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Introduction: The Friedreich Ataxia Rating Scale-Activities of Daily Living (FARS-ADL) is a validated and highly utilized measure for evaluating patients with Friedreich Ataxia. While construct validity of FARS-ADL has been shown for spinocerebellar ataxia (SCA), content validity has not been established., Methods: Individuals with SCA1 or SCA3 (n = 7) and healthcare professionals (HCPs) with SCA expertise (n = 8) participated in qualitative interviews evaluating the relevance, clarity, and clinical meaningfulness of FARS-ADL for assessment of individuals with SCA. Interviews were recorded, transcribed, coded, and analyzed by ATLAS.Ti v22 software., Results: FARS-ADL concepts most frequently reported by individuals with SCA were difficulty walking (n = 7/7), falls (n = 6/7), speech difficulties (n = 4/7), and swallowing (n = 3/7). Individuals with SCA reported that all FARS-ADL items were relevant; Gait and Walking (n = 7/7), Bladder Function (n = 6/7), and Falling (n = 6/7) were considered extremely relevant. All HCPs (n = 8/8) reported that most FARS-ADL items were relevant to individuals with SCA; Quality of Sitting Position was considered least relevant. HCPs reported meaningful change as 1-2 point score change in individual FARS-ADL items (n = 7/7), 1-3 point change in total score (n = 6/6), and stability on any item and/or total score over ≥ 1 year, depending on SCA subtype (n = 5/8). Cognitive debriefing supported clarity and comprehension of FARS-ADL. Suggested improvements included refining response options for Dressing, Falling, Walking, and Bladder Function items., Conclusion: The findings confirm the content validity of most FARS-ADL items for use in individuals with mild-to-moderate SCA1 and SCA3, and offer suggested improvements for response options., Competing Interests: Declarations. Conflict of Interest: Michele Potashman, Melissa Wolfe Beiner, Vlad Coric, and Gil L’Italien are employed by, and own shares in, Biohaven Pharmaceuticals, Inc. Katja Rudell, Naomi Suminski, Rinchen Doma, and Maggie Heinrich are employees of Parexel and were commissioned by Biohaven Pharmaceuticals, Inc. to conduct the study. Sheng-Han Kuo, Theresa Zesiwicz, Bart van de Warrenburg, Liana S. Rosenthal, Terry D. Fife, Giovanni Ristori, Matthis Synofzik, and Susan Perlman received consultancy fees from Biohaven Pharmaceuticals, Inc. for participating in the interviews. Linda Abetz-Webb received consultancy fees from Parexel for this study. Sheng-Han Kuo has received consultancy fees from Biohaven Pharmaceuticals, Inc., Praxis Precision Medicines, and Sage Therapeutics. Liana S. Rosenthal receives salary support for her role as the site Principal Investigator for research studies with Biohaven Pharmaceuticals, Inc., Pfizer, and EIP Pharma, and for serving on the Clinical Events Committee for a research study with functional neuromodulation. She also serves on the steering committees for the Parkinson Study Group’s research study with both UCB Pharmaceuticals and Bial Pharmaceuticals. Dr. Rosenthal also served on an advisory board for Reata Pharmaceuticals, Biogen Pharmaceuticals, Biohaven Pharmaceuticals, Inc., and as a one-time consultant for UCB Pharmaceuticals. Theresa Zesiwicz has received personal compensation for serving on the advisory boards of Boston Scientific, Reata Pharmaceuticals, and Steminent Biotherapeutics; and received personal compensation as senior editor for Neurodegenerative Disease Management and as a consultant for Steminent Biotherapeutics. Royalties: royalty payments as co-inventor of varenicline for treating imbalance and nonataxic imbalance. Grants: research grant support as Principal Investigator for studies from AbbVie, Biogen Pharmaceuticals, Biohaven Pharmaceuticals, Inc., Boston Scientific, Bukwang Pharmaceuticals, Cala Health, Cavion, Friedreich’s Ataxia Research Alliance; Houston Methodist Research Institute, National Institutes of Health, Retrotope, and Takeda Development Center Americas. Bart van de Warrenburg has served on advisory boards and/or as consultant for Servier, VICO Therapeutics, Biohaven Pharmaceuticals, Inc., and uniQure. Royalties: BSL—Springer Nature. Grants: Radboud University Medical Center, ZonMw, Gossweiler Foundation, Hersenstichting, NWO, and Christina Foundation. Jeremy D. Schmahmann has served on the Editorial Board for The Cerebellum since 1999. Consultancy: Biohaven Pharmaceuticals, Inc. Site Principal Investigator: Biohaven Pharmaceuticals, Inc. clinical trials in ataxia and multiple system atrophy. Research support, commercial entities: Biohaven Pharmaceuticals, Inc. support of clinical trials. Research support, academic entities: National Ataxia Foundation. Research support, foundations, and societies: National Ataxia Foundation, 2019, Principal Investigator license fee payments. Technology or inventions: Brief Ataxia Rating Scale (BARS) and Brief Ataxia Rating Scale revised (BARS2), copyright held by The General Hospital Corporation; Cerebellar Cognitive Affective/Schmahmann syndrome Scale, copyright held by The General Hospital Corporation; Patient-Reported Outcome Measure of Ataxia, copyright held by The General Hospital Corporation; and Cerebellar Neuropsychiatric Rating Scale, copyright held by The General Hospital Corporation. Matthis Synofzik has received consultancy honoraria from Ionis, UCB Pharmaceuticals, Prevail, Orphazyme, Biogen Pharmaceuticals, Servier, Reata Pharmaceuticals, Gen-Orph, AviadoBio, Zevra, Lilly, and Solaxa, all unrelated to the present manuscript. Ethical Approval: The study (BHV-4157-SCA-VAL) was approved by a centralized independent institutional review board (IRB; Salus Institutional Review Board, Austin, TX, USA) on 15 July 2022. IRB approval was not required for HCP interviews conducted in the United States or Europe. HCPs received consultancy fees for participating in the interviews. All eligible individuals with SCA and the HCPs provided informed consent to participate in the interviews and could withdraw at any time. The study was conducted in accordance with the 1964 Declaration of Helsinki., (© 2025. The Author(s).)

