The molecular mechanism of ferroptosis and its relationship with Parkinson's disease.

Neurodegenerative diseases such as Parkinson's disease (PD) have complex pathogenetic mechanisms. Genetic, age, and environmental factors are all related to PD. Due to the unclear pathogenesis of PD and the lack of effective cure methods, it is urgent to find new targets for treating PD patients. Ferroptosis is a form of cell death that is reliant on iron and exhibits distinct morphological and mechanistic characteristics compared to other types of cell death. It encompasses a range of biological processes, including iron/lipid metabolism and oxidative stress. In recent years, research has found that ferroptosis plays a crucial role in the pathophysiological processes of neurodegenerative diseases and stroke. Therefore, ferroptosis is also closely related to PD, This article reviews the core mechanisms of ferroptosis and elucidates the correlation between PD and ferroptosis. In addition, new compounds that have emerged in recent years to exert anti PD effects by inhibiting the ferroptosis signaling pathway were summarized. I hope to further elaborate the relationship between ferroptosis and PD through the review of this article, and provide new strategies for developing PD treatments targeting ferroptosis.

The evolving regulatory system of advanced therapy medicinal products in China: a documentary analysis using the World Health Organization Global Benchmarking Tool standards.

Advanced therapy medicinal products (ATMPs) are rapidly evolving to offer new treatment options. The scientific, technical, and clinical complexities subject drug regulatory authorizes to regulatory challenges. To advance the regulatory capacity for ATMPs, the National Medical Products Administration in China made changes to the drug regulatory system and developed regulatory science with the goal of addressing patient needs and encouraging innovation. This study aimed to systematically identify the regulatory evidence on ATMPs in China under the guidance of an overarching framework from the World Health Organization Global Benchmarking Tool. It was found that China's administrative authorities at all levels have issued a number of policy documents to promote the development of ATMPs, covering biopharmaceutical products research and development (n = 14), biopharmaceutical industry development (n = 9), high-quality development of medical institutions (n = 1), specific development plans/projects (n = 6) and specific regional development (n = 4). The legal and regulatory framework of ATMPs in China has been established and is subject to continuous adjustment in various aspects including regulations (n = 3), departmental rules or administrative normative documents (n = 22), and technical guidance (n = 15). As the regulatory reform continues, the drug review processes have been revised, and various technical standards have been launched, which aim to establish a regulatory approach that oversees the full life-cycle development of ATMPs in the country. The limited number of investigational new drug applications and approved ATMPs suggests a lag remains between the translation of advanced therapeutic technologies into clinically available medical products. To accelerate the translational research of ATMP in countries such as China, developing and adopting real-world evidence generated from clinical use in designated healthcare facilities to support scientific decision-making in ATMP regulation is warranted. The enhancement of regulatory capacity building and multi-stakeholder collaborations should also be encouraged to facilitate the timely evaluation of promising ATMPs to meet more patient needs.

Deep Brain Stimulation Modulates the Visual Pathway to Improve Freezing of Gait in Parkinson's Disease Patients.

OBJECTIVE: To investigate the involvement of the visual cortex in improving freezing of gait (FoG) after subthalamic nucleus (STN) deep brain stimulation (DBS) in Parkinson's disease (PD) patients using whole-brain seed-based functional connectivity. METHODS: A total of 66 PD patients with FoG who underwent bilateral STN-DBS were included in our study. Patients were divided into a FoG responder group and an FoG nonresponder group according to whether FoG improved 1 year after DBS. We compared the differences in clinical characteristics, brain structural imaging, and seed-based functional connectivity between the 2 groups. The locations of active contacts were further analyzed. RESULTS: All PD patients benefited from STN-DBS. No significant differences in the baseline characteristics or brain structures were found between the 2 groups. Seed-based functional connectivity analysis revealed that better connectivity in bilateral primary visual areas was associated with better clinical improvement in FoG (P < 0.05 familywise error corrected). Further analysis revealed that this disparity was associated with the location of the active contacts within the rostral region of the sensorimotor subregion in the FoG responder group, in contrast to the findings in the FoG nonresponder group. CONCLUSIONS: This study suggested that DBS in the rostral region of the STN sensorimotor subregion may alleviate FoG by strengthening functional connectivity in primary visual areas, which has significant implications for guiding surgical strategies for FoG in the future.

Reduced maximal range of ocular movements and its response to acute levodopa challenge in Parkinson's disease.

