Bile acid metabolites predict multiple sclerosis progression and supplementation is safe in progressive disease.

Background: Bile acid metabolism is altered in multiple sclerosis (MS) and tauroursodeoxycholic acid (TUDCA) supplementation ameliorated disease in mouse models of MS. Methods: Global metabolomics was performed in an observational cohort of people with MS followed by pathway analysis to examine relationships between baseline metabolite levels and subsequent brain and retinal atrophy. A double-blind, placebo-controlled trial, was completed in people with progressive MS (PMS), randomized to receive either TUDCA (2g daily) or placebo for 16 weeks. Participants were followed with serial clinical and laboratory assessments. Primary outcomes were safety and tolerability of TUDCA, and exploratory outcomes included changes in clinical, laboratory and gut microbiome parameters. Results: In the observational cohort, higher primary bile acid levels at baseline predicted slower whole brain, brain substructure and specific retinal layer atrophy. In the clinical trial, 47 participants were included in our analyses (21 in placebo arm, 26 in TUDCA arm). Adverse events did not significantly differ between arms (p=0.77). The TUDCA arm demonstrated increased serum levels of multiple bile acids. No significant differences were noted in clinical or fluid biomarker outcomes. Central memory CD4+ and Th1/17 cells decreased, while CD4+ naïve cells increased in the TUDCA arm compared to placebo. Changes in the composition and function of gut microbiota were also noted in the TUDCA arm compared to placebo. Conclusion: Bile acid metabolism in MS is linked with brain and retinal atrophy. TUDCA supplementation in PMS is safe, tolerable and has measurable biological effects that warrant further evaluation in larger trials with a longer treatment duration.

Data-driven multi-objective optimization for electric vehicle charging infrastructure.

This paper presents a data-driven methodology combining simulation and multi-objective optimization to efficiently implement transportation policy commitments, using as a case study the electric vehicle (EV) charging infrastructure in Newcastle upon Tyne, United Kingdom. The methodology leverages a baseline simulation model developed by our industry partner, Arup Group Limited, to estimate EV demand and quantities from 2020 to 2050. Four future energy scenarios are considered, and a multi-objective optimization approach is employed to determine the optimal types, locations, and quantities of charging points, along with the corresponding total capital and operational expenditures and charging point operating hours. Quantitatively, the variations of the portions of different types of charging points for the four scenarios are relatively small and within 3% range of the total number of charging points. The optimal solutions put priority on the slower charging points, with faster charging points having smaller portions each around 10%-13%.

The Potential of N-acetyl Cysteine in Behavioral Addictions and Related Compulsive and Impulsive Behaviors and Disorders: a Scoping Review.

Purpose of Review: Behavioral addictions (also termed disorders due to addictive behaviors) contain impulsive and compulsive features and have been shown to involve glutamate dysregulation. N-acetylcysteine (NAC), a well-tolerated cysteine pro-drug and antioxidant, may reduce addictive behaviors by restoring glutamate homeostasis. The current review details and discusses the use of NAC in behavioral addictions and related impulsive and compulsive behaviors, including gambling disorder, problematic use of the internet, problematic video gaming, compulsive sexual behavior, problematic shopping/buying, problematic stealing, repetitive self-injurious behavior, and binge eating disorder. Recent Findings: Preliminary results have indicated the usefulness of NAC in gambling disorder, self-injurious behaviors, and compulsive sexual behaviors. Preclinical studies indicate that NAC is effective in improving binge eating behavior, but clinical trials are limited to a small open-label trial and case report. Studies are lacking on the efficacy of NAC in problematic use of the internet, problematic video gaming, problematic stealing, and problematic shopping/buying. Summary: NAC demonstrates potential for use in behavioral addictions and compulsive behaviors, particularly in gambling disorder and self-injury. However, more studies are needed to assess the effectiveness of NAC in other behavioral addictions and the mechanisms by which NAC improves these conditions.

Exercise leads to metabolic changes associated with improved strength and fatigue in people with MS.