The functional Scale for the Assessment and Rating of Ataxia (f-SARA) assesses Gait, Stance, Sitting, and Speech. It was developed as a potentially clinically meaningful measure of spinocerebellar ataxia (SCA) progression for clinical trial use. Here, we evaluated content validity of the f-SARA. Qualitative interviews were conducted among individuals with SCA1 (n = 1) and SCA3 (n = 6) and healthcare professionals (HCPs) with SCA expertise (USA, n = 5; Europe, n = 3). Interviews evaluated symptoms and signs of SCA and relevance of f-SARA concepts for SCA. HCP cognitive debriefing was conducted. Interviews were recorded, transcribed, coded, and analyzed by ATLAS.TI software. Individuals with SCA1 and 3 reported 85 symptoms, signs, and impacts of SCA. All indicated difficulties with walking, stance, balance, speech, fatigue, emotions, and work. All individuals with SCA1 and 3 considered Gait, Stance, and Speech relevant f-SARA concepts; 3 considered Sitting relevant (42.9%). All HCPs considered Gait and Speech relevant; 5 (62.5%) indicated Stance was relevant. Sitting was considered a late-stage disease indicator. Most HCPs suggested inclusion of appendicular items would enhance clinical relevance. Cognitive debriefing supported clarity and comprehension of f-SARA. Maintaining current abilities on f-SARA items for 1 year was considered meaningful for most individuals with SCA1 and 3. All HCPs considered meaningful changes as stability in f-SARA score over 1-2 years, 1-2-point change in total f-SARA score, and deviation from natural history. These results support content validity of f-SARA for assessing SCA disease progression in clinical trials., (© 2024. The Author(s).)

Antibodies conjugated to bioactive compounds allow targeted delivery of therapeutics to cell types of choice based on that antibody's specificity. Here we develop a new type of conjugate that consists of a nanobody and a peptidic ligand for a G protein-coupled receptor (GPCR), fused via their C-termini. We address activation of parathyroid hormone receptor-1 (PTHR1) and improve the signaling activity and specificity of otherwise poorly active N-terminal peptide fragments of PTH by conjugating them to nanobodies (VHHs) that recognize PTHR1. These C-to-C conjugates show biological activity superior to that of the parent fragment peptide in vitro. In an exploratory experiment in mice, a VHH-PTH peptide conjugate showed biological activity, whereas the corresponding free peptide did not. The lead conjugate also possesses selectivity for PTHR1 superior to that of PTH(1-34). This design approach, dubbed "conjugation of ligands and antibodies for membrane proteins" (CLAMP), can yield ligands with high potency and specificity.

Myelography was performed postoperatively in 34 children with posterior fossa medulloblastomas. In 15 patients, there was myelographic evidence of intraspinal spread. This was more common in younger patients. The spread varied from a single nodule to extensive disease with spinal block. The lumbosacral canal was affected most often. Three patients with positive myelograms had negative cerebrospinal fluid cytology. Only one patient had symptoms referrable to the spine.