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BACKGROUND: Dysphagia is a common symptom and may be a cause of death in patients with spinocerebellar ataxias (SCAs). However, little is known about at which disease stage dysphagia becomes clinically relevant. Therefore, our study aims to investigate the prevalence of dysphagia in different disease stages of SCA 1, 2, 3 and 6. METHODS: We studied 237 genetically confirmed patients with SCA 1, 2, 3, 6 from the Clinical Research Consortium for SCAs and investigated the prevalence of self-reported dysphagia and the association between dysphagia and other clinical characteristics. We further stratified ataxia severity and studied the prevalence of dysphagia at each disease stage. RESULTS: Dysphagia was present in 59.9% of SCA patients. Patients with dysphagia had a longer disease duration and more severe ataxia than patients without dysphagia (patients with dysphagia vs. without dysphagia, disease duration (years): 14.51 ± 8.91 vs. 11.22 ± 7.82, p = .001, scale for the assessment and rating of ataxia [SARA]: 17.90 ± 7.74 vs. 13.04 ± 7.51, p = .000). Dysphagia was most common in SCA1, followed by SCA3, SCA 6, and SCA 2. Dysphagia in SCA1 and 3 was associated robustly with ataxia severity, whereas this association was less obvious in SCA2 and 6, demonstrating genotype-specific clinical variation. CONCLUSION: Dysphagia is a common clinical symptom in SCAs, especially in the severe disease stage. Understanding dysphagia in SCA patients can improve the care of these patients and advance knowledge on the roles of the cerebellum and brainstem control in swallowing.

Background: In the field of postoperative care, infections caused by Gram-positive bacteria pose a major clinical challenge. Vancomycin is a key therapeutic agent whose efficacy is greatly influenced by renal function, particularly by augmented renal clearance (ARC). The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) estimated glomerular filtration rate (eGFR) is an easy and commonly used method to predict ARC; however, it is not well studied to determine vancomycin dose. In this study, we examined the effectiveness of the CKD-EPI equation in determining ARC and optimizing the dose of vancomycin for surgical ward patients. Methodology: A retrospective observational study was conducted to examine 158 surgical ward patients receiving vancomycin. Data on demographics, medical history, and vancomycin dosing were collected. Renal function was evaluated using the CKD-EPI equation, with ARC defined as eGFR ≥ 96.5 mL/min/1.73 m2. Vancomycin pharmacokinetics were calculated using the ClinCalc tool. Results: ARC was in 54% of the patients. Compared with patients without ARC, those with ARC were younger and had lower serum creatinine levels. They also required higher vancomycin doses but had lower trough concentrations and 24-hour area-under-the-curve values. A significant correlation was observed between eGFR and vancomycin clearance, with eGFR > 96.5 mL/min/1.73 m2 necessitating higher vancomycin doses (> 45 mg/kg/day) to achieve the desired area under the curve to minimum inhibitory concentration ratio. Conclusion: For surgical ward patients with CKD-EPI eGFR ≥ 96.5 mL/min/1.73 m2, a vancomycin dosage of > 45 mg/kg/day may be recommended to reach effective therapeutic levels. Overall, this study emphasizes the importance of tailoring vancomycin therapy depending on renal function to ensure efficacy and mitigate the risk of antimicrobial resistance in surgical ward patients. [ABSTRACT FROM AUTHOR]

The role of the cerebellum in amnestic mild cognitive impairment (aMCI), typically a prodromal stage of Alzheimer's disease, is not fully understood. We studied the lobule-specific cerebello-cerebral connectivity in 15 cognitively normal and 16 aMCI using resting-state functional MRI. Our analysis revealed weaker connectivity between the cognitive cerebellar lobules and parietal lobe in aMCI. However, stronger connectivity was observed in the cognitive cerebellar lobules with certain brain regions, including the precuneus cortex, posterior cingulate gyrus, and caudate nucleus in participants with worse cognition. Leveraging these measurable changes in cerebello-parietal functional networks in aMCI could offer avenues for future therapeutic interventions. [ABSTRACT FROM AUTHOR]

