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Chien Tai Hong,1,2 Han-Hwa Hu,1,2 Lung Chan,1,2,* Chyi-Huey Bai3,4,* 1Department of Neurology, Shuang-Ho Hospital, Taipei Medical University, New Taipei City, Taiwan; 2Department of Neurology, School of Medicine, College of Medicine, Taipei Medical University, Taipei City, Taiwan; 3School of Public Health, College of Public Health, Taipei Medical University, Taipei City, Taiwan; 4Department of Public Health, College of Medicine, Taipei Medical University, Taipei City, Taiwan *These authors contributed equally to this work Background: People with Parkinson’s disease (PwP) are speculated to be at a low risk of cerebrovascular and cardiovascular disease (CVD) because they have fewer vascular risk factors and lower smoking rate. However, emerging evidence suggests that PwP are at higher risk of CVD, which introduces controversy to the notion that there is no association between Parkinson’s disease (PD) and CVD. Hence, we conducted a meta-analysis to analyze the risk of CVD in PwP.Methods: Electronic databases were searched using terms related to PD and CVD. Articles were included in the meta-analysis only if they employed clear diagnostic criteria for PD and CVD. The reference lists of the relevant articles were reviewed to identify eligible studies not found during the keyword search.Results: The enrolled studies were categorized into case–control and cohort studies, and the former was further divided into postmortem (three) and clinical (four) studies. In the clinical case–control studies group, PD was more associated with CVD (OR: 2.89, 95% CI: 1.36–6.13). Three studies were enrolled in the cohort studies group, and the merged results demonstrated that PwP were at higher risk of CVD during the follow-up period (HR: 1.84, 95% CI: 1.34–2.54).Conclusion: PD is associated with CVD, which may be due to the shared pathogeneses between the two diseases or PD-related effects. PwP should be more aware of the risk of CVD despite having fewer traditional vascular risk factors. Keywords: Parkinson’s disease, cerebrovascular disease, cardiovascular disease, meta-analysis, case-control, cohort, cerebral multimorbidity

Parkinson's disease (PD) is a common neurodegenerative disorder characterized by progressive symptoms, underscoring the urgent need for predictive blood biomarkers. Plasma extracellular vesicles (EVs) offer a promising platform for biomarker development, with neurofilament light chain (NfL) emerging as a potential candidate for neurological diseases. This study evaluated plasma EV NfL as a biomarker for disease progression in a PD cohort.A total of 55 patients with PD (PwP) and 58 healthy controls (HCs) were followed, with PwP completing an average of 3.96 visits and HCs 2.25 visits. Plasma EVs were isolated and validated, and EV NfL levels were measured using an immunomagnetic reduction assay. Generalized estimating equations and Spearman correlations assessed relationships between clinical symptom progression and biomarkers. Although no significant differences in plasma EV NfL levels were observed between PwP and HCs over time, changes in plasma EV NfL significantly correlated with motor symptom progression, specifically with adjusted-total and akinetic-rigidity subscores of the Unified PD Rating Scale (UPDRS) Part III. Additionally, changes in UPDRS Part II scores were significantly associated with plasma EV NfL levels. These findings suggest that plasma EV NfL reflects motor symptom progression in PwP, highlighting its potential as a valuable biomarker for monitoring disease progression and guiding clinical trials in PD.

Neurodegenerative diseases, including Alzheimer's Disease (AD) and Parkinson's Disease (PD) are common complications of diabetes, arising from insulin resistance, inflammation, and other pathological processes in the central nervous system. The potential of numerous antidiabetic agents to modify neurodegenerative disease progression, both preclinically and clinically, has been assessed. These agents may provide additional therapeutic benefits beyond glycemic control. Introduced in the twenty-first century, glucagon-like peptide-1 receptor agonists (GLP-1RAs) are a class of antidiabetic drugs noted not only for their potent glucose-lowering effects but also for their cardiovascular and renal protective benefits. Various GLP-1RAs have been demonstrated to have significant benefits in in vitro and in vivo models of neurodegenerative diseases through modulating a variety of pathogenic mechanisms, including neuroinflammation, autophagy, mitochondrial dysfunction, and the abnormal phosphorylation of pathognomonic proteins. These agents also have substantial protective effects on cognitive and behavioral functions, such as motor function. However, clinical trials investigating GLP-1RAs in diseases such as AD, PD, mild cognitive impairment, psychiatric disorders, and diabetes have yielded mixed results for cognitive and motor function. This review examines the link between diabetes and neurodegenerative diseases, explores the effects of antidiabetic agents on neurodegeneration, provides a concise overview of the GLP-1 pathway, and discusses both preclinical and clinical trial outcomes of GLP-1RAs for neurodegenerative diseases, including their effects on cognition in AD and PD. This review also proposed new strategies for the design of future clinical trials on GLP-1 RAs for both AD and PD., (© 2024. The Author(s).)

Behavioural symptoms are common manifestations of Parkinson's disease (PD). Early behavioural symptoms characterise mild behavioural impairment (MBI). The prevalence and intensity of MBI in people with PD (PwP) have been studied across various cohorts. However, methodological differences have obscured our understanding of MBI in these individuals. This systematic review examines and synthesises findings from relevant studies, enhancing understanding of the symptoms and implications of MBI in PD. Nine studies from five separate research institutions were identified. The conceptualisation of MBI varied considerably, affecting the reported prevalence rates of MBI in individuals with early-stage PD. Among PwP, MBI was associated higher education and impaired cognition. Affective dysregulation and impulse control disorders were primary contributors to MBI; abnormal perception was least contributor. This systematic review underscores the specific characteristics and incidence of MBI in early-stage PD. Mood and impulse control disorders are primary concerns associated with MBI. Future longitudinal studies are required to clarify the progression of these symptoms and evaluate MBI's potential as an indicator for PD-related dementia or increased dependency., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: The role of the cerebellum in Parkinson's disease (PD), particularly in tremor-dominant subtypes, is increasingly recognized. Magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) provide anatomical and metabolic insights, suggesting compensatory hyperactivity or degenerative changes in the cerebellum in PD. Volumetric analysis of cerebellar structures in MRI images, combined with metabolic profiles from MRS, offers possibilities for differentiating PD from essential tremor (ET). The cerebellum may be a potential therapeutic target due to its role in neurocircuitry of PD and ET., Methods: Brain structural data were obtained using MRI, and cerebellar metabolic profiles, focusing on the quantification of N-acetylaspartate (NAA), choline, and creatine peaks were obtained using MRS. This study enrolled patients with ET and PD, both with and without tremor, as well as disease controls with cerebellar atrophy (including spinocerebellar ataxia and multiple system atrophy). Volumetric analysis of cerebellar structures was performed. Differences in MRI and MRS parameters were analyzed using one-way analysis of covariance with a significance threshold of p < 0.05., Results: From November 2018 to March 2023, 111 patients were enrolled, including 29 ET, 29 cerebellar atrophy, 12 PD without tremor, and 41 PD with tremor. No significant differences in cerebellar volume and N-acetylaspartate/creatine and choline/creatine ratios were found between ET and PD with tremor., Conclusions: This preliminary retrospective study suggests similarities in cerebellar structures and metabolic profiles between ET and PD, highlighting the need for advanced imaging techniques to better differentiate between these conditions. Future research should integrate clinical data, such as tremor severity and cognitive assessments, to explore the relationships with cerebellar MRI parameters.