Introduction: Although restriction of vertical ocular range of motion is known to be the hallmark of progressive supranuclear palsy (PSP), the maximal amplitude of ocular movement has not been quantitatively assessed despite of accumulating evidences of oculomotor dysfunction in Parkinson's disease (PD). Here, we evaluated the maximal oculomotor range and its response to levodopa in PD, and compare findings to atypical parkinsonism. Methods: We recruited 159 healthy controls (HC) as well as 154 PD, 30 PSP, and 16 multiple system atrophy (MSA) patients. Oculomotor range was assessed using a kinetic perimeter-adapted device for the vertical and horizontal axes (four positions). Parameters were reassessed after levodopa challenge and compared among PD, PSP, and MSA patients. Results: Maximum oculomotor range in PD patients was reduced as compared to HC. Levodopa improved oculomotor range in all directions; corrective effects of upward range positively correlated with improvements in Unified Parkinson's Disease Rating Scale III and bradykinesia sub-scores among PD patients. Although oculomotor range was markedly restricted among PSP and MSA patients, the beneficial effects of levodopa was less pronounced. Reduced oculomotor range of motion was more significant among PSP as compared to PD or MSA patients; MSA patients did not significantly differ from PD patients. The range of upward gaze was optimally sensitive for differentiating among PD, PSP, and MSA patients. Conclusion: Maximum oculomotor range was reduced among PD patients significantly improved by levodopa treatment. Variations in, as well as the positively effects of levodopa on, the range of upward gaze assist diagnostic differentiation among PD, PSP, and MSA patients.

Efficacy and safety of traditional Chinese medicine for cancer-related fatigue: a systematic literature review of randomized controlled trials.

BACKGROUND: Cancer-related fatigue (CRF) is an extremely common and long-term condition that affects the physical and mental health of oncology patients. While the treatment for CRF with western medicine and non-pharmacological therapy remains uncertain and challenging, traditional Chinese medicine (TCM) has become a trending option for the patients. Based on the findings from randomized controlled trials (RCTs), this study aims to identify and evaluate the evidence about the efficacy and safety of TCM for CRF. METHODS: A systematic literature search was conducted according to the PRISMA literature research guidelines. Seven electronic databases including PubMed, the Cochrane Library, Embase, Web of Science, Scopus, China National Knowledge Infrastructure (CNKI) and Wanfang database were searched to identify RCTs which investigated TCM in the treatment of CRF published since inception to December 2022. RCTs comparing TCM with no treatment, placebo, or pharmacological interventions were considered eligible for this review. The Consolidated Standards of Reporting Trials Statement extensions for Chinese herbal medicine Formulas (CONSORT-CHM) and the Cochrane Collaboration's Risk of Bias tool were used in this review to evaluate the quality and the risk of bias of all included trials. RESULTS: A total of 82 RCTs were included in this review, regardless of whether they were published in English or Chinese. After data extraction and results evaluation, 78 trials demonstrated overall efficacy in using TCM for CRF patients compared with the control group, in which 33 trials showed that the efficacy rate was statistically significant (p < 0.05 or p < 0.01). TCM was also shown to be beneficial in improving the scores of relevant scales (e.g., PFS, QoL, TCM syndrome score, other fatigue scales etc.) or physical tests indicators (e.g., cytokines, blood test etc.). The most common herbs found in Chinese medicine were Astragali Radix, Ginseng Radix and Codonopsis Radix. Some TCM products, such as Kangai Injection, Buzhong Yiqi Decoction and Shenqi Fuzheng Injection could provide a reference for medication in this review. A range of non-serious, reversible adverse effects associated with the use of TCM was also reported. However, the result of evaluation showed that none of the trials fully met all the CONSORT-CHM criteria, the quality of included trials was generally poor and the risk of bias was mostly uncertain. CONCLUSION: There is some evidence supporting the efficacy and safety of TCM in managing CRF in this systematic review. However, no clear conclusion can be made due to the inadequate reporting of efficacy and adverse reactions. In view of some concerns about the existing evidence after the evaluation, it is essential to standardize the comprehensive identification and efficacy measurement standards, improve the quality of RCTs and conduct more multicomponent therapies to provide an updated reference for CRF patients medication in the future. The protocol of this systematic review has been registered on PROSPERO (CRD42023413625). [ https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023413625 ].

Is there a role for traditional and complementary medicines in managing chronic fatigue? a systematic review of randomized controlled trials.