Spherical piezoelectric motors (SPMs) represent a promising actuator technology applicable to the development of motion control systems with multiple degrees of freedom. However, few SPMs have made it successfully to market, as an effective and systematic rotor orientation analysis and manipulation technique has yet to be developed. This study thus developed a novel triplet-stator SPM design that integrates electrode configuration to excite lateral vibrations and offers two fundamental rotor orientations for each set of piezoelectric plates by changing the contact position between the rotor and stator. To accomplish omnidirectional orientations for the proposed SPM system, we present a systematic orientation analysis based on spherical coordinates. We further apply the concept of vector composition to derive new composite orientations by adjusting the magnitude ratio of the provided torques between three stators. An orientation angle representation accounting for the rotor dynamics is used to validate the correctness of the synthesized orientation vectors both in simulation and experiments. The orientation analysis results in a three-dimensional sphere containing eight vector spaces corresponding to eight stator actuation modes, in which an arbitrary rotor orientation reference command can be generated under the designed actuation modes. Experimental results were well correlated with simulations, thereby verifying the effectiveness of the proposed SPM system design and orientation analysis. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate the association between drug exposure and disease severity in SCA types 1, 2, 3 and 6. The Clinical Research Consortium for Spinocerebellar Ataxias (CRC-SCA) enrolled 319 participants with SCA1, 2, 3, and 6 from 12 medical centers in the United States and repeatedly measured clinical severity by the Scale for Assessment and Rating of Ataxia (SARA), the Unified Huntington's Disease Rating Scale part IV (UHDRS-IV), and the 9-item Patient Health Questionnaire during July 2009 to May 2012. We employed generalized estimating equations in regression models to study the longitudinal effects of coenzyme Q10 (CoQ10), statin, and vitamin E on clinical severity of ataxia after adjusting for age, sex, and pathological CAG repeat number. Cross-sectionally, exposure to CoQ10 was associated with lower SARA and higher UHDRS-IV scores in SCA1 and 3. No association was found between statins, vitamin E, and clinical outcome. Longitudinally, CoQ10, statins, and vitamin E did not change the rates of clinical deterioration indexed by SARA and UHDRS-IV scores within 2 years. CoQ10 is associated with better clinical outcome in SCA1 and 3. These drug exposures did not appear to influence clinical progression within 2 years. Further studies are warranted to confirm the association.

Background Real-world experience with combinations of short-course rifapentine-based regimens and integrase strand-transfer inhibitor–containing antiretroviral therapy (ART) in management of latent tuberculous infection (LTBI) is limited among people with human immunodeficiency virus (PWH). Methods From August 2019 to October 2022, PWH receiving 3 months of weekly rifapentine plus isoniazid (3HP) or 1 month of daily rifapentine plus isoniazid (1HP) in combination with ART were included. The primary outcome was virologic response within 12 months after LTBI treatment; secondary outcomes included treatment completion rate and safety of LTBI regimens. Results During the study period, 479 PWH (94.6% male; median age, 43 years) were included: 142 received 1HP and bictegravir (BIC)-containing regimens (1HP/BIC group), 46 1HP and dolutegravir (DTG)-containing regimens (1HP/DTG group), 38 3HP and BIC-containing regimens (3HP/BIC group), 214 3HP and DTG-containing regimens (3HP/DTG group), 17 1HP and other ART regimens (1HP/others group), and 22 3HP/other ART regimens (3HP/others group). In the intention-to-treat analysis, the proportions of PWH maintaining plasma HIV-1 RNA <200 copies/mL within 12 months after LTBI treatment completion were 96.5% (1HP/BIC), 100% (1HP/DTG), 100% (3HP/BIC), 95.8% (3HP/DTG), 100% (1HP/others), and 100% (3HP/others). The overall completion rates were >80% for all treatment groups, whereas >50% of the included PWH experienced any adverse event. LTBI regimens and ART combinations were not associated with virologic response and completion rate. Conclusions Combinations of short-course rifapentine-based regimens and integrase strand-transfer inhibitor-containing ART maintained viral suppression for most PWH within 12 months of LTBI treatment completion with low rates of grade 3 or higher adverse events. [ABSTRACT FROM AUTHOR]