OBJECTIVE: The goal of this exploratory study was to evaluate the effects of an exercise intervention - progressive resistance training (PRT) on the metabolome of people with MS (pwMS) and to link these to changes in clinical outcomes. METHODS: 14 pwMS with EDSS <4.0 and 13 age- and sex-matched healthy controls completed a 12-week in-person PRT exercise intervention. Outcome measures included: plasma metabolomics analysis, cardiovascular fitness tests, EDSS, timed 25-foot walk (T25FW), six-minute walk test (6MWT), hip strength, and modified fatigue impact scale (MFIS). We identified changes in the metabolome with PRT intervention in both groups using individual metabolite abundance and weighted correlation network defined metabolite module eigenvalues and then examined correlations in changes in metabolite modules with changes in various clinical outcomes. RESULTS: In both groups PRT intervention improved hip strength, distance walked in 6WMT, speed of walking, while fatigue (MFIS) was improved in pwMS. Fatty acid, phospholipid, and sex steroid metabolism were significantly altered by PRT in pwMS but not in controls. Changes in fatigue (MFIS score) were strongly inversely correlated and hip strength was moderately correlated with change in sex steroid metabolite module in pwMS. A similar relationship was noted between change in dehydroepiandrosterone sulfate abundance (sex steroid metabolite) and fatigue in pwMS. We also noted an inverse correlation between changes in fatty acid metabolism and cardiovascular fitness in pwMS. INTERPRETATION: PRT-induced metabolic changes may underlie improved clinical parameters in pwMS and may warrant investigation as potential therapeutic targets in future studies.

Liquid biopsy using the nanotube-CTC-chip: capture of invasive CTCs with high purity using preferential adherence in breast cancer patients.

In this paper, we report the development of the nanotube-CTC-chip for isolation of tumor-derived epithelial cells (circulating tumor cells, CTCs) from peripheral blood, with high purity, by exploiting the physical mechanisms of preferential adherence of CTCs on a nanotube surface. The nanotube-CTC-chip is a new 76-element microarray technology that combines carbon nanotube surfaces with microarray batch manufacturing techniques for the capture and isolation of tumor-derived epithelial cells. Using a combination of red blood cell (RBC) lysis and preferential adherence, we demonstrate the capture and enrichment of CTCs with a 5-log reduction of contaminating WBCs. EpCAM negative MDA-MB-231/luciferase-2A-green fluorescent protein (GFP) cells were spiked in the blood of wild mice and enriched using an RBC lysis protocol. The enriched samples were then processed using the nanotube-CTC-chip for preferential CTC adherence on the nanosurface and counting the GFP cells yielded anywhere from 89% to 100% capture from the droplets. Electron microscopy (EM) studies showed focal adhesion with filaments from the cell body to the nanotube surface. We compared the nanotube preferential adherence to collagen adhesion matrix (CAM) scaffolding, reported as a viable strategy for CTC capture in patients. The CAM scaffolding on the device surface yielded 50% adherence with 100% tracking of cancer cells (adhered vs. non-adhered) versus carbon nanotubes with >90% adherence and 100% tracking for the same protocol. The nanotube-CTC-chip successfully captured CTCs in the peripheral blood of breast cancer patients (stage 1-4) with a range of 4-238 CTCs per 8.5 ml blood or 0.5-28 CTCs per ml. CTCs (based on CK8/18, Her2, EGFR) were successfully identified in 7/7 breast cancer patients, and no CTCs were captured in healthy controls (n = 2). CTC enumeration based on multiple markers using the nanotube-CTC-chip enables dynamic views of metastatic progression and could potentially have predictive capabilities for diagnosis and treatment response.

Sexual dimorphism in Parkinson's disease: differences in clinical manifestations, quality of life and psychosocial functioning between males and females.

INTRODUCTION: Sex-related differences in clinical manifestations and consequences of Parkinson's disease (PD) have been poorly explored. Better understanding of sexual dimorphism in neurologic diseases such as PD has been announced as a research priority. The aim of our study was to determine independent sex differences in clinical manifestations and subtypes, psychosocial functioning, quality of life (QoL) and its domains between male and female individuals with PD. PATIENTS AND METHODS: A comprehensive list of demographics, motor symptoms and subtypes, nonmotor features, health-related quality of life (HRQoL), psychosocial functioning and general aspects of daily life was assessed in 157 individuals (108 males and 49 females) with idiopathic PD. In order to control for potential confounding variables, we applied Orthogonal Partial Least Squares - Discriminant Analysis (OPLS-DA) to explore the strength of each feature to discriminate male and female patients with PD. RESULTS: While no sex difference was found in the total Unified Parkinson's Disease Rating Scale (UPDRS) score and cumulative daily dose of levodopa, females had significantly more severe anxiety (mean difference =2.2 [95% confidence interval, CI: 0.5-4.0], P=0.011), worse nutritional status (23.8 [standard deviation, SD =4.2] vs 25.8 [SD =2.6], P=0.003) and poorer QoL (28.3 [SD =15.7] vs 17.9 [SD =14.2], P<0.001). Based on multivariate discriminant analysis, emotional well-being, bodily discomfort, social support, mobility and communication domains of HRQoL, together with anxiety, depression and psychosocial functioning, were the strongest features with more severe/worse status in females after adjustment for potential statistical confounders. CONCLUSION: Our study provides a comprehensive understanding of sexual dimorphism in PD. Anxiety, depression, specific domains of HRQoL (mobility, emotional well-being, social support and bodily discomfort) and psychosocial functioning were significantly worse in female individuals with PD. Sexual dimorphism in PD highlights the features that are more likely to be affected in each sex and should be specifically targeted when managing male and female individuals with PD.