Introduction: Chronic fatigue syndrome (CFS) is an increasingly common condition that is challenging to treat due to unclear etiology and a lack of consensus on clinical diagnosis and treatment guidance. Many affected people resorted to using traditional and complementary medicines (T&CMs). However, the evidence for T&CMs for CFS has been inconclusive and continues to evolve. The study aims to identify, summarize and assess the most recent evidence on the efficacy and safety of T&CMs for CFS. Methods: Randomized controlled trials (RCTs) investigating T&CMs for CFS published in English of Chinese between 1 January 2013 and 31 December 2022 were searched from 7 databases. RCTs comparing T&CMs with no treatment, placebo, or pharmacological medicine were included, irrespective of language or blinding. The Consolidated Standards of Reporting Trials Statement extensions for Chinese herbal medicine Formulas (CONSORT-CHM) and the Cochrane Collaboration's Risk of Bias tool were used to evaluate the quality and risk of bias of included studies. Results: A total of 62 RCTs investigating 43 types of T&CMs and involving 5,231 participants with CFS were included in this review. The primary outcome measures mainly included the scoring of fatigue symptoms using the validated tool Fatigue Scale-14 (FS-14) or the TCM syndrome score. The main interventions showing overall efficacy were Chaihu Guizhi Decoction and Buzhong Yiqi combined with Xiao Chaihu Decoction, and 148 ingredients were identified, including Astragali Radix, Glycyrrhizae Radix et Rhizoma, Atractylodis Macrocephalae Rhizoma, and Bupleuri Radix. The most significant effect was the improvement of fatigue, followed by TCM-diagnosed symptoms and other psychological conditions. No serious adverse effect had been reported. However, the quality of the RCTs included RCTs were found to be suboptimal, and the risk of bias remained uncertain. Conclusion: Some evidence from RCTs supported the efficacy and safety of T&CM in CFS. However, given the methodological and quality heterogenicity of the included studies, the recommendations of T&CMs in treating CFS remain inconclusive. To develop better quality evidence about T&CMs for CFS, future studies should employ more objective diagnosis standards and outcome measurements, larger sample size, and better bias control, and ensure the compliance with the corresponding reporting guidelines. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022362268, identifier CRD42022362268.

Pharmacoeconomic evaluation of anti-obesity drugs for chronic weight management: a systematic review of literature.

Introduction: Pharmacological therapy is recommended as a second-line alternative to reverse obesity. Currently, five anti-obesity drugs (AODs) have been approved by the U.S. Food and Drug Administration (FDA) for chronic weight management. The aim of this paper is to investigate the pharmacoeconomic evaluation of AODs through a systematic review with a special focus on methodological considerations. Methods: We searched the general and specific databases to identify the primary pharmacoeconomic evaluation of AODs. Results: A total of 18 full-text articles and three conference abstracts were included in this review. Most of the economic assessments were still about Orlistat. And the observations we could make were consistent with the previous systematic review. A few studies were on the combined therapies (i.e. PHEN/TPM ER and NB ER) compared to different comparators, which could hardly lead to a generalized summary of the cost-effectiveness. Most recently, pharmacoeconomic evidence on the newest GLP 1 RA approved for the indication of obesity or obesity with at least one comorbidity emerged gradually. Modelling-based cost-utility analysis is the major type of assessment method. In the modelling studies, a manageable number of the key health states and the state transitions were structured to capture the disease progression. In particular, the principal structure of the decision model adopted in the three studies on the newly approved drug was nearly the same, which enables more in-depth comparisons and generalizations of the findings. Conclusion: This study provided an up-to-date overview of the strengths and areas for improvement in the methodological design of the pharmacoeconomic evaluation of the licensed drugs for chronic weight management. Future modelling evaluations would benefit from a better understanding of the long-term weight loss effects of the current therapeutic options and the weight rebound process after the discontinuation of treatment. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022302648, identifier CRD42022302648.

Comparative analysis of disease modelling for health economic evaluations of systemic therapies in advanced hepatocellular carcinoma.