Background Monitoring the trends of pre-treatment drug resistance (PDR) and resistance-associated mutations (RAMs) among antiretroviral-naïve people with HIV (PWH) is important for the implementation of HIV treatment and control programmes. We analysed the trends of HIV-1 PDR after the introduction of second-generation integrase strand-transfer inhibitors (INSTIs) in 2016 in Taiwan, when single-tablet regimens of non-nucleoside reverse-transcriptase inhibitor (NNRTI-) and INSTI-based antiretroviral therapy became the preferred treatments. Materials and methods In this multicentre study, we included newly diagnosed, antiretroviral-naïve PWH who underwent tests for RAMs between 2016 and 2022. Pre-treatment genotypic resistance testing was performed, along with HIV-1 subtyping and determinations of plasma HIV RNA load and CD4 lymphocyte counts. RAMs were analysed using the Stanford University HIV Drug Resistance Database and only RAMs conferring at least low-level resistance were included. Results From 2016 to 2022, pre-treatment blood samples from 3001 newly diagnosed PWH, which constituted 24.3% of newly diagnosed PWH in Taiwan during the study period, were tested. Of the PWH with analysable gene sequences, the HIV-1 PDR prevalence to NNRTIs, nucleoside reverse-transcriptase inhibitors (NRTIs), first- and second-generation INSTIs and PIs was 10.0%, 2.1%, 2.5%, 0.6% and 0.4%, respectively. While the trends of PDR remained stable for NRTIs, INSTIs and PIs, there was a significantly increasing trend of PDR to NNRTIs from 6.0% in 2016% to 13.1% in 2022 (P  = 0.001). Conclusions After the introduction of second-generation INSTIs in Taiwan, the trends of HIV-1 PDR to NRTIs and INSTIs remained low. Furthermore, there was no significant decrease of the prevalence of PDR toward NNRTIs between 2016 and 2022. [ABSTRACT FROM AUTHOR]

Background: Fatigue is a prevalent and debilitating symptom in neurological disorders, including spinocerebellar ataxias (SCAs). However, the risk factors of fatigue in the SCAs as well as its impact have not been well investigated. Objectives: To study the prevalence of fatigue in SCAs, the factors contributing to fatigue, and the influence of fatigue on quality of life. Methods: Fatigue was assessed in 418 participants with SCA1, SCA2, SCA3, and SCA6 from the Clinical Research Consortium for the Study of Cerebellar Ataxia using the Fatigue Severity Scale. We conducted multi‐variable linear regression models to examine the factors contributing to fatigue as well as the association between fatigue and quality of life. Results: Fatigue was most prevalent in SCA3 (52.6%), followed by SCA1 (36.7%), SCA6 (35.7%), and SCA2 (35.6%). SCA cases with fatigue had more severe ataxia and worse depressive symptoms. In SCA3, those with fatigue had a longer disease duration and longer pathological CAG repeat numbers. In multi‐variable models, depressive symptoms, but not ataxia severity, were associated with more severe fatigue. Fatigue, independent of ataxia and depression, contributed to worse quality of life in SCA3 and SCA6 at baseline, and fatigue continued affecting quality of life throughout the disease course in all types of SCA. Conclusions: Fatigue is a common symptom in SCAs and is closely related to depression. Fatigue significantly impacts patients' quality of life. Therefore, screening for fatigue should be considered a part of standard clinical care for SCAs. [ABSTRACT FROM AUTHOR]