Heterogeneous Determinants of Quality of Life in Different Phenotypes of Parkinson's Disease.

OBJECTIVES: Health-related quality of life (HRQoL) is considered a very important outcome indicator in patients with Parkinson's disease (PD). A broad list of motor and non-motor features have been shown to affect HRQoL in PD, however, there is a dearth of information about the complexity of interrelationships between determinants of HRQoL in different PD phenotypes. We aimed to find independent determinates and the best structural model for HRQoL, also to investigate the heterogeneity in HRQoL between PD patients with different phenotypes regarding onset-age, progression rate and dominant symptom. METHODS: A broad spectrum of demographic, motor and non-motor characteristics were collected in 157 idiopathic PD patients, namely comorbidity profile, nutritional status, UPDRS (total items), psychiatric symptoms (depression, anxiety), fatigue and psychosocial functioning through physical examination, validated questionnaires and scales. Structural equation model (SEM) and multivariate regressions were applied to find determinants of Parkinson's disease summary index (PDSI) and different domains of HRQoL (PDQ-39). RESULTS: Female sex, anxiety, depression and UPDRS-part II scores were the significant independent determinants of PDSI. A structural model consisting of global motor, global non-motor and co-morbidity indicator as three main components was able to predict 89% of the variance in HRQoL. In older-onset and slow-progression phenotypes, the motor domain showed smaller contribution on HRQoL and the majority of its effects were mediated through non-motor features. Comorbidity component was a significant determinant of HRQoL only among older-onset and non-tremor-dominant PD patients. Fatigue was not a significant indicator of non-motor component to affect HRQoL in rapid-progression PD. CONCLUSIONS: Our findings showed outstanding heterogeneities in the pattern and determinants of HRQoL among PD phenotypes. These factors should be considered during the assessments and developing personalized interventions to improve HRQOL in PD patients with different phenotypes or prominent feature.

A novel 6-item screening questionnaire for Parkinsonism: validation and comparison between different instruments.

BACKGROUND: Several instruments have been developed to screen Parkinson's disease (PD); yet, there is no consensus on the items, number of questions, and diagnostic accuracy. We aimed to develop a new questionnaire combining the best items with highest validity to screen parkinsonism and to compare its diagnostic value with that of the previous instruments using the same database. METHODS: 157 patients with parkinsonism and 110 healthy controls completed a comprehensive screening questionnaire consisting of 25 items on different PD symptoms used in previous studies. To select the optimal items, clinical utility index (CUI) was calculated and those who met at least good negative utility (CUI ≥0.64) were selected. Receiver operating characteristics (ROC) curves analysis was used to compare the area under the curve (AUC) of different screening instruments. RESULTS: Six items on 'stiffness & rigidity', 'tremor & shaking', 'troublesome buttoning', 'troublesome arm swing', 'feet stuck to floor' and 'slower daily activity' demonstrated good CUI. The new screening instrument had the largest AUC (0.977) compared to other instruments. CONCLUSIONS: We selected a new set of six items to screen parkinsonism, which showed higher diagnostic values compared to the previously developed questionnaires. This screening instrument could be used in population-based PD surveys in poor-resource settings.

Cross-cultural validity, reliability, and psychometric properties of the persian version of the scales for outcomes in Parkinson's disease-psychosocial questionnaire.