BACKGROUND: The objective of this study was to systematically analyse methodological and structural assumptions utilised in model-based health economic evaluations of systemic advanced hepatocellular carcinoma (HCC) therapies, discuss the existing challenges, and develop methodological recommendations for future models in advanced HCC. METHODS: We performed literature searches using five databases (Embase, PubMed, Web of Science, Econlit, and CNKI) up to December 4, 2022. Technology appraisals from Canada, England, Australia, and the United States were also considered. Model-based full economic evaluations of systemic advanced HCC therapies in English or Chinese met the eligibility criteria. The reporting quality was assessed by using the Consolidated Health Economic Evaluation Reporting Standards 2022 checklist. RESULTS: Of 12,863 records retrieved, 55 were eligible for inclusion. Markov model (n = 29, 53%) and partitioned survival model (n = 27, 49%) were the most commonly used modelling techniques. Most studies were based on health-state-driven structure (n = 51, 93%), followed by treatment-line-driven structure (n = 2, 4%) and combination structure (n = 1, 2%). Only three studies (5%) adopted external real-world data to extrapolate the overall survival or calibrate the extrapolation. Few studies reported the assumptions of transition probabilities. Utility modelling approaches were state-based (n = 51, 93%) and time-to-death (n = 1, 2%). Only 13 studies (24%) reported five types of model validation. Economic evaluation results of specific treatment strategies varied among studies. CONCLUSIONS: Disease modelling for health economic evaluations of systemic therapies in advanced HCC has adopted various modelling approaches and assumptions, leading to marked uncertainties in results. By proposing methodological recommendations, we suggest that future model-based studies for health economic evaluation of HCC therapies should follow good modelling practice guidelines and improve modelling methods to generate reliable health and economic evidence.

Evaluation of Nocturnal Symptoms in Chinese Parkinson's Disease Patients Based on the PDSS-2 Scale: A Multicenter Cross-Sectional Study.

BACKGROUND: Nocturnal symptoms have a significant effect on the quality of life in Parkinson's disease (PD) patients. OBJECTIVE: This study aimed to investigate the prevalence and associated factors of nocturnal symptoms in Chinese PD patients. METHODS: This multicenter cross-sectional study included 1,500 patients with primary PD from 18 centers in China was carried out between February 2019 and February 2020. Questionnaires including Parkinson's disease sleep scale 2 (PDSS-2), Parkinson's disease questionnaire 8 (PDQ-8), Beck depression inventory (BDI), and generalized anxiety disorder scale 7 (GAD-7) were used to assess nocturnal symptoms, quality of life, depression, and anxiety. RESULTS: Among 1,500 Chinese PD patients, 576 (38.4%) reported nocturnal symptoms. Of them, 59.2% were older than 65 years. The PDQ-8 total score was higher in patients with nocturnal symptoms (p < 0.01). Moderate and severe depression was reported more often in patients with nocturnal symptoms (p < 0.01), and the occurrence and severity of anxiety were higher as well (p < 0.01). Longer disease duration and higher Hoehn-Yahr (HY) stage were independently associated with nocturnal symptoms (p < 0.01). Education level, depression, disease course, HY stage, and nocturnal symptoms were related to the quality of life in Chinese PD patients (p < 0.01). CONCLUSION: Our study found that 38.4% of Chinese PD patients have nocturnal symptoms, even in early and mid-stage PD. Nocturnal symptoms were associated with worse quality of life and higher incidences of depression and anxiety. Nocturnal symptoms should be included in the assessment and care plan, especially in patients with longer disease courses and higher HY stages.

Systematic analysis of randomised controlled trials of Chinese herb medicine for non-alcoholic steatohepatitis (NASH): implications for future drug development and trial design.