Background: Stromal fibrosis is highly associated with therapeutic resistance and poor survival in esophageal squamous cell carcinoma (ESCC) patients. Low expression of plasma gelsolin (pGSN), a serum abundant protein, has been found to correlate with inflammation and fibrosis. Here, we evaluated pGSN expression in patients with different stages of cancer and therapeutic responses, and delineated the molecular mechanisms involved to gain insight into therapeutic strategies for ESCC., Methods: Circulating pGSN level in ESCC patients was determined by enzyme-linked immunosorbent assay analysis, and the tissue microarray of tumors was analyzed by immunohistochemistry staining. Cell-based studies were performed to investigate cancer behaviors and molecular mechanisms, and mouse models were used to examine the pGSN-induced tumor suppressive effects in vivo., Results: Circulating pGSN expression is distinctively decreased during ESCC progression, and low pGSN expression correlates with poor therapeutic responses and poor survival. Methylation-specific PCR analysis confirmed that decreased pGSN expression is partly attributed to the hypermethylation of the GSN promoter, the gene encoding pGSN. Importantly, cell-based immunoprecipitation and protein stability assays demonstrated that pGSN competes with oncogenic tenascin-C (TNC) for the binding and degradation of integrin αvβ3, revealing that decreased pGSN expression leads to the promotion of oncogenic signaling transduction in cancer cells and fibroblasts. Furthermore, overexpression of pGSN caused the attenuation of TNC expression and inactivation of cancer-associated fibroblast (CAF), thereby leading to tumor growth inhibition in mice., Conclusions: Our results demonstrated that GSN methylation causes decreased secretion of pGSN, leading to integrin dysregulation, oncogenic TNC activation, and CAF formation. These findings highlight the role of pGSN in therapeutic resistance and the fibrotic tumor microenvironment of ESCC., (© 2024. The Author(s).)

Introduction: Parkinson disease (PD) caused substantially disability. The impairment of fine motor skills (FMSs) is correlated with the severity of functional disability (FD) cross-sectionally in people with PD (PwP). The present study investigated the decline in FMSs and the predictive value of baseline FMSs for the progression of FD., Methods: People with moderate-to-advanced PD who received two evaluations within 1-5 years were identified from the Taiwan Data Bank of Persons with Disability database. The World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0) was used to evaluate FD, and FMSs including pen-holding, buttoning, and knotting were assessed., Results: Our study included 2,271 people with moderate-to-advanced PD. We observed annual progression of FD in each domain of the WHODAS 2.0, with no difference between the sexes. The most significant correlation between FD and FMSs was that of decline in buttoning ability and deterioration of summary WHODAS 2.0 scores. Deterioration in FD across all domains of WHODAS 2.0 was associated with at least one FMS. The extent of disability in all three types of FMS at baseline was also correlated with deterioration of motility. Additionally, baseline disability in buttoning was significantly correlated with cognitive decline, and disability in knotting was significantly associated with the progression of FD., Conclusion: FMSs may be reliable markers for further FD, particularly in the areas of cognition, motility, and life activity. Because of the significant FD observed in people with moderate-to-advanced PD, the availability of predictors is essential for applying precautionary measures and providing appropriate treatment., Competing Interests: Declaration of competing interest The authors declare that there are no competing interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Vitamin B12 and folic acid could reduce blood homocysteine levels, which was thought to slow down the progression of Alzheimer's disease (AD), but previous studies regarding the effect of vitamin B12 and folic acid in treatment of AD have not reached conclusive results. We searched PubMed and Embase until January 12, 2023. Only randomized control trials involving participants clearly diagnosed with AD and who received vitamin B12 and folic acid were enrolled. Five studies that met the criteria were selected for inclusion in the meta-analysis. Changes in cognitive function were measured based on either the Mini-Mental State Examination (MMSE) or the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog). Changes in daily life function and the level of blood homocysteine were also investigated. After a 6-month treatment, administration of vitamin B12 and folic acid improved the MMSE scores more than placebo did (SMD = 0.21, 95% CI = 0.01 to 0.32, p = 0.04) but did not significantly affect ADAS-Cog scores (SMD = 0.06, 95% CI = -0.22 to 0.33, p = 0.68) or measures of daily life function. Blood homocysteine levels were significantly decreased after vitamin B12 and folic acid treatment. Participants with AD who received 6 months of vitamin B12 and folic acid supplementation had better MMSE scores but had no difference in ADAS-Cog scores. Daily life function did not improve after treatment.

Synaptic dysfunction plays a key role in Parkinson's disease (PD), and plasma extracellular vesicle (EV) synaptic proteins are emerging as biomarkers for neurodegenerative diseases. Assessment of plasma EV synaptic proteins for their efficacy as biomarkers in PD and their relationship with disease progression was conducted. In total, 144 participants were enrolled, including 101 people with PD (PwP) and 43 healthy controls (HCs). The changes in plasma EV synaptic protein levels between baseline and 1-year follow-up did not differ significantly in both PwP and HCs. In PwP, the changes in plasma EV synaptic protein levels were significantly associated with the changes in Unified Parkinson's Disease Rating Scale (UPDRS)-II and III scores. Moreover, PwP with elevated levels (first quartile) of any one plasma EV synaptic proteins (synaptosome-associated protein 25, growth-associated protein 43 or synaptotagmin-1) had significantly greater disease progression in UPDRS-II score and the postural instability and gait disturbance subscore in UPDRS-III than did the other PwP after adjustment for age, sex, and disease duration. The promising potential of plasma EV synaptic proteins as clinical biomarkers of disease progression in PD was suggested. However, a longer follow-up period is warranted to confirm their role as prognostic biomarkers., Competing Interests: CH, CC, RY, LC No competing interests declared, (© 2023, Hong et al.)

Urea electrolysis holds tremendous promise to provide green and sustainable energy and environmental solutions, because it can simultaneously remedy urea-containing wastewater and provide energy-saving hydrogen. However, the development of this emerging technology remains challenging mainly due to a dearth of high-performance electrocatalysts for efficient urea oxidation reaction (UOR). Perovskite fluorides have the advantages of intrinsic 3D diffusion pathways, robust architecture, and tunable chemical composition, thus receiving increasing attention in many applications. In this work, the UOR performances of a series of ABF 3 samples (A = K; B = Ni/Mn, Ni/Co, Co/Mn) with various compositions are investigated in a systematic fashion for the first time. Among the binary samples, KNMF41 (Ni/Mn atomic ratio = 4:1) is the optimal sample with reduced overpotential (reaching 100 mA cm -2 at 1.43 V), low Tafel slope (40 mV dec -1 ), enhanced reaction rate constant (6.3 × 10 5 cm 3 mol -1 s -1 ), and high turnover frequency (TOF, 0.19 s -1 at 1.60 V) toward urea oxidation. By comparing with NiCo and CoMn samples, the binary NiMn design is confirmed to endow the perovskite fluoride with higher electrocatalytic activity, thanks to the directed adsorption of urea molecules on the adjacent NiMn active sites. This work presents a targeted synthetic strategy for obtaining efficient electrocatalysts., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: The effect of cholinesterase inhibitor (ChEI) on mild cognitive impairment (MCI) is controversial. Brain age has been shown to predict Alzheimer's disease conversion from MCI., Objective: The study aimed to show that brain age is related to cognitive outcomes of ChEI treatment in MCI., Methods: Brain MRI, the Clinical Dementia Rating (CDR) and Mini-Mental State Exam (MMSE) scores were retrospectively retrieved from a ChEI treatment database. Patients who presented baseline CDR of 0.5 and received ChEI treatment for at least 2 years were selected. Patients with stationary or improved cognition as verified by the CDR and MMSE were categorized to the ChEI-responsive group, and those with worsened cognition were assigned to the ChEI-unresponsive group. A gray matter brain age model was built with a machine learning algorithm by training T1-weighted MRI data of 362 healthy participants. The model was applied to each patient to compute predicted age difference (PAD), i.e. the difference between brain age and chronological age. The PADs were compared between the two groups., Results: 58 patients were found to fit the ChEI-responsive criteria in the patient data, and 58 matched patients that fit the ChEI-unresponsive criteria were compared. ChEI-unresponsive patients showed significantly larger PAD than ChEI-responsive patients (8.44±8.78 years versus 3.87±9.02 years, p = 0.0067)., Conclusions: Gray matter brain age is associated with cognitive outcomes after 2 years of ChEI treatment in patients with the CDR of 0.5. It might facilitate the clinical trials of novel therapeutics for MCI.

