Creation of an incus recess for a middle-ear microphone using a drill or laser ablation: a comparison of equivalent noise level and middle ear transfer function.

PURPOSE: Studies have assessed the trauma and change in hearing function from the use of otological drills on the ossicular chain, but not the effects of partial laser ablation of the incus. A study of the effectiveness of a novel middle-ear microphone for a cochlear implant, which required an incus recess for the microphone balltip, provided an opportunity to compare methods and inform a feasibility study of the microphone with patients. METHODS: We used laser Doppler vibrometry with an insert earphone and probe microphone in 23 ears from 14 fresh-frozen cadavers to measure the equivalent noise level at the tympanic membrane that would have led to the same stapes velocity as the creation of the incus recess. RESULTS: Drilling on the incus with a diamond burr created peak noise levels equivalent to 125.1-155.0 dB SPL at the tympanic membrane, whilst using the laser generated equivalent noise levels barely above the baseline level. The change in middle ear transfer function following drilling showed greater variability at high frequencies, but the change was not statistically significant in the three frequency bands tested. CONCLUSIONS: Whilst drilling resulted in substantially higher equivalent noise, we considered that the recess created by laser ablation was more likely to lead to movement of the microphone balltip, and therefore decrease performance or result in malfunction over time. For patients with greatly reduced residual hearing, the greater consistency from drilling the incus recess may outweigh the potential benefits of hearing preservation with laser ablation.

How a Digital Case Management Platform Affects Community-Based Palliative Care of Sub-Saharan African Cancer Patients: Clinician-Users' Perspectives.

BACKGROUND: Symptom control among cancer patients is a Tanzanian public health priority impacted by limited access to palliative care (PC) specialists and resources. Mobile Palliative Care Link (mPCL), a mobile/web application, aims to extend specialist access via shared care with local health workers (LHWs) with the African Palliative care Outcome Scale (POS) adapted for regular, automated symptom assessment as a core feature. OBJECTIVE: The aim of the study is to assess clinicians' attitudes, beliefs, and perceptions regarding mPCL usability and utility with their patients within a government-supported, urban Tanzanian cancer hospital setting. METHODS: We used a mixed methods approach including surveys, qualitative interviews, and system usage data to assess clinicians' experience with mPCL in a field study where discharged, untreatable cancer patients were randomized to mPCL or phone-contact POS collection. RESULTS: All six specialists and 10 LHWs expressed overall satisfaction with mPCL among 49 intervention arm patients. They perceived mPCL as a way to stay connected with patients and support remote symptom control. Timely access to POS responses and medical records were identified as key benefits. Some differences in perceptions of mPCL use and utility were seen between clinician groups; however, both expressed strong interest in continuing app use, recommending it to colleagues, and extending use throughout Tanzania. Primary use was for clinical status communication and care coordination. Pain and other symptom progression were the most frequently reported reasons for provider-patient interactions accounting for 34% (n = 44) and 12% (n = 15) of reasons, respectively. Usage barriers included time required to create a new clinical record, perceived need for response to non-urgent reminders or alerts, and training. necessary for competent use. System-level implementation barriers included variable patient access to smartphones and SIM cards and unreliable Internet access. CONCLUSION: This work demonstrates broad clinician desire for digital health tools to support remote community-based PC among cancer patients, particularly pain management.

Comparison of an Implantable Middle Ear Microphone and Conventional External Microphone for Cochlear Implants: A Clinical Feasibility Study.

OBJECTIVES: All commercially available cochlear implant (CI) systems use an external microphone and sound processor; however, external equipment carries lifestyle limitations. Although totally implantable devices using subcutaneous microphones have been developed, these are compromised by problems with soft tissue sound attenuation, feedback, and intrusive body noise. This in vivo pilot study evaluates a middle ear microphone (MEM) that aims to overcome these issues and compares hearing performance with that of an external CI microphone. DESIGN: Six adult participants with an existing CI were implanted with a temporary MEM in the contralateral ear. Signals from the MEM were routed via a percutaneous plug and cable to the CI sound processor. Testing was performed in the CI microphone and MEM conditions using a range of audiometric assessments, which were repeated across four visits. RESULTS: Performance of the MEM did not differ significantly from that of the CI on the assessments of Auditory Speech Sounds Evaluation loudness scaling at either 250 or 1000 Hz, or in the accuracy of repeating keywords presented at 70 dB. However, the MEM had significantly poorer aided sound-field thresholds, particularly at higher frequencies (≥4000 Hz), and significantly poorer performance on Arthur Boothroyd words presented at 55 dB, compared with the CI. CONCLUSION: In this pilot study, the MEM showed comparable performance to that of an external CI microphone across some audiometric assessments. However, performance with the MEM was poorer than the CI in soft-level speech (55 dB) and at higher frequencies. As such, the benefits of MEM need to be considered against the compromises in hearing performance. However, with future development, MEM is a potentially promising technology.