BACKGROUND: Non-alcoholic steatohepatitis (NASH) is a liver disease currently lacking an approved therapy, resulting in significant clinical demand. Traditional Chinese medicines (TCMs) have been commonly used to manage NASH. This study aimed to systematically analyse the randomised controlled trials (RCTs) using TCMs for NASH management. METHODS: A systematic literature review was performed by following PRISMA guidelines 2020 in six electronic databases: PubMed, Web of Science, Scopus, Embase, the Cochrane Library, and China National Knowledge Infrastructure, from inception until August 2022. RCTs using TCMs for NASH were included in the analysis, irrespective of language or blinding. RESULTS: 112 RCTs were included in this review, with 10,573 NASH participants. 108 RCTs were conducted in China, and 4 RCTs were in other countries. Herbal medicine decoction was the major dosage form used for treating NASH (82/112). 11 TCMs products have been approved for NASH treatment (8 in China, 2 in Iran, and 1 in Japan). Classic prescriptions, such as "Huang Lian Jie Du decoction", "Yin Chen Hao decoction", and "Yi Guan Jian" were used in some studies. The TCMs treatment of NASH involved the use of 199 different plants, with the top 5 herbs being Salviae Miltiorrhizae Radix Et Rhizoma, Alismatis Rhizoma, Bupleuri Radix, Poria, and Curcumae Radix. "Salviae Miltiorrhizae Radix Et Rhizoma + Bupleuri Radix/Alismatis Rhizoma" were the mostly common drug-pair in the herbs network analysis. Nowadays, "Bupleuri Radix/Alismatis Rhizoma + Atractylodis Macrocephalae Rhizoma" are increasingly applied in herbal formulas for NASH. Based on the PICOS principles, the included studies varied in terms of the population, intervention, comparator, outcomes, and study design. However, some studies reported unstandardised results and failed to report diagnostic standards, inclusion or exclusion criteria, or sufficient patient information. CONCLUSION: Adopting Chinese classic prescriptions or drug-pair may provide a basis for developing new drugs of NASH management. Further research is needed to refine the clinical trial design and obtain more convincing evidence for using TCMs to treat NASH.

Application of implementation science framework to develop and adopt regulatory science in different national regulatory authorities.

Introduction: The purpose of developing and adopting regulatory science (RS) for drug regulatory authorities (DRAs) is to enhance regulatory capacity by advancing the scientific approach for the evaluation of health-related products. While many DRAs around the world advocate the concept of RS, the implementation approaches of RS vary according to local needs and have not been systemically examined. This study aimed to systematically identify the evidence about how RS was developed, adopted, and advanced by the selected DRAs, and analyzed and compared the implementation experiences of RS development under the guidance of an implementation science framework. Methods: Documentary analysis of government documents and a scoping literature review were conducted, and data analysis was performed under the guidance of the PRECEDE-PROCEED Model (PPM). DRAs in the United States, the European Union, Japan, and China had officially launched RS initiatives and were therefore selected as the target countries in this study. Results: There is no common consensus on the definition of RS among the DRAs. However, these DRAs shared the same goal of developing and adopting RS, which was used to develop new tools, standards, and guidelines that could improve the effectiveness and efficiency of the risk and benefit assessment of the regulated products. Each DRA had decided its own priority areas for RS development and thus set specific objectives that might be technology-based (e.g., toxicology and clinical evaluation), process-based (e.g., partnership with healthcare systems and high-quality review/consultation services), or product-based (e.g., drug-device combination products and innovative emerging technologies). To advance RS, considerable resources had been allocated for staff training, advancing information technology and laboratory infrastructure, and funding research projects. DRAs also took multifaceted approaches to expand scientific collaborations through public-private partnerships, research funding mechanisms, and innovation networks. Cross-DRA communications were also reinforced through horizon scanning systems and consortiums to better inform and assist the regulatory decision-making process. The output measurements might be scientific publications, funded projects, DRAs interactions, and evaluation methods and guidelines. Improved regulatory efficiency and transparency leading to benefits to public health, patient outcomes, and translation of drug research and development as the key primary outcomes of RS development were anticipated but not yet clearly defined. Conclusion: The application of the implementation science framework is useful for conceptualizing and planning the development and adoption of RS for evidence-based regulatory decision-making. Continuous commitment to the RS development and regular review of the RS goals by the decision-makers are important for DRAs to meet the ever-changing scientific challenges in their regulatory decision-making process.

Guillain-Barre syndrome after myocardial infarction: a case report and literature review.

BACKGROUND: Guillain-Barre syndrome after myocardial infarction occurs infrequently, and its occurrence following percutaneous coronary intervention is extremely rare. Due to the high mortality rate of myocardial infarction and the disability of Guillain-Barre syndrome, early identification of Guillain-Barre syndrome after myocardial infarction and early intervention can decrease the mortality rate, lead to early recovery, and provide a better outcome. CASE PRESENTATION: Herein, we reported a rare case of Guillain-Barre syndrome after myocardial infarction treated with percutaneous coronary intervention. The patient was a 75-year-old woman from China who was admitted to hospital due to sudden loss of consciousness. Electrocardiography showed acute myocardial infarction in the right ventricle and inferior and posterior walls. The patient underwent emergency percutaneous intervention of the posterior collateral artery of the right coronary artery. Soon after, her condition worsened resulting in limb weakness and numbness. Unfortunately, she continued to develop respiratory failure, and treated with intravenous immunoglobulin and ventilator-assisted breathing. A physical examination showed hypotonia of all four limbs, complete quadriplegia, bulbar palsy, dysarthria, and tendon areflexia. Serum immunoglobulin (Ig) G anti-ganglioside antibody analysis was positive with anti-GT1a antibodies (+ +), anti-GM1 antibodies ( +), anti-GM2 antibodies ( +), and anti-GM4 antibodies ( +), and he was diagnosed with Guillain-Barre syndrome after myocardial infarction. She was discharged due to poor response to treatment. The patient died two days after being discharged. CONCLUSIONS: Myocardial infarction and/or percutaneous coronary intervention may activate immune-mediated response and cause severe complications. Clinician should be alert to Guillain-Barre syndrome after myocardial infarction and/or percutaneous coronary intervention.

