; IC 99 %, 0,81 à 0,83) était statistiquement supérieur aux autres moniteurs, y compris au iMAP, mais à faibles débits, l'iMAP (coefficient de corrélation, 0,58; IC 99 %, 0,58 à 0,60) était supérieure à tous les moniteurs de DC minimalement invasifs (toutes les comparaisons, P < 0,001). CONCLUSION: Aucun des moniteurs de DC minimalement invasif n'a donné de bons résultats à tous les débits testés. La tension artérielle moyenne invasive était le moniteur qui a suivi de plus près les changements de DC dans des états critiques de débit.

Skilled Home Healthcare Clinician and Staff Perspectives on Communication With Physicians: A Multisite Qualitative Study.

Communication between physicians who order, and clinicians who provide skilled home healthcare (SHHC), is critical to well-coordinated care. The views of SHHC staff on communication with physicians have not been well studied. The objective of this study was to explore how SHHC staff view the communication processes with physicians who order SHHC services. Using purposive and snowball sampling, we conducted semistructured interviews with 22 SHHC staff across multiple regions of the United States. Qualitative thematic content analysis was used to analyze the data. SHHC staff experienced significant barriers to effective communication with physicians, including not being able to communicate in a timely manner when necessary for patient care, and challenges identifying the correct physician to coordinate care and sign SHHC orders. Key strategies to enhance communication focused on creating standardized processes to streamline communication, setting expectations for response times in communication, and improving the Centers for Medicare & Medicaid Services Home Health Certification and Plan of Care form (commonly referred to as the "CMS-485"/Plan of Care). SHHC staff experience significant communication challenges with physicians who order SHHC services that can compromise care coordination and delivery. Modifications to workflows are urgently needed to improve efficiency and quality of communication, care coordination, and quality of care.

Intermuscular Coherence in the Presence of Electrical Stimulation.

The nervous system uses oscillations to convey information efficiently. Inter-muscular coherence in the 15-35 Hz range is thought to represent common cortical drive to muscles, but is also in the frequency band in which electrical stimulation is applied to restore movement following neurological disease or injury. We wished to determine if, when stimulation is applied at the peak frequency of the coherence spectra it was still possible to determine voluntary effort. Using healthy human subjects we stimulated muscles in the arms and legs, separate experiments, while recording EMG activity from pairs of muscles including the stimulated muscles. Offline coherence analysis was performed. When stimulation is greater than motor threshold, and applied at the peak of the coherence spectra a new peak appears in the spectra, presumably representing a new frequency of oscillation within the nervous system. This does not appear at lower stimulation levels, or with lower frequencies. The nervous system is capable of switching oscillatory frequencies to account for noise in the environment.

Results of a randomized double-blind study evaluating luvadaxistat in adults with Friedreich ataxia.

OBJECTIVES: Friedreich ataxia (FRDA) is a rare disorder with progressive neurodegeneration and cardiomyopathy. Luvadaxistat (also known as TAK-831; NBI-1065844), an inhibitor of the enzyme d-amino acid oxidase, has demonstrated beneficial effects in preclinical models relevant to FRDA. This phase 2, randomized, double-blind, placebo-controlled, parallel-arm study evaluated the efficacy and safety of oral luvadaxistat in adults with FRDA. METHODS: Adult patients with FRDA were randomized 2:1:2 to placebo, luvadaxistat 75 mg twice daily (BID), or luvadaxistat 300 mg BID for 12 weeks. The primary endpoint changed from baseline at week 12 on the inverse of the time to complete the nine-hole peg test (9-HPT-1 ), a performance-based measure of the function of the upper extremities and manual dexterity. Comparisons between luvadaxistat and placebo were made using a mixed model for repeated measures. RESULTS: Of 67 randomized patients, 63 (94%) completed the study. For the primary endpoint, there was no statistically significant difference in change from baseline on the 9-HPT-1 (seconds-1 ) at week 12 between placebo (0.00029) and luvadaxistat 75 mg BID (-0.00031) or luvadaxistat 300 mg BID (-0.00059); least squares mean differences versus placebo (standard error) were -0.00054 (0.000746) for the 75 mg dose and -0.00069 (0.000616) for the 300 mg dose. Luvadaxistat was safe and well tolerated; the majority of reported adverse events were mild in intensity. INTERPRETATION: Luvadaxistat was safe and well tolerated in this cohort of adults with FRDA; however, it did not demonstrate efficacy as a treatment for this condition.