Noise helps cochlear implant listeners to categorize vowels.

Theoretical studies demonstrate that controlled addition of noise can enhance the amount of information transmitted by a cochlear implant (CI). The present study is a proof-of-principle for whether stochastic facilitation can improve the ability of CI users to categorize speech sounds. Analogue vowels were presented to CI users through a single electrode with independent noise on multiple electrodes. Noise improved vowel categorization, particularly in terms of an increase in information conveyed by the first and second formant. Noise, however, did not significantly improve vowel recognition: the miscategorizations were just more consistent, giving the potential to improve with experience.

Artificial Intelligence: Innovation to Assist in the Identification of Sono-anatomy for Ultrasound-Guided Regional Anaesthesia.

Ultrasound-guided regional anaesthesia (UGRA) involves the targeted deposition of local anaesthesia to inhibit the function of peripheral nerves. Ultrasound allows the visualisation of nerves and the surrounding structures, to guide needle insertion to a perineural or fascial plane end point for injection. However, it is challenging to develop the necessary skills to acquire and interpret optimal ultrasound images. Sound anatomical knowledge is required and human image analysis is fallible, limited by heuristic behaviours and fatigue, while its subjectivity leads to varied interpretation even amongst experts. Therefore, to maximise the potential benefit of ultrasound guidance, innovation in sono-anatomical identification is required.Artificial intelligence (AI) is rapidly infiltrating many aspects of everyday life. Advances related to medicine have been slower, in part because of the regulatory approval process needing to thoroughly evaluate the risk-benefit ratio of new devices. One area of AI to show significant promise is computer vision (a branch of AI dealing with how computers interpret the visual world), which is particularly relevant to medical image interpretation. AI includes the subfields of machine learning and deep learning, techniques used to interpret or label images. Deep learning systems may hold potential to support ultrasound image interpretation in UGRA but must be trained and validated on data prior to clinical use.Review of the current UGRA literature compares the success and generalisability of deep learning and non-deep learning approaches to image segmentation and explains how computers are able to track structures such as nerves through image frames. We conclude this review with a case study from industry (ScanNav Anatomy Peripheral Nerve Block; Intelligent Ultrasound Limited). This includes a more detailed discussion of the AI approach involved in this system and reviews current evidence of the system performance.The authors discuss how this technology may be best used to assist anaesthetists and what effects this may have on the future of learning and practice of UGRA. Finally, we discuss possible avenues for AI within UGRA and the associated implications.

mPalliative Care Link: Examination of a Mobile Solution to Palliative Care Coordination Among Tanzanian Patients With Cancer.

PURPOSE: Late-stage cancer patient symptom control is a national priority in Tanzania. Mobile health promises to improve the reach of a limited pool of palliative care specialists through interprofessional, community-based care coordination. This work assessed the effectiveness of a smartphone- or Web-based app, mPalliative Care Link (mPCL), to extend specialist access via shared data and communication with local health workers. Central to mPCL is the African Palliative care Outcome Scale (POS), adapted for automated mobile symptom assessment and response. METHODS: Adult patients with incurable cancer were randomly assigned at hospital discharge to mPCL versus phone-contact POS collection. Sociodemographic, clinical, and POS data were obtained at baseline. Twice-weekly POS responses were collected and managed via mPCL or phone contact with clinician study personnel for up to 4 months, on the basis of study arm assignment. Patient end-of-study care satisfaction was assessed via phone survey. RESULTS: Forty-nine patients per arm participated. Comparison of baseline characteristics showed an insignificant trend toward more women (P = .07) and higher discharge morphine use (P = .09) in the mPCL group compared with phone-contact and significant between-group differences in cancer types (P = .003). Proportions of deaths were near equal between groups (mPCL: 27%; phone-contact: 29%). Overall symptom severity was significantly lower in the phone-contact group (P < .0001), and symptom severity decreased over time in both groups (P = .0001); however, between-group change in overall symptoms over time did not vary significantly (P = .34). Care satisfaction was generally high in both groups. CONCLUSION: Higher symptom severity scores in the mPCL arm likely reflect between-group sociodemographic and clinical differences and clinical support of phone-contact arm participants. Similar rates of care satisfaction in both groups suggest that mPCL may support symptom-focused care coordination in a more efficient and scalable manner than phone contact. A broader study of mPCL's cost efficiency and utility in Tanzania is needed.