Neuromelanin magnetic resonance imaging of substantia nigra and locus coeruleus in Parkinson's disease with freezing of gait.

Background: The downregulation of monoamines, especially dopamine in substantia nigra (SN) and norepinephrine in locus coeruleus (LC), may be responsible for freezing of gait (FOG) pathological basis in Parkinson's disease (PD). Methods: Thirty-two Parkinson's disease patients with freezing of gait (PD-FOG), 32 Parkinson's disease patients without freezing of gait (PD-NFOG) and 32 healthy controls (HC) underwent neuromelanin magnetic resonance imaging (NM-MRI). The volume, surface area and contrast to noise ratio (CNR) of SN and LC were measured and compared. The correlation analyses were conducted between the measurements of SN and LC with clinical symptoms. We plotted the receiver operating characteristic (ROC) curve and determined the sensitivity and specificity of the CNR of SN and LC for discriminating the PD-FOG from the PD-NFOG. Results: Both PD-FOG and PD-NFOG showed decreased volume, surface area and CNR of SN compared with HC. The PD-FOG exhibited decreased volume and surface area of LC compared with both PD-NFOG and HC groups, and decreased CNR of LC compared with HC group. The volume, surface area and CNR of SN were negatively correlated with the Unified Parkinson's Disease Rating Scale part III scores. The illness durations in PD patients were negatively correlated with the volume, surface area of SN, while not the CNR. And the volume and surface area of LC were negatively correlated with new freezing of gait questionnaire scores. ROC analyses indicated that the area under the curve (AUC) was 0.865 and 0.713 in the CNR of SN and LC, respectively, in PD versus HC, whereas it was 0.494 and 0.637 respectively, in PD-FOG versus PD-NFOG. Among these, for discriminating the PD from the HC, the sensitivity and specificity in the CNR of the SN was 90.6 and 71.9%, respectively, when the cut-off value was set at 2.101; the sensitivity and specificity in the CNR of the LC was 90.6 and 50.0%, respectively, when the cut-off value for CNR was set at 1.411. Conclusion: The dopaminergic changes in the SN were found across both PD-FOG and PD-NFOG, whilst LC noradrenergic neuron reduction was more evident in PD-FOG.

A case report of autoimmune GFAP astrocytopathy presenting with abnormal heart rate variability and blood pressure variability.

BACKGROUND: Autonomic dysfunctions including bladder dysfunction, gastrointestinal dysfunction and orthostasis are common symptoms of autoimmune glial fibrillary acidic protein astrocytopathy (A-GFAP-A); however, cardiac autonomic dysfunction and abnormal circadian rhythm of blood pressure, which can lead to poor prognosis and even sudden cardiac death, has never been reported in A-GFAP-A patient. CASE PRESENTATION: A 68-year-old male Chinese patient presented to our hospital with headache, fever, progressive disturbance of consciousness, dysuria, and limb weakness. Abnormal heart rate variability and non-dipper circadian rhythm of blood pressure gradually developed during hospitalization, which is rare in A-GFAP-A. He had positive GFAP IgG in cerebrospinal fluid (CSF). Enhanced brian MRI showed uneven enhancement and T2 hyperintense lesions of medulla oblongata; Cervical spine MRI showed T2 hyperintense lesions in medulla oblongata and upper margin of the T2 vertebral body. A contrast-enhanced thoracic spine MRI showed uneven enhancement and T2 hyperintense lesions of T1 to T6 vertebral segments. After treatment with intravenous immunoglobulin and corticosteroids, the patient's symptoms, including autonomic dysfunction, alleviated dramatically. Finally, his heart rate variability and blood pressure variability became normal. CONCLUSIONS: Our case broadens the spectrum of expected symptoms in A-GFAP- A syndromes as it presented with heart rate variability and blood pressure variability.