Objectives. Considering the influence of different motor and nonmotor features of Parkinson's disease (PD), it is important to evaluate the psychosocial functioning of the patients. For this purpose, the scales for outcomes in Parkinson's disease-psychosocial questionnaire (SCOPA-PS) has been previously designed. The aim of our study was to assess the cross-cultural validation and psychometric properties of the Persian version of the SCOPA-PS. Methods. One hundred and ten nondemented idiopathic Parkinson's disease (IPD) patients were consecutively recruited from an outpatient referral movement disorder clinic. Eligible patients filled up a number of questionnaires including the Persian version of SCOPA-PS during the face-to-face interview session and clinical examination to measure disease severity, nonmotor psychiatric symptoms, and health-related quality of life (HRQoL). Results. The highest and lowest correlation coefficients of internal consistency were reported for item 7 on "asking for help" (r = 0.765) and item 5 on "sexual problems" (r = 0.553). Cronbach's alpha reliability coefficient of the entire scale was 0.87 (95% CI: 0.83-0.90). The Hoehn and Yahr stage (r = 0.34, P < 0.001), Schwab and England ADL scale (r = -0.55, P < 0.001), anxiety (r = 0.64, P < 0.001), depression (r = 0.71, P < 0.001), and fatigue (r = 0.35, P < 0.001) were significantly correlated with the total score of the SCOPA-PS questionnaire. Conclusions. The Persian version of SCOPA-PS is a highly reliable and valid scale to measure psychosocial functioning in IPD patients with different sex, age-group, and educational level, which could be applied in future researches. Disease severity scales, depression, anxiety, fatigue, and different domains of HRQoL were all associated with psychosocial functioning in PD patients.

Comparison of the Psychological Symptoms and Disease-Specific Quality of Life between Early- and Typical-Onset Parkinson's Disease Patients.

The impact of Parkinson's disease (PD) on psychological status and quality of life (QoL) may vary depending on age of disease onset. The aim of this study was to compare psychological symptoms and disease-specific QoL between early onset versus the rest of the PD patients. A total number of 140 PD patients with the mean current age of 61.3 (SD = 10.4) yr were recruited in this study. PD patients with the onset age of ≤50 yr were defined as "early-onset" (EOPD) group (n = 45), while the ones with >50 yr at the time of diagnosis were categorized as the "typical-onset" (TOPD) patients (n = 95). Different questionnaires and scales were used for between-group comparisons including PDQ39, HADS (hospital anxiety and depression scale), FSS (fatigue severity scale), MNA (mininutritional assessment), and the UPDRS. Depression score was significantly higher in EOPD group (6.3 (SD = 4.5) versus 4.5 (SD = 4.2), P = 0.02). Among different domains of QoL, emotion score was also significantly higher in the EOPD group (32.3 (SD = 21.6) versus 24.4 (SD = 22.7), P = 0.05). Our findings showed more severe depression and more impaired emotional domain of QoL in early-onset PD patients. Depression and anxiety play an important role to worsen QoL among both EOPD and TOPD patients, while no interaction was observed in the efficacy of these two psychiatric symptoms and the onset age of PD patients.

Reliability and validity of the persian version of the fatigue severity scale in idiopathic Parkinson's disease patients.

As one of the most frequent symptoms, measurement of fatigue is an issue of interest in Parkinson's disease (PD). The fatigue severity scale (FSS) is one of the recommended questionnaires for this purpose. The aim of our study was to evaluate psychometric properties of the Persian version of the FSS (FSS-Per) to assess fatigue in PD patients. Ninety nondemented idiopathic Parkinson's disease (IPD) patients were consecutively recruited from an outpatient referral movement disorder clinic. In addition to the disease severity scales, the FSS-Per was used for fatigue measurement. The internal consistency coefficient was larger than 0.8 for all of the items with a total Cronbach's alpha of 0.96 (95% CI: 0.95-0.97). The FSS-Per score correlated with the UPDRS score (r = 0.55, P < 0.001) and the "Hoehn and Yahr" (HY) stage (r = 0.48, P < 0.001). The total score of the FSS-Per significantly discriminated IPD patients with more severe disability (HY stage > 2) versus those with less severe disease (HY stage ≤2) (AUC = 0.81 (95% CI: 0.72-0.90)). The FSS-Per fulfilled a high internal consistency and construct validity to measure the severity of fatigue in Iranian IPD patients. These acceptable psychometric properties were reproducible in subgroups of IPD patients regarding different levels of education, disease severity, sex and age groups.