Evaluating machine learning techniques for archaeological lithic sourcing: a case study of flint in Britain.

It is 50 years since Sieveking et al. published their pioneering research in Nature on the geochemical analysis of artefacts from Neolithic flint mines in southern Britain. In the decades since, geochemical techniques to source stone artefacts have flourished globally, with a renaissance in recent years from new instrumentation, data analysis, and machine learning techniques. Despite the interest over these latter approaches, there has been variation in the quality with which these methods have been applied. Using the case study of flint artefacts and geological samples from England, we present a robust and objective evaluation of three popular techniques, Random Forest, K-Nearest-Neighbour, and Support Vector Machines, and present a pipeline for their appropriate use. When evaluated correctly, the results establish high model classification performance, with Random Forest leading with an average accuracy of 85% (measured through F1 Scores), and with Support Vector Machines following closely. The methodology developed in this paper demonstrates the potential to significantly improve on previous approaches, particularly in removing bias, and providing greater means of evaluation than previously utilised.

A Mobile App to Improve Symptom Control and Information Exchange Among Specialists and Local Health Workers Treating Tanzanian Cancer Patients: Human-Centered Design Approach.

BACKGROUND: Improving access to end-of-life symptom control interventions among cancer patients is a public health priority in Tanzania, and innovative community-based solutions are needed. Mobile health technology holds promise; however, existing resources are limited, and outpatient access to palliative care specialists is poor. A mobile platform that extends palliative care specialist access via shared care with community-based local health workers (LHWs) and provides remote support for pain and other symptom management can address this care gap. OBJECTIVE: The aim of this study is to design and develop mobile-Palliative Care Link (mPCL), a web and mobile app to support outpatient symptom assessment and care coordination and control, with a focus on pain. METHODS: A human-centered iterative design framework was used to develop the mPCL prototype for use by Tanzanian palliative care specialists (physicians and nurses trained in palliative care), poor-prognosis cancer patients and their lay caregivers (patients and caregivers), and LHWs. Central to mPCL is the validated African Palliative Care Outcome Scale (POS), which was adapted for automated, twice-weekly collection of quality of life-focused patient and caregiver responses and timely review, reaction, and tracking by specialists and LHWs. Prototype usability testing sessions were conducted in person with 21 key informants representing target end users. Sessions consisted of direct observations and qualitative and quantitative feedback on app ease of use and recommendations for improvement. Results were applied to optimize the prototype for subsequent real-world testing. Early pilot testing was conducted by deploying the app among 10 patients and caregivers, randomized to mPCL use versus phone-contact POS collection, and then gathering specialist and study team feedback to further optimize the prototype for a broader randomized field study to examine the app's effectiveness in symptom control among cancer patients. RESULTS: mPCL functionalities include the ability to create and update a synoptic clinical record, regular real-time symptom assessment, patient or caregiver and care team communication and care coordination, symptom-focused educational resources, and ready access to emergency phone contact with a care team member. Results from the usability and pilot testing demonstrated that all users were able to successfully navigate the app, and feedback suggests that mPCL has clinical utility. User-informed recommendations included further improvement in app navigation, simplification of patient and caregiver components and language, and delineation of user roles. CONCLUSIONS: We designed, built, and tested a usable, functional mobile app prototype that supports outpatient palliative care for Tanzanian patients with cancer. mPCL is expressly designed to facilitate coordinated care via customized interfaces supporting core users-patients or caregivers, LHWs, and members of the palliative care team-and their respective roles. Future work is needed to demonstrate the effectiveness and sustainability of mPCL to remotely support the symptom control needs of Tanzanian cancer patients, particularly in harder-to-reach areas.

A Mobile Health Tool for Peer Support of Individuals Reentering Communities After Incarceration.