Benchmarking Drug Regulatory Systems for Capacity Building: An Integrative Review of Tools, Practice, and Recommendations.

BACKGROUND: Benchmarking has been increasingly used on drug regulatory systems to achieve sustainable pharmaceutical system strengthening. This study aimed to identify the scope, tools and benefits of benchmarking regulatory capacities and the most recent development in such phenomenon. Method: This study employed an integrative and critical review of the literature and documents on benchmarking drug regulatory capacities identified from 6 databases and 5 websites of related organizations and government agencies in compliance with the Preferred Reporting Items for Systematic Review (PRISMA) guidelines. RESULTS: Forty-three studies and 6 documents about regulatory benchmarking published between 2005 and 2022 were included in this review. Five benchmarking assessment tools or programmes recommended or adopted by international organizations or government agencies had been identified, which collectively covered 12 major regulatory functions (4 at system level and 8 at operational level) involving 9 indicator categories and 382 sub-indicators. Benchmarking drug regulatory systems was reportedly employed at national, regional and international levels for either internal assessment (mostly on regulatory system establishment, drug review process and post marketing surveillance) or external evaluation (mostly on regulatory standards, drug review process and pharmacovigilance systems) to assess current status, monitor performance, determine major challenges and inform actions for capacity building. Priority of actions in areas such as regulatory process, resources allocation, cooperation and communication, and stakeholder engagement have been suggested for strengthening drug regulatory systems. Nevertheless, the evidence about benchmarking in optimizing regulatory capacities remained underreported. CONCLUSION: This integrative review depicted a framework for decision-makers about why and how benchmarking drug regulatory systems should be undertaken. For effective benchmarking, well-informed decisions about the goals, the scope, the choice of reference points and benchmarking tools are essential to guide the implementation strategies. Further studies about the positive effects of regulatory benchmarking are warranted to engage continuous commitment to the practice.

Cerebral blood flow alterations specific to freezing of gait in Parkinson's disease.

BACKGROUND: Freezing of gait (FOG) have been associated with deficits in the cortico-basal ganglia-thalamic network. However, the resting-state cerebral blood flow (CBF) alterations specific to FOG in Parkinson's disease (PD) remain unknown. METHODS: In total, sixty PD individuals, including 30 PD with FOG (PD-FOG) and 30 PD without FOG (PD-NFOG), and 30 healthy controls (HC) underwent arterial spin labeling magnetic resonance image. The CBF were voxel-wise compared among the three groups and validated in a different cohort of PD-FOG and PD-NFOG. RESULTS: The results revealed that patients with PD-FOG had increased CBF in bilateral thalamus and the left caudate nucleus and decreased CBF in the left inferior parietal cortex compared to patients with PD-NFOG. The inter-group differences of CBF between PD-FOG and PD-NFOG was confirmed in a different cohort in the validation analysis. Moreover, the CBF in left caudate nucleus was positively correlated with severity of FOG in PD-FOG patients. CONCLUSIONS: Perfusion alterations in both cortical and subcortical regions in the cortico-basal ganglia-thalamic network are related to the development of FOG in PD patients.

Novel Non-invasive Transcranial Electrical Stimulation for Parkinson's Disease.

Conventional transcranial electrical stimulation (tES) is a non-invasive method to modulate brain activity and has been extensively used in the treatment of Parkinson's disease (PD). Despite promising prospects, the efficacy of conventional tES in PD treatment is highly variable across different studies. Therefore, many have tried to optimize tES for an improved therapeutic efficacy by developing novel tES intervention strategies. Until now, these novel clinical interventions have not been discussed or reviewed in the context of PD therapy. In this review, we focused on the efficacy of these novel strategies in PD mitigation, classified them into three categories based on their distinct technical approach to circumvent conventional tES problems. The first category has novel stimulation modes to target different modulating mechanisms, expanding the rang of stimulation choices hence enabling the ability to modulate complex brain circuit or functional networks. The second category applies tES as a supplementary intervention for PD hence amplifies neurological or behavioral improvements. Lastly, the closed loop tES stimulation can provide self-adaptive individualized stimulation, which enables a more specialized intervention. In summary, these novel tES have validated potential in both alleviating PD symptoms and improving understanding of the pathophysiological mechanisms of PD. However, to assure wide clinical used of tES therapy for PD patients, further large-scale trials are required.