Background: Corneal neovascularization (CoNV) is the second major cause of blindness. Vascular endothelial growth factor (VEGF) inhibitors, e.g. , bevacizumab, have been used to prevent CoNV., Aim: We conducted an updated systematic review and meta-analysis of clinical trials to examine the efficacy and safety of anti-VEGF in CoNV., Methods: A literature search was conducted using three electronic databases. Mean difference (MD), standard mean difference (SMD), and relative risk (RR) are used to estimate the effect size., Results: Nine randomized controlled and three non-randomized trials were obtained. The pooled results demonstrated a significant reduction of CoNV area/Length (SMD = -1.17, 95%CI: -1.58 to -0.75), best corrected visual acuity (MD = -0.54, 95%CI: -0.91 to -0.17), and graft rejection (RR = 0.44, 95%CI: 0.24 to 0.8) and failure (RR = 0.39, 95%CI: 0.19 to 0.78) rates in the anti-VEGF group than the placebo group. A non-significant reduction of the epithelial defect was also observed in the bevacizumab group compared with the placebo (RR = 0.56, 95%CI: 0.30 to 1.06). Compared with a placebo, the unsynthesizable trials also support that bevacizumab improves visual acuity, CoNV, graft rejection, and failure rates. Trials reporting other comparisons revealed the superiority of combined remedy with bevacizumab compared to other treatments in reducing CoNV., Conclusion: Anti-VEGF agents, mainly bevacizumab, are an effective and safe treatment for CoNV of all causes and prevent corneal graft rejection and failure in corneal transplantation., Competing Interests: Conflict-of-interest statement: All authors declared no competing interests, (©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: Although endovascular treatment (EVT) is beneficial for large vessel occlusion in anterior circulation stroke, whether these benefits exist for basilar artery occlusion (BAO) remains unclear. This systematic review and meta-analysis compared the outcomes of patients with BAO undergoing EVT and standard medical treatment (SMT)., Methods: The PubMed, Embase, and Cochrane Library databases were searched for eligible randomized control trials (RCTs) and non-RCTs involving patients with acute ischemic stroke and BAO undergoing EVT or SMT. The following outcomes were assessed: 90-day functional outcomes (favorable outcome and functional independence: modified Rankin scale [mRS] score of 0-3 or 0-2, respectively), mortality, and symptomatic intracranial hemorrhage (sICH) incidence. The summary effect sizes were determined as risk ratios (RRs) through the Mantel-Haenszel method with a random-effects model., Results: Four RCTs and four non-RCTs were included. Compared with SMT, EVT resulted in a higher proportion of patients with 90-day mRS scores of 0-3 (RR: 1.54 [1.16-2.06] in RCTs and 1.88 [1.11-3.19] in non-RCTs), a higher proportion of patients achieving functional independence (90-day mRS score of 0-2; RR: 1.83 [1.07-3.12] and 1.84 [0.97-3.48], respectively), a lower risk of mortality (RR: 0.76 [0.65-0.89] and 0.72 [0.62-0.83], respectively), and a higher sICH risk (RR: 5.98 [2.11-16.97] and 4.95 [2.40-10.23], respectively). Severe neurological deficits, intravenous thrombolysis, and higher posterior circulation Acute Stroke Prognosis Early Computed Tomography Score (pc-ASPECTS) were associated with EVT benefits., Conclusion: In patients with BAO, EVT results in superior functional outcomes, lower mortality risk, and higher sICH risk than does SMT, independent of age and sex. Higher National Institutes of Health Stroke Scale scores, intravenous thrombolysis, and higher pc-ASPECTSs before treatment are associated with greater benefits from EVT.

Purpose: Warfarin is associated with paradoxical procoagulant effect that leads to a transient hypercoagulable state and acute ischemic stroke (AIS). This clinical dilemma is further confounded when the patient has multiple comorbidities and the optimal treatment strategies are unclear., Case Report: We report a 78-year-old male with valvular heart disease, congestive heart failure, and atrial fibrillation, who received bioprosthetic valve replacement and developed AIS related to the paradoxical procoagulant effect of warfarin. Emergent cerebral angiography with mechanical thrombectomy was performed, and recanalization was successfully achieved. After shifting warfarin to nonvitamin K oral anticoagulant (NOAC), the paradoxical procoagulant effect ameliorated., Conclusion: This report describes the roles of endovascular therapy and NOAC in patients with similar highly complex conditions and has clinical relevance for therapeutic plans in the clinical setting.