Individuals just released from prison, or returning citizens (RCs), face high mortality rates during the reentry period, with cardiovascular disease (CVD) being a leading cause. Peer mentors can support RCs' health, but they traditionally work in person, which may not always be feasible, particularly during pandemic outbreaks such as COVID-19. We used human-centered design to build a prototype of RCPeer, a web/mobile application (app) to support peer-led reentry efforts through CVD risk screening, action planning, linkage to resources addressing reintegration needs (e.g., housing, transportation), and goal-setting. We assessed feasibility, acceptability, and usability of RCPeer using mixed-methods. System Usability Scale (SUS) scores were 68 for peers and 66 for RCs, indicating good usability. Qualitative data suggests that RCPeer can support reentry tasks through RCs and peers sharing data, strengthen RC-peer relationships, and facilitate RCs meeting their goals. Future work is needed to enhance usability for RCs with limited technology experience.

A narrative review of the logistic and economic feasibility of cochlear implants in lower-income countries.

Objectives: Globally, less than 1% of people who could benefit from a cochlear implant have one and the problem is particularly acute in lower-income countries. Here we give a narrative review of the economic and logistic feasibility of cochlear implant programmes in lower-income countries and discuss future developments that would enable better healthcare. We review the incidence and aetiology of hearing loss in low- and middle-income countries, screening for hearing loss, implantation criteria, issues concerning imaging and surgery, and the professional expertise required. We also review the cost of cochlear implantation and ongoing costs. Findings: The cost effectiveness of cochlear implants in lower-income countries is more limited by the cost of the device than the cost of surgery, but there are also large ongoing costs that will deter many potential users. Conclusions: We conclude that the main barriers to the future uptake of cochlear implants are likely to be logistical rather than technical and cochlear implant provision should be considered as part of a wider programme to improve the health of those with hearing loss.

Inappropriate Use of the "Rosowski Criteria" and "Modified Rosowski Criteria" for Assessing the Normal Function of Human Temporal Bones.

Important research by Rosowski et al. [Twenty-Seventh Meeting of the Association for Research in Otolaryngology, 2004, p. 275] has led to a standard practice by the American Society for Testing Materials [West Conshohocken: ASTM International; 2014] to assess normal function of temporal bones used in the development of novel middle ear actuators and sensors. Rosowki et al. [Audiol Neurotol. 2007; 12(4): 265-76] have since suggested that the original criteria are too restrictive and have proposed modified criteria. We show that both the original and modified criteria are inappropriate for assessing individual temporal bones. Moreover, we suggest that both the original and modified Rosowski criteria should be applied with caution when assessing whether mean data from a study are within physiological norms because the multiple comparisons resulting from verification at each frequency will lead to very liberal rejection. The standard practice, however, has led to the collection of more extensive and consistent data. We suggest that it is now opportune to use these data to further modify the Rosowski criteria.

Perceptual Differences Between Low-Frequency Analog and Pulsatile Stimulation as Shown by Single- and Multidimensional Scaling.

Cochlear-implant users who have experienced both analog and pulsatile sound coding strategies often have strong preferences for the sound quality of one over the other. This suggests that analog and pulsatile stimulation may provide different information or sound quality to an implant listener. It has been well documented that many implant listeners both prefer and perform better with multichannel analog than multichannel pulsatile strategies, although the reasons for these differences remain unknown. Here, we examine the perceptual differences between analog and pulsatile stimulation on a single electrode. A multidimensional scaling task, analyzed across two dimensions, suggested that pulsatile stimulation was perceived to be considerably different from analog stimulation. Two associated tasks using single-dimensional scaling showed that analog stimulation was perceived to be less Clean on average than pulsatile stimulation and that the perceptual differences were not related to pitch. In a follow-up experiment, it was determined that the perceptual differences between analog and pulsatile stimulation were not dependent on the interpulse gap present in pulsatile stimulation. Although the results suggest that there is a large perceptual difference between analog and pulsatile stimulation, further work is needed to determine the nature of these differences.

Implantable microphones as an alternative to external microphones for cochlear implants.

Totally implantable cochlear implants may be able to address many of the problems cochlear implant users have around cosmetic appearances, discomfort, and restriction of activities. The major technological challenges that need to be solved to develop a totally implantable device relate to implanted microphone performance. Previous attempts at implanting microphones for cochlear implants have not performed as well as conventional cochlear implant microphones, and in addition have struggled with extraneous body or surface contact noise. Microphones can be implanted under the skin or act as sensors in the middle ear; however, evidence from middle ear implants suggest body and contact noise can be overcome by converting ossicular chain movements into digital signals. This article reviews implantable microphone systems and discusses the technology behind them.

Realizing Informed Consent in Times of Controversy: Lessons from the SUPPORT Study.

This Essay examines the elegantly simple idea that consent to medical treatment or participation in human research must be "informed" to be valid. It does so by using as a case study the controversial clinical research trial known as the Surfactant, Positive Pressure, and Oxygenation Randomized Trial ("SUPPORT"). The Essay begins by charting, through case law and the adoption of the common rule, the evolution of duties to secure fully informed consent in both research and treatment. The Essay then utilizes the SUPPORT study, which sought to pinpoint the level of saturated oxygen that should be provided to extremely low birth weight infants to demonstrate modern complexities and shortcomings of the duty to secure informed consent. This Essay shows how the duty is measured by foreseeability of risks and benefits in human research and why federal regulators believed the trade-offs in risk and benefits from differing oxygen levels administered in the support study were foreseeable. It then explores the contours of the duty to secure informed consent when applied to researchers who also serve as treating physicians, highlighting how common law duties differ in jurisdictions that apply the professional standard and those that apply the patient-centered material risk standard. This Essay provides new insight into what the law must do to make real the notion that [e]very human being of adult years and sound mind has a right to determine what shall be done with his body."

Unraveling the essential role of CysK in CDI toxin activation.

Contact-dependent growth inhibition (CDI) is a widespread mechanism of bacterial competition. CDI(+) bacteria deliver the toxic C-terminal region of contact-dependent inhibition A proteins (CdiA-CT) into neighboring target bacteria and produce CDI immunity proteins (CdiI) to protect against self-inhibition. The CdiA-CT(EC536) deployed by uropathogenic Escherichia coli 536 (EC536) is a bacterial toxin 28 (Ntox28) domain that only exhibits ribonuclease activity when bound to the cysteine biosynthetic enzyme O-acetylserine sulfhydrylase A (CysK). Here, we present crystal structures of the CysK/CdiA-CT(EC536) binary complex and the neutralized ternary complex of CysK/CdiA-CT/CdiI(EC536) CdiA-CT(EC536) inserts its C-terminal Gly-Tyr-Gly-Ile peptide tail into the active-site cleft of CysK to anchor the interaction. Remarkably, E. coli serine O-acetyltransferase uses a similar Gly-Asp-Gly-Ile motif to form the "cysteine synthase" complex with CysK. The cysteine synthase complex is found throughout bacteria, protozoa, and plants, indicating that CdiA-CT(EC536) exploits a highly conserved protein-protein interaction to promote its toxicity. CysK significantly increases CdiA-CT(EC536) thermostability and is required for toxin interaction with tRNA substrates. These observations suggest that CysK stabilizes the toxin fold, thereby organizing the nuclease active site for substrate recognition and catalysis. By contrast, Ntox28 domains from Gram-positive bacteria lack C-terminal Gly-Tyr-Gly-Ile motifs, suggesting that they do not interact with CysK. We show that the Ntox28 domain from Ruminococcus lactaris is significantly more thermostable than CdiA-CT(EC536), and its intrinsic tRNA-binding properties support CysK-independent nuclease activity. The striking differences between related Ntox28 domains suggest that CDI toxins may be under evolutionary pressure to maintain low global stability.

Diversification of ß-Augmentation Interactions between CDI Toxin/Immunity Proteins.

Contact-dependent growth inhibition (CDI) is a widespread mechanism of inter-bacterial competition mediated by the CdiB/CdiA family of two-partner secretion proteins. CdiA effectors carry diverse C-terminal toxin domains (CdiA-CT), which are delivered into neighboring target cells to inhibit growth. CDI(+) bacteria also produce CdiI immunity proteins that bind specifically to cognate CdiA-CT toxins and protect the cell from auto-inhibition. Here, we compare the structures of homologous CdiA-CT/CdiI complexes from Escherichia coli EC869 and Yersinia pseudotuberculosis YPIII to explore the evolution of CDI toxin/immunity protein interactions. Both complexes share an unusual ß-augmentation interaction, in which the toxin domain extends a ß-hairpin into the immunity protein to complete a six-stranded anti-parallel sheet. However, the specific contacts differ substantially between the two complexes. The EC869 ß-hairpin interacts mainly through direct H-bond and ion-pair interactions, whereas the YPIII ß-hairpin pocket contains more hydrophobic contacts and a network of bridging water molecules. In accord with these differences, we find that each CdiI protein only protects target bacteria from its cognate CdiA-CT toxin. The compact ß-hairpin binding pocket within the immunity protein represents a tractable system for the rationale design of small molecules to block CdiA-CT/CdiI complex formation. We synthesized a macrocyclic peptide mimic of the ß-hairpin from EC869 toxin and solved its structure in complex with cognate immunity protein. These latter studies suggest that small molecules could potentially be used to disrupt CDI toxin/immunity complexes.

Geriatric alcohol use disorder: a review for primary care physicians.

Alcohol use disorder in the geriatric population is a growing public health problem that is likely to continue to increase as the baby boomer generation ages. Primary care providers play a critical role in the recognition and management of these disorders. This concise review will focus on the prevalence, risk factors, screening, and clinical management of geriatric alcohol use disorder from a primary care perspective.

Crystallographic and spectroscopic insights into heme degradation by Mycobacterium tuberculosis MhuD.

Mycobacterium heme utilization degrader (MhuD) is a heme-degrading protein from Mycobacterium tuberculosis responsible for extracting the essential nutrient iron from host-derived heme. MhuD has been previously shown to produce unique organic products compared to those of canonical heme oxygenases (HOs) as well as those of the IsdG/I heme-degrading enzymes from Staphylococcus aureus. Here, we report the X-ray crystal structure of cyanide-inhibited MhuD (MhuD-heme-CN) as well as detailed (1)H nuclear magnetic resonance (NMR), UV/vis absorption, and magnetic circular dichroism (MCD) spectroscopic characterization of this species. There is no evidence for an ordered network of water molecules on the distal side of the heme substrate in the X-ray crystal structure, as was previously reported for canonical HOs. The degree of heme ruffling in the crystal structure of MhuD is greater than that observed for HO and less than that observed for IsdI. As a consequence, the Fe 3dxz-, 3dyz-, and 3dxy-based MOs are very close in energy, and the room-temperature (1)H NMR spectrum of MhuD-heme-CN is consistent with population of both a (2)Eg electronic state with a (dxy)(2)(dxz,dyz)(3) electron configuration, similar to the ground state of canonical HOs, and a (2)B2g state with a (dxz,dyz)(4)(dxy)(1) electron configuration, similar to the ground state of cyanide-inhibited IsdI. Variable temperature, variable field MCD saturation magnetization data establishes that MhuD-heme-CN has a (2)B2g electronic ground state with a low-lying (2)Eg excited state. Our crystallographic and spectroscopic data suggest that there are both structural and electronic contributions to the α-meso regioselectivity of MhuD-catalyzed heme cleavage. The structural distortion of the heme substrate observed in the X-ray crystal structure of MhuD-heme-CN is likely to favor cleavage at the α- and γ-meso carbons, whereas the spin density distribution may favor selective oxygenation of the α-meso carbon.

Dysregulation of ubiquitin homeostasis and ß-catenin signaling promote spinal muscular atrophy.

The autosomal recessive neurodegenerative disease spinal muscular atrophy (SMA) results from low levels of survival motor neuron (SMN) protein; however, it is unclear how reduced SMN promotes SMA development. Here, we determined that ubiquitin-dependent pathways regulate neuromuscular pathology in SMA. Using mouse models of SMA, we observed widespread perturbations in ubiquitin homeostasis, including reduced levels of ubiquitin-like modifier activating enzyme 1 (UBA1). SMN physically interacted with UBA1 in neurons, and disruption of Uba1 mRNA splicing was observed in the spinal cords of SMA mice exhibiting disease symptoms. Pharmacological or genetic suppression of UBA1 was sufficient to recapitulate an SMA-like neuromuscular pathology in zebrafish, suggesting that UBA1 directly contributes to disease pathogenesis. Dysregulation of UBA1 and subsequent ubiquitination pathways led to ß-catenin accumulation, and pharmacological inhibition of ß-catenin robustly ameliorated neuromuscular pathology in zebrafish, Drosophila, and mouse models of SMA. UBA1-associated disruption of ß-catenin was restricted to the neuromuscular system in SMA mice; therefore, pharmacological inhibition of ß-catenin in these animals failed to prevent systemic pathology in peripheral tissues and organs, indicating fundamental molecular differences between neuromuscular and systemic SMA pathology. Our data indicate that SMA-associated reduction of UBA1 contributes to neuromuscular pathogenesis through disruption of ubiquitin homeostasis and subsequent ß-catenin signaling, highlighting ubiquitin homeostasis and ß-catenin as potential therapeutic targets for SMA.