Diagnostic Test to Identify Parkinson's Disease from the Blood Sera of Chinese Population: A Cross-Sectional Study.

Background: Parkinson's disease (PD) is a neurodegenerative disease, a hallmark by the formation of misfolded and aggregated α-synuclein proteins. The expression of potential microRNA (miRNA) candidates isolated from serum and cerebrospinal fluid (CSF) exosomes of PD patients was assessed for their diagnostic value and their potential role as biomarkers for PD was explored. In this study, we characterize the expression level of miRNAs in the exosomes of blood sera and cerebrospinal fluid and explore their potential role as biomarkers for PD. Materials and Methods: A total of 209 patients having an onset of PD, along with 60 neurodegenerative (ND) disorders and 50 healthy controls were enrolled. Blood samples and CSF samples were collected and exosomes were isolated. The isolated exosomes were characterized using CD63 detection and exosomal RNA was extracted. Serum miRNA profiling was carried out by synthesizing cDNA from the purified RNA and miRNA transcripts were determined by qRT-PCR using SYBR Green PremixScript. microRNA profiling strategy was employed for extracting the exosomal miRNAs from the exosomes. Results: Five common miRNAs viz. miR-151a-5p, miR-24, mir-485-5p, mir-331-5p, and mir-214 were found to be upregulated with statistical significance in both the serum exosome and CSF exosomes. The investigation revealed that serum and CSF exosomal miRNA molecules are definitive biomarkers for PD with proper specificity and sensitivity. Conclusions: The significant level of miR-151a-5p, miR-24, mir-485-5p, mir-331-5p, and mir-214 was observed in the serum and CSF which may be established as a biomarker for the diagnosis of PD.

The relationship between ecological executive function and stigma among patients with epilepsy: The mediating effect of social support.

OBJECTIVE: Stigma is a key determinant of mental health among patients with epilepsy (PWE). In prior work, many PWE have been found to exhibit impaired executive function (EF) and to lack sufficient social support. This study was developed to explore factors that may influence stigma in PWE with a focus on the associations among EF, social support, and stigma in this patient population. METHODS: A questionnaire was administered to 121 patients with primary epilepsy as a means of collecting clinical and demographic details. The severity of EF impairment, social support levels, and stigma were analyzed using the Behavior Rating Inventory of Executive Function-Adult (BRIEF-A), the Social Support Rating Scale, and the Kilifi Stigma Scale for Epilepsy-Chinese (KSSE-C). Descriptive analyses were used to evaluate demographic details, and parameters associated with stigma were identified through multiple linear stepwise analyses. Spearman's correlation analyses and moderated mediation analyses were utilized to examine relationships between impaired EF, social support, and stigma. Significant mediation effects were identified using the SPSS PROCESS macro via a bootstrap approach. RESULTS: Up to 95.9% of the 121 PWE in this study were affected by stigma, with differneces in stigma being associated with long-term residence (urban or rural), family monthly income, disease control status (controlled or uncontrolled), and medication types. Multiple stepwise linear regression analyses revealed that the number of years of education (t = - 4.58, P < 0.001), family monthly income per capita (t = -3.43, P = 0.001), and age of first episode (t = -2.71, P = 0.008) for PWE were negatively correlated with stigma scores, while long-term residence (t = 2.79, P = 0.006), course of disease (t = 3.65, P < 0.001), disease control (t = 2.79, P = 0.006), and types of medication (t = 2.73, P = 0.007) were positively correlated with stigma scores. Impaired EF was found to be significantly associated with stigma (ß = 0.64, P < 0.001), and social support was able to mediate the association between stigma and impaired EF (ß = 0.64, P < 0.001). Non-parametric bootstrap analysis results revealed the indirect impact of EF through social support (95% bootstrap CI = 0.11, 0.22), with the indirect influence of social support accounting for 44.3% of the overall effect of stigma. CONCLUSIONS: These results offer new insight into the interactive mechanisms that underlie stigma and EF, in addition to clarifying the ability of social support to mediate this relationship. These data thus highlight valuable theoretical and methodological approaches to preventing stigma in PWE, suggesting that stigma in PWE can be effectively reduced by bolstering EF, and social support plays a mediating effect in this context.