The incidence of type 2 diabetes mellitus has risen globally, from 108 million cases in 1980 to 422 million cases in 2014. Although controlling glycemic levels in patients with diabetes is crucial, insulin and sulfonylureas can cause hypoglycemic episodes and even potentially fatal events such as comas, seizures, life-threatening arrhythmias, and myocardial infarctions. Several antibiotics have been documented to cause hypoglycemic episodes; the use of antibiotics along with insulin or sulfonylureas might further increase the risk of hypoglycemia. Therefore, researchers must determine which antibiotics carry a risk of inducing severe hypoglycemic events. The prevalence of H. pylori infection remains high in most countries, and the infection is often treated with triple therapy involving amoxicillin, clarithromycin, and a proton pump inhibitor (PPI). Several case reports have reported that hypoglycemia can occur when used with patients who also take diabetes medication. Therefore, we hypothesized that patients with diabetes have an increased risk of hypoglycemic episodes when being treated with triple therapy for H. pylori infection. By analyzing medical records from Taiwan's National Health Insurance Research Database, we found a significant association between hypoglycemia and triple therapy treatment for diabetic patients with peptic ulcer disease. Prescribing triple therapy to patients with diabetes and peptic ulcers significantly increased the risk of a hypoglycemic episode (adjusted odds ratio [aOR] = 1.75, 95% confidence interval [CI]: 1.64 to 1.88, P < 0.001). Similarly, the highest aOR (5.77, 95% CI 4.82 to 6.92) was found in patients with diabetes and peptic ulcers who had hypoglycemic episodes within 30 days after triple therapy treatment. Many patients with diabetes require H.pylori eradication for peptic ulcer treatment, and vigilance toward the risk of hypoglycemia in this population is thus necessary., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background/aim: Stem cell therapy and regenerative medicine are promising for treating Parkinson's disease (PD) not only for the potential for cell replacement but also for the paracrine effect of stem cell secretion, especially proteins and nucleotide-enriched exosomes. This study investigated the neuroprotective effect of exosomes secreted from human adipocyte-derived stem cells (hADSCs) on PD., Materials and Methods: hADSCs were isolated from the visceral fat tissue of individuals without PD who underwent bariatric surgery and were validated using surface markers and differentiation ability. Exosomes were isolated from the culture medium of hADSCs through serial ultracentrifugation and validated. Condensed exosomes were administered intravenously to 12-week-old MitoPark mice, transgenic parkinsonism mouse model with conditional knockout of mitochondrial transcription factor A in dopaminergic neurons, monthly for 3 months. Motor function, gait, and memory were assessed monthly, and immunohistochemical analysis of neuronal and inflammatory markers was performed at the end of the experiments., Results: The hADSC-derived exosome-treated mice exhibited better motor function in beam walking and gait analyses than did the untreated mice. In the novel object recognition tests, the exosome-treated mice retained better memory function. Immunohistochemical analysis revealed that although exosome treatment did not prevent the loss of dopaminergic neurons in the substantia nigra of mice, it down-regulated microglial activation and neuroinflammation in the midbrain., Conclusion: hADSC-derived exosomes were neuroprotective in this in vivo mouse model of PD, likely because of their anti-inflammatory effect. Use of hADSC-derived exosomes may offer several beneficial effects in stem cell therapy. Since they can also be produced at an industrial level, they are a promising treatment option for PD and other neurodegenerative diseases., (Copyright © 2023, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Objective: To investigate the diagnostic value of ultrasound for patients with axillary lymph node-negative breast cancer (ALNNBC)., Methods: A retrospective analysis was performed on the clinical data of 204 breast cancer patients who were admitted by Quanzhou First Hospital Affiliated to Fujian Medical University between October 2020 and May 2022. According to the results of axillary lymph node (ALN) examination, the patients were assigned to a positive group(n=102) and a negative group(n=102). All patients underwent diagnosis with color Doppler ultrasound, with pathological diagnosis as the "gold standard" to determine the sensitivity and specificity of ultrasonic diagnosis. A receiver operating characteristic(ROC) curve was established to analyze the efficiency of ultrasonic diagnosis and compare the ultrasonographic features and flow grades between the two groups., Results: Differences were statistically significant between the two groups in ultrasonographic features of lesions(negative vs positive, all p<0.05), including morphological irregularity(59.8% vs 85.3%), spiky margins(19.6% vs 63.7%), posterior echo attenuation(19.6% vs 44.1%) and microcalcification(40.2% vs 55.89%). The negative group had a lower proportion of patients with grade 2-3 ultrasound blood flow when compared with the positive group(32.4% vs 56.86%), and the difference was statistically significant(p<0.05). Ultrasonic diagnosis of ALNNBC had a sensitivity of 88.24%(90/102), a specificity of 92.16%(94/102), a coincidence rate of 90.20% (184/204), a 95% CI of 0.845-0.928, and an AUC of 0.879., Conclusions: Ultrasonic diagnosis of ALNNBC is relatively efficient as ultrasonographic features and ultrasound blood flow signals can provide a scientific basis for the diagnosis of ALNNBC., Competing Interests: Conflicts of interest: None., (Copyright: © Pakistan Journal of Medical Sciences.)

Magnetic resonance-guided focused ultrasound (MRgFUS) is a new surgical treatment for Parkinson's disease (PD). Previous experience with radiofrequency lesionectomy and deep brain stimulation (DBS) has identified several candidate targets for MRgFUS intended to alleviate the motor symptoms of PD. The main advantage of MRgFUS is that it is incisionless. MRgFUS has certain limitations and is associated with adverse effects. The present study reviews the literature on conventional surgical interventions for PD, discusses recent studies on MRgFUS, and the comparison between DBS and MRgFUS for PD. The reviews aims to provide an essential reference for neurologists to select the appropriate treatments for patients with PD., Competing Interests: Declaration of competing interest Kevin Wen-Kai Tsai is the employee of InSightec Ltd, the manufacture of MRgFUS. Other authors declare no conflict of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Gut microbiota (GM) are involved in the pathophysiology of Alzheimer's disease (AD) and might correlate to the machinery of the gut-brain axis. Alteration of the GM profiles becomes a potential therapy strategy in AD. Here, we found that plasmon-activated water (PAW) therapy altered GM profile and reduced AD symptoms in APPswe/PS1dE9 transgenic mice (AD mice). GM profile showed the difference between AD and WT mice. PAW therapy in AD mice altered GM profile and fecal microbiota transplantation (FMT) reproduced GM profile in AD mice. PAW therapy and FMT in AD mice reduced cognitive decline and amyloid accumulation by novel object recognition (NOR) test and amyloid PET imaging. Immunofluorescent staining and western blot analysis of β-amyloid (Aβ) and phosphorylated (p)-tau in the brain of AD mice were reduced in PAW therapy and FMT. The inflammatory markers, interleukin (IL)-6, IL-1β, and tumor necrosis factor (TNF)-α and pro-inflammatory indicator of arginase-1/CD86 ratio were also reduced. Furthermore, immunohistochemistry (IHC) analysis of occludin and claudin-5 in the intestine and AXL in the brain were increased to correlate with the abundant GM in PAW therapy and FMT. Our results showed the machinery of gut-brain axis, and PAW might be a potential therapeutic strategy in AD.

Background: Metformin is a potent antiglycemic agent, but its importance has receded owing to the launch of novel antidiabetic medications. The benefit of metformin includes not only blood sugar control but also anti-inflammation, autophagy activation, and neuroprotection. This study investigated the risk of cardiovascular disease (CVD) in people with type II diabetes mellitus (T2DM) who adhered to metformin after adding on a second-line antiglycemic agent., Objectives: The purpose of this study was to investigate the benefits of metformin in CVD prevention in patients with T2DM., Design: We designed the study by comparing the incident rate of CVD events in patients with T2DM who received metformin continually and who ceased metformin during 2002-2014., Methods: Medical information was obtained from the National Health Insurance Research Database, and patients with T2DM receiving second-line antiglycemic agents were categorized into metformin-adherent and nonadherent groups according to prescription claims. The study outcomes were the incidence of CVD hospitalization, including stroke (ischemic and hemorrhagic) and myocardial infarction (MI)., Results: A total of 31,384 patients with T2DM constituted the metformin-adherent group and were 1:1 matched to nonadherent patients. Metformin adherence was associated with a lower risk of hospitalization due to stroke [adjusted hazard ratio (aHR) = 0.51, 95% confidence interval (CI): 0.43-0.59, p  < 0.001] and MI (aHR = 0.47, 95% CI: 0.43-0.53, p  < 0.001). The risk reduction persisted in both ischemic and hemorrhagic strokes. Our subgroup analysis revealed that the protective effect on stroke and MI hospitalization persisted in metformin-adherent patients, both sexes, patients aged ⩽65 or >65 years, and patients with or without concurrent insulin treatment., Conclusions: This study revealed that metformin adherence in patients with T2DM who required a first-line treatment may reduce the risk of subsequent CVD. Despite the availability of numerous novel antiglycemic agents, metformin adherence by patients who require a combination of antiglycemic agents provides an additional benefit of CVD protection., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s), 2023.)

Objective: Metformin is widely used as the first-line drug for type 2 diabetes mellitus and has numerous benefits apart from lowering blood glucose. However, metformin-retained regimen is challenged by newly launching, powerful glucose-lowering antiglycemic agents. This population-based cohort study examined the association between metformin adherence and the risk of dementia and Parkinson's disease (PD)., Methods: Diabetic patients with metformin-included combination antiglycemic therapy were identified from the National Health Insurance Research Database and categorized into metformin-adherent and -nonadherent groups according to the medical record of the first year prescription. Patients contraindicated with metformin, severe diabetic complications, and poor drug compliance were excluded. The study outcome was the diagnosis of dementia or PD., Results: A total of 31 384 matched pairs were included after using propensity score matching and both groups were followed up for an average of 5 years. Metformin adherence was associated with a significantly lower risk of dementia (adjusted hazard risk ratio = 0.72, P < .001) but not PD (adjusted hazard risk ratio = 0.97, P = .825). Subgroup analysis revealed that the risk of dementia was significantly reduced in metformin-adherent patients, both male and female, aged >65 or ≤ 65 years, and with or without concurrent insulin treatment. This effect was not influenced by concurrent insulin treatment, which may eliminate the bias caused by the severity of diabetes mellitus., Conclusion: Despite the launching of numerous new oral antiglycemic agents, metformin may provide further benefit on lowering risk of dementia beyond conventional glycemic control according to the real-world evidence., Competing Interests: Disclosure The authors have no multiplicity of interest to disclose., (Copyright © 2023. Published by Elsevier Inc.)

Background: Inflammation contributes substantially to the pathogenesis of Parkinson's disease (PD). Plasma extracellular vesicle (EV)-derived cytokines are emerging biomarkers of inflammation. We conducted a longitudinal study of the plasma EV-derived cytokine profiles of people with PD (PwP)., Methods: A total of 101 people with mild to moderate PD and 45 healthy controls (HCs) were recruited, and they completed motor assessments (Unified Parkinson Disease Rating Scale [UPDRS]) and cognitive tests at baseline and 1-year follow-up. We isolated the participants' plasma EVs and analyzed their levels of cytokines, including interleukin (IL)-1β, IL-6, IL-10, tumor necrosis factor (TNF)-α, and transforming growth factor (TGF)-β., Results: We noted no significant changes in the plasma EV-derived cytokine profiles of the PwPs and HCs between baseline and the 1-year follow-up. Among the PwP, changes in plasma EV-derived IL-1β, TNF-α and IL-6 levels were significantly associated with changes in the severity of postural instability and gait disturbance (PIGD) and cognition. Baseline plasma EV-derived IL-1β, TNF-α, IL-6, and IL-10 levels were significantly associated with the severity of PIGD and cognitive symptoms at follow-up, and PwP with elevated IL-1β and IL-6 levels exhibited significant progression of PIGD over the study period., Conclusion: These results suggested the role of inflammation in PD progression. In addition, baseline levels of plasma EV-derived proinflammatory cytokines can be used to predict the progression of PIGD, the most severe motor symptom of PD. Additional studies with longer follow-up periods are necessary, and plasma EV-derived cytokines may serve as effective biomarkers of PD progression.

Systemic lupus erythematosus (SLE) potentially involves multiple parts of the ocular system, including the lacrimal glands and the cornea. The present study sought to assess the risk of aqueous-deficient dry eye disease (DED) and corneal surface damage in patients with SLE. We conducted a population-based cohort study using Taiwan's National Health Insurance research database to compare the risks of DED and corneal surface damage between subjects with and without SLE. Proportional hazard regression analyses were used to calculate the adjusted hazard ratio (aHR) and 95% confidence interval (CI) for the study outcomes. The propensity score matching procedure generated 5083 matched pairs with 78,817 person-years of follow-up for analyses. The incidence of DED was 31.90 and 7.66 per 1000 person-years in patients with and without SLE, respectively. After adjusting for covariates, SLE was significantly associated with DED (aHR: 3.30, 95% CI: 2.88-3.78, p < 0.0001) and secondary Sjögren's syndrome (aHR: 9.03, 95% CI: 6.86-11.88, p < 0.0001). Subgroup analyses demonstrated that the increased risk of DED was augmented among patients with age < 65 years and female sex. In addition, patients with SLE had a higher risk of corneal surface damage (aHR: 1.81, 95% CI: 1.35-2.41, p < 0.0001) compared to control subjects, including recurrent corneal erosion (aHR: 2.98, 95% CI: 1.63-5.46, p = 0.0004) and corneal scar (aHR: 2.23, 95% CI: 1.08-4.61, p = 0.0302). In this 12-year nationwide cohort study, we found that SLE was associated with increased risks of DED and corneal surface damage. Regular ophthalmology surveillance should be considered to prevent sight-threatening sequelae among patients with SLE.

Background: Accurate estimation of prolonged length of hospital stay after acute ischemic stroke provides crucial information on medical expenditure and subsequent disposition. This study used artificial neural networks to identify risk factors and build prediction models for a prolonged length of stay based on parameters at the time of hospitalization., Methods: We retrieved the medical records of patients who received acute ischemic stroke diagnoses and were treated at a stroke center between January 2016 and June 2020, and a retrospective analysis of these data was performed. Prolonged length of stay was defined as a hospital stay longer than the median number of days. We applied artificial neural networks to derive prediction models using parameters associated with the length of stay that was collected at admission, and a sensitivity analysis was performed to assess the effect of each predictor. We applied 5-fold cross-validation and used the validation set to evaluate the classification performance of the artificial neural network models., Results: Overall, 2,240 patients were enrolled in this study. The median length of hospital stay was 9 days. A total of 1,101 patients (49.2%) had a prolonged hospital stay. A prolonged length of stay is associated with worse neurological outcomes at discharge. Univariate analysis identified 14 baseline parameters associated with prolonged length of stay, and with these parameters as input, the artificial neural network model achieved training and validation areas under the curve of 0.808 and 0.788, respectively. The mean accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of prediction models were 74.5, 74.9, 74.2, 75.2, and 73.9%, respectively. The key factors associated with prolonged length of stay were National Institutes of Health Stroke Scale scores at admission, atrial fibrillation, receiving thrombolytic therapy, history of hypertension, diabetes, and previous stroke., Conclusion: The artificial neural network model achieved adequate discriminative power for predicting prolonged length of stay after acute ischemic stroke and identified crucial factors associated with a prolonged hospital stay. The proposed model can assist in clinically assessing the risk of prolonged hospitalization, informing decision-making, and developing individualized medical care plans for patients with acute ischemic stroke., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Yang, Bamodu, Chan, Chen, Hong, Huang and Chung.)

Background: Prolonged length of stay (LOS) following targeted temperature management (TTM) administered after cardiac arrest may affect healthcare plans and expenditures. This study identified risk factors for prolonged LOS in patients with cardiac arrest receiving TTM and explored the association between LOS and neurological outcomes after TTM., Methods: The retrospective cohort consisted of 571 non-traumatic cardiac arrest patients aged 18 years or older, treated with cardiopulmonary resuscitation (CPR), had a Glasgow Coma Scale score < 8, or were unable to comply with commands after the restoration of spontaneous circulation (ROSC), and received TTM less than 12 hours after ROSC. Prolonged LOS was defined as LOS beyond the 75th quartile of the entire cohort. We analyzed and compared relevant variables and neurological outcomes between the patients with and without prolonged LOS and established prediction models for estimating the risk of prolonged LOS., Results: The patients with in-hospital cardiac arrest had a longer LOS than those with out-of-hospital cardiac arrest ( p = 0.0001). Duration of CPR ( p = 0.02), underlying heart failure ( p = 0.001), chronic obstructive pulmonary disease ( p = 0.008), chronic kidney disease ( p = 0.026), and post-TTM seizures ( p = 0.003) were risk factors for prolonged LOS. LOS was associated with survival to hospital discharge, and patients with the lowest and highest Cerebral Performance Category scores at discharge had a shorter LOS. A logistic regression model based on parameters at discharge achieved an area under the curve of 0.840 to 0.896 for prolonged LOS prediction, indicating the favorable performance of this model in predicting LOS in patients receiving TTM., Conclusions: Our study identified clinically relevant risk factors for prolonged LOS following TTM and developed a prediction model that exhibited adequate predictive performance. The findings of this study broaden our understanding regarding factors associated with hospital stay and can be beneficial while making clinical decisions for patients with cardiac arrest who receive TTM., Competing Interests: The authors declare no conflict of interest., (Copyright: © 2023 The Author(s). Published by IMR Press.)

Background: Plasma extracellular vesicle (EV) contents are promising biomarkers of Parkinson's disease (PD). The pathognomonic proteins of PD, including α-synuclein, tau, and β-amyloid, are altered in people with PD (PwP) and are associated with clinical presentation in previous cross-sectional studies. However, the dynamic changes in these plasma EV proteins in PwP and their correlation with clinical progression remain unclear., Objective: We investigated the dynamic changes in plasma EV α-synuclein, tau, and β-amyloid and their correlation with/prediction of clinical progression in PwP., Design: A cohort study., Methods: In total, 103 PwP and 37 healthy controls (HCs) completed baseline assessment and 1-year follow-up. Clinical assessments included Unified Parkinson's Disease Rating Scale (UPDRS) parts II and III, Mini-Mental State Examination (MMSE), and Montreal Cognitive Assessment (MoCA). Plasma EVs were isolated, and immunomagnetic reduction-based immunoassay was used to assess α-synuclein, tau, and β-amyloid 1-42 (Aβ1-42) levels within the EVs., Results: Compared with HCs, significant differences were noted in the annual changes in all three EV pathognomonic proteins in PwP. Although the absolute changes in plasma EV pathognomonic proteins did not significantly correlate with clinical changes, PwP with elevated baseline plasma EV tau (upper-half) levels demonstrated significantly greater decline in motor and cognition, and increased plasma EV α-synuclein levels were associated with postural instability and the gait disturbance motor subtype. For PwP with elevated levels of all three biomarkers, clinical deterioration was significant, as indicated by UPDRS-II scores, postural instability and gait disturbance subscores of UPDRS-III, and MMSE score., Conclusion: The combination of plasma EV α-synuclein, tau, and Aβ1-42 may identify PwP with a high risk of deterioration. Our findings can elucidate the interaction between these pathognomonic proteins, and they may serve as treatment response markers and can be applied in treatment approaches for disease modification., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s), 2023.)

Background: This study re-explored the predictive validity of Stroke Prognostication using Age and National Institutes of Health Stroke Scale (SPAN) index in patients who received different treatments for acute ischemic stroke (AIS) and developed machine learning-boosted outcome prediction models., Methods: We evaluated the prognostic relevance of SPAN index in patients with AIS who received intravenous tissue-type plasminogen activator (IV-tPA), intra-arterial thrombolysis (IAT) or non-thrombolytic treatments (non-tPA), and applied machine learning algorithms to develop SPAN-based outcome prediction models in a cohort of 2145 hospitalized AIS patients. The performance of the models was assessed and compared using the area under the receiver operating characteristic curves (AUCs)., Results: SPAN index ≥100 was associated with higher mortality rate and higher modified Rankin Scale at discharge in AIS patients who received the different treatments. Compared to the lower AUCs for the SPAN-alone model across all groups, the AUCs of the logistic regression-boosted model were 0.838, 0.857, 0.766 and 0.875 for the whole cohort, non-tPA, IV-tPA and IAT groups, respectively. Similarly, the AUCs of the generated artificial neural network were 0.846, 0.858, 0.785 and 0.859 for the whole cohort, non-tPA, IV-tPA and IAT groups, respectively, while for gradient boosting decision tree model, we computed 0.850, 0.863, 0.779 and 0.815., Conclusions: SPAN index has prognostic relevance in patients with AIS who received different treatments. The generated machine learning-based models exhibit good performance for predicting the functional recovery of AIS; thus, their proposed clinical application to aid outcome prediction and decision-making for the patients with AIS.

Purpose: Symptoms and medication use in patients with Parkinson's disease (PD) affect the quality of life of patients and caregivers, yet prior research seldom focused on their experiences with medications. This study explored comprehensive living and medication experience from patients with PD and their caregivers., Methods: Patients diagnosed with PD for ≥2 years, with or without their caregivers, were recruited from an outpatient clinic in Taiwan. Semi-structured in-depth interviews were conducted based on the Common Sense Model. A qualitative content analysis was used to identify salient themes from verbatim transcripts., Results: In total, 15 patients and eight caregivers were interviewed. Five themes were derived: (1) symptoms and help-seeking behaviours before a diagnosis, (2) emotional impacts and life adaptations after a PD diagnosis, (3) life affected by medications, (4) experiences of caregivers in taking care of PD patients, and (5) communication between doctors and patients., Conclusions: Patients frequently adjusted their daily schedules to live with PD and the medication side effects. Caregivers struggle to overcome caring burdens and to stay positive to support patients. More attention on providing medication information, mental support, and communication between stakeholders is needed to improve the quality of life of patients and caregivers.

Patients with Parkinson's disease (PD) exhibit distinct gut microbiota, which may promote gut-derived inflammation. Rifaximin is a nonabsorbable antibiotic that can modify gut microbiota. The present study investigated the effect of rifaximin on gut microbiota and inflammation status in PD. The study examined the effect of long-term rifaximin treatment on in vivo transgenic PD mice (MitoPark) and short-term rifaximin treatment on patients with PD. Rifaximin treatment caused a significant change in gut microbiota in the transgenic PD mice; in particular, it reduced the relative abundance of Prevotellaceae UCG-001 and increased the relative abundance of Bacteroides , Muribaculum , and Lachnospiraceae UCG-001 . Rifaximin treatment attenuated serum interleukin-1β, interleukin-6 and tumor necrosis factor-α, claudin-5 and occludin, which indicated the reduction of systemic inflammation and the protection of the blood-brain barrier integrity. The rifaximin-treated MitoPark mice exhibited better motor and memory performance than did the control mice, with lower microglial activation and increased neuronal survival in the hippocampus. In the patients with PD, 7-day rifaximin treatment caused an increase in the relative abundance of Flavonifractor 6 months after treatment, and the change in plasma proinflammatory cytokine levels was negatively associated with the baseline plasma interleukin-1α level. In conclusion, the present study demonstrated that rifaximin exerted a neuroprotective effect on the transgenic PD mice by modulating gut microbiota. We observed that patients with higher baseline inflammation possibly benefited from rifaximin treatment. With consideration for the tolerability and safety of rifaximin, randomized controlled trials should investigate the disease-modification effect of long-term treatment on select patients with PD.

Background: Left atrial appendage thrombus (LAAT) is the main cause of cardioembolism in patients with nonvalvular atrial fibrillation (AF). Emerging evidence indicates that direct oral anticoagulants (DOACs) may be a preferred, safer choice for patients with LAAT. However, current guidelines indicate vitamin K antagonist (VKA) as the preferred treatment for LAAT. We conducted a meta-analysis to compare the efficacy of VKA and DOAC for the treatment of LAAT. Methods: The search was conducted in the PubMed, Embase, Google Scholar, and Cochrane Library databases from inception to July 2022, with the language restricted to English. A first analysis was conducted to evaluate the risk of LAAT under VKA or DOAC treatment. A second analysis was conducted to compare the resolution of LAAT under VKA and DOAC treatment. Results: In 13 studies comparing LAAT incidence rates under VKA and DOAC treatment, significant superiority of DOAC was detected (pooled RR = 0.65, 95% CI = 0.47-0.90, p = 0.009) with moderate heterogeneity being identified in the pooled studies. In 13 studies comparing LAAT resolution under VKA and DOAC use, treatment with DOAC exhibited a significantly increased probability of LAAT resolution compared with VKA (pooled odds ratio = 1.52, 95% CI = 1.02-2.26, p = 0.040). Conclusions: This meta-analysis suggests a superiority of DOAC over VKA with respect to LAAT incidence in people with AF and the likelihood of LAAT resolution. Due to their established safety profile, DOAC is a preferable choice for anticoagulation, although further randomized controlled studies are warranted to provide further evidence of their suitability as a new recommended treatment.

Background and Objectives: Status epilepticus that continues after the initial benzodiazepine and a second anticonvulsant medication is known as refractory status epilepticus (RSE). Management is highly variable because adequately powered clinical trials are missing. We aimed to determine whether propofol and midazolam were equally effective in controlling RSE in the intensive care unit, focusing on management in resource-limited settings., Methods: Patients with RSE treated with midazolam or propofol between January 2015 and December 2018 were retrospectively identified among 9 centers across 4 continents from upper-middle-income economies in Latin America and high-income economies in North America, Europe, and Asia. Demographics, Status Epilepticus Severity Score, etiology, treatment details, and discharge modified Rankin Scale (mRS) were collected. The primary outcome measure was good functional outcome defined as a mRS score of 0-2 at hospital discharge., Results: Three hundred eighty-seven episodes of RSE (386 patients) were included, with 162 (42%) from upper-middle-income and 225 (58%) from high-income economies. Three hundred six (79%) had acute and 79 (21%) remote etiologies. Initial RSE management included midazolam in 266 (69%) and propofol in 121 episodes (31%). Seventy episodes (26%) that were initially treated with midazolam and 42 (35%) with propofol required the addition of a second anesthetic to treat RSE. Baseline characteristics and outcomes of patients treated with midazolam or propofol were similar. Breakthrough (odds ratio [OR] 1.6, 95% CI 1.3-2.0) and withdrawal seizures (OR 2.0, 95% CI 1.7-2.5) were associated with an increased number of days requiring continuous intravenous anticonvulsant medications (cIV-ACMs). Prolonged EEG monitoring was associated with fewer days of cIV-ACMs (1-24 hours OR 0.5, 95% CI 0.2-0.9, and &gt;24 hours OR 0.7, 95% CI 0.5-1.0; reference EEG &lt;1 hour). This association was seen in both, high-income and upper-middle-income economies, but was particularly prominent in high-income countries. One hundred ten patients (28%) were dead, and 80 (21%) had good functional outcomes at hospital discharge., Discussion: Outcomes of patients with RSE managed in the intensive care unit with propofol or midazolam infusions are comparable. Prolonged EEG monitoring may allow physicians to decrease the duration of anesthetic infusions safely, but this will depend on the implementation of RSE management protocols. Goal-directed management approaches including EEG targets may hold promise for patients with RSE., Classification of Evidence: This study provides Class III data that propofol and midazolam are equivalently efficacious for RSE., (© 2022 American Academy of Neurology.)

Background and Aims: People with Parkinson disease (PwP) exhibit gut dysbiosis and considerable gastrointestinal (GI) symptoms. Probiotics, beneficial strains of microorganisms, supplement and optimize the intestinal environment and alleviate GI symptoms among elderly people. We conducted a systematic review and meta-analysis of clinical trials to investigate the effects of probiotics on PwP., Methods: We searched the PubMed, Embase, and Cochrane Library databases. Major outcomes were the effects on GI symptoms, including bowel movement and stool characteristics. This study was registered with PROSPERO (CRD42021262036)., Results: Six randomized controlled trials (RCTs) and two open-label studies were included. Most of the probiotic regimens were based on Lactobacillus and Bifidobacterium. Six studies investigated the benefit of probiotics for GI symptoms, especially for PwP with functional constipation, and two RCTs assessed probiotics' effect on systematic metabolism and inflammation. In the meta-analysis, probiotic treatment significantly increased the frequency of bowel movements among PwP (mean difference [MD]: 1.06 /week, 95% confidence interval [CI]: 0.61 to 1.51, p < 0.001, I 2 = 40%). Additionally, probiotic treatment significantly normalized stool consistency (standard MD: 0.61, 95% CI = 0.31 to 0.91, p < 0.001, I 2 = 0%)., Conclusions: Although the probiotic compositions varied, probiotic treatment significantly attenuated constipation for PwP and exhibited possible systematic effects on inflammation and metabolism. Given the tolerability of probiotics, the present meta-analysis may provide more consolidated evidence of the benefit of probiotics on constipation in PwP and a possible new therapeutic approach for disease modification.

Age, sex, and body mass index (BMI) were associated with obstructive sleep apnea (OSA). Although various methods have been used in OSA prediction, this study aimed to develop predictions using simple and general predictors incorporating machine learning algorithms. This single-center, retrospective observational study assessed the diagnostic relevance of age, sex, and BMI for OSA in a cohort of 9, 422 patients who had undergone polysomnography (PSG) between 2015 and 2020. The participants were randomly divided into training, testing, and independent validation groups. Multivariable logistic regression (LR) and artificial neural network (ANN) algorithms used age, sex, and BMI as predictors to develop risk-predicting models for moderate-and-severe OSA. The training-testing dataset was used to assess the model generalizability through five-fold cross-validation. We calculated the area under the receiver operating characteristic curve (AUC), accuracy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of the independent validation set to assess the performance of the model. The results showed that age, sex, and BMI were significantly associated with OSA. The validation AUCs of the generated LR and ANN models were 0.806 and 0.807, respectively. The independent validation set's accuracy, sensitivity, specificity, PPV, and NPV were 76.3%, 87.5%, 57.0%, 77.7%, and 72.7% for the LR model, and 76.4%, 87.7%, 56.9%, 77.7%, and 73.0% respectively, for the ANN model. The LR- and ANN-boosted models with the three simple parameters effectively predicted OSA in patients referred for PSG examination and improved insight into risk stratification for OSA diagnosis.

Glutathione S-transferases (GSTs) belong to one class of phase 2 detoxification enzymes which are important in metabolism and/or detoxification of various electrophilic endogenous metabolites and xenobiotics. From the available database, we found that GSTM2 gene expression is lower in high stages of bladder urothelial carcinoma than in stage 1 and normal bladder tissue. GSTM2 overexpression retards invasion, migration and tumor sphere formation of bladder cancer cells. Analysis of GSTM2 promoter activity shows that one SP1 site located at - 48 to - 40 bp is important for GSTM2 gene expression in BFTC 905 cells. An SP1 inhibitor, mithramycin A, inhibits GSTM2 promoter activity and protein expression. SP1 overexpression also increases GSTM2 expression in BFTC 905 and 5637 cells. Eight potential phytochemicals were analyzed for GSTM2 promoter activation, and results indicated that baicalein, berberrubine, chalcone, curcumin, resveratrol, and wogonin can increase promoter activity. In endogenous GSTM2 expression, berberrubine and resveratrol activated GSTM2 mRNA and protein expression the most. A DNA methylation inhibitor, 5-aza-deoxycytidine, can decrease GSTM2 gene methylation level and then increase its gene expression; 50 μM berberrubine decreased the GSTM2 gene methylation level, providing a mechanism for activating GSTM2 gene expression. Berberrubine and resveratrol also increased SP1 protein expression as one of the mechanisms for GSTM2 gene expression. In summary, berberrubine and resveratrol activates GSTM2 expression which inhibits cell proliferation, migration, and invasion of bladder cancer cells. The GSTM2 expression mechanism is partially via SP1 activation, and the effect of berberrubine is also partly via DNA CpG demethylation., (Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: Endovascular thrombectomy (EVT) is an effective therapy in acute ischemic stroke (AIS) with large vessel occlusion, especially for those who are unsuitable for intravenous thrombolysis. However, the safety and efficacy of EVT in AIS patients who receiving oral anticoagulants (OACs) is unclear, especially for the risk of symptomatic intracranial hemorrhage (sICH).  METHODS: Database of PubMed, Embase, and Cochrane Library were searched from Jan 1, 2000, through the final search date of Jun 2, 2021. Eligible studies for enrollment required outcomes reported for events of sICH, mortality, functional status, and successful reperfusion. Meta-analysis was conducted to compare the outcomes difference after EVT between AIS patients with or without OACs use. The primary safety outcome was sICH after EVT, and the primary efficacy outcome was functional status at 3 months.  RESULTS: One thousand nine hundred forty studies were screened for eligibility and 15 of them were included in the meta-analysis. Compared the OACs group to control arm, vitamin K antagonists (VKAs) was associated with higher risk of sICH (OR 1.49, 95% CI 1.10-2.02) and mortality (OR 1.67, 95% CI 1.35-2.06). Poor functional outcomes were noted both in the VKAs and direct oral anticoagulants (DOACs) groups (OR 0.62, 95% CI 0.54-0.71 and OR 0.61, 95% CI 0.53-0.71, respectively). No differences in successful reperfusion were observed., Conclusions: Comparing with DOACs, VKAs use was associated with a higher risk of sICH and mortality after EVT. Patients who did not receive OACs exhibited more favorable outcomes. The successful reperfusion did not differ between groups. However, results for mortality and functional outcomes have to be interpreted with caution since they are based on non-randomized data and unadjusted proportions., (© 2022. The Author(s).)

Background: Rasagiline monotherapy is approved in early Parkinson's disease (PD) for motor benefit. However, the efficacy and optimal rasagiline dosage in improving Unified Parkinson's Disease Rating Scale (UPDRS) subscale scores between Japanese and Caucasian individuals remain uncertain., Aims: To investigate the efficacy of rasagiline monotherapy and evaluate differences between early PD patients in Eastern and Western countries., Methods: The study design involved the meta-analysis of randomized controlled trials identified using electronic databases., Results: The mean difference (MD) in total UPDRS scores indicated no significant difference between the 1 and 2 mg rasagiline (MD = -0.00, 95% confidence interval (CI) = -0.82 to 0.81). Compared with the placebo, the MD of UPDRS part I scores significantly improved in the 1 mg (MD = -0.33, 95% CI = -0.57 to -0.10) but not in the 2 mg. For UPDRS part II scores, the MD significantly improved in the 1 mg (MD = -0.87, 95% CI = -1.48 to -0.27) and 2 mg (MD = -0.98, 95% CI = -1.28 to -0.68). Regarding the UPDRS part III, the MD significantly improved in both (1 mg: MD = -2.41, 95% CI = -3.26 to -1.56; 2 mg: MD = -2.05, 95% CI = -2.64 to -1.46). The most commonly reported adverse events were headaches, back pain, and dizziness, with no statistical difference between the 1 mg rasagiline and placebo groups. Subgroup analysis revealed similar effects between Asian and Western participants., Conclusion: Rasagiline monotherapy at 1 mg per day is recommended for patients with early PD because of the benefits for motor, nonmotor functions, and safety.

Existing prognostic models to predict the neurological recovery in patients with cardiac arrest receiving targeted temperature management (TTM) either exhibit moderate accuracy or are too complicated for clinical application. This necessitates the development of a simple and generalizable prediction model to inform clinical decision-making for patients receiving TTM. The present study explores the predictive validity of the Cardiac Arrest Survival Post-resuscitation In-hospital (CASPRI) score in cardiac arrest patients receiving TTM, regardless of cardiac event location, and uses artificial neural network (ANN) algorithms to boost the prediction performance. This retrospective observational study evaluated the prognostic relevance of the CASPRI score and applied ANN to develop outcome prediction models in a cohort of 570 patients with cardiac arrest and treated with TTM between 2014 and 2019 in a nationwide multicenter registry in Taiwan. In univariate logistic regression analysis, the CASPRI score was significantly associated with neurological outcome, with the area under the receiver operating characteristics curve (AUC) of 0.811. The generated ANN model, based on 10 items of the CASPRI score, achieved a training AUC of 0.976 and validation AUC of 0.921, with the accuracy, precision, sensitivity, and specificity of 89.2%, 91.6%, 87.6%, and 91.2%, respectively, for the validation set. CASPRI score has prognostic relevance in patients who received TTM after cardiac arrest. The generated ANN-boosted, CASPRI-based model exhibited good performance for predicting TTM neurological outcome, thus, we propose its clinical application to improve outcome prediction, facilitate decision-making, and formulate individualized therapeutic plans for patients receiving TTM., (© 2022. The Author(s).)

Tremor is a common movement disorder. Essential tremor (ET) is the most common etiology of tremor, while hands tremor is the most disabling type of tremor. This study aimed to explore the effects of Botulinum toxin (BoNT) on tremor within 6 weeks of treatment, and the muscular weakness adverse effect within 6 weeks specifically in randomized controlled trials. PubMed, Embase, and Cochrane Library databases were searched. Tremor severity and grip strength after BoNT treatment were investigated. BoNT significantly attenuated hand tremor severity in patients with either essential tremor (ET), Parkinson's disease or multiple sclerosis (Standardized mean difference [SMD] = -0.59, 95% confidence interval [CI], -0.95 to -0.24, p = 0.001, I 2 = 46%). Regarding people with ET, BoNT significantly reduced their tremor severity, including hands tremor and head tremor within 6 weeks of treatment (SMD = -0.58, 95% CI, -0.28 to -0.88, p = 0.002, I 2 = 0%). Electromyography (EMG) but not anatomical guidance BoNT injection provided significant benefit on the relief of tremor in both conditions. The principal adverse event was weakness, but it did not worse within 6 weeks of BoNT treatment (SMD = -0.35, 95% CI, -0.83 to 0.12, p = 0.07, I 2 = 57%), as assessed by the subjective grip strength. In conclusion, BoNT was an effective treatment for the hand tremor and ET, and EMG guidance injection was preferred. In addition, the muscular weakness adverse effect was not significant.

Objective: The Addenbrooke's Cognitive Examination III (ACE-III) is a 100-points cognitive test used in detecting dementia in many countries. There has been no validation study of the ACE-III in patients with suspected dementia in a Taiwanese population, where the language is traditional Chinese. We aimed to culturally adapt and validate the ACE-III as a cognitive assessment tool for differentiating between people with and without dementia presenting to healthcare professionals in Taiwan with possible dementia., Methods: We culturally adapted the ACE-III for Taiwan (T-ACE-III) and tested it with consenting patients with suspected dementia in northern Taiwan who had been through the diagnostic process. We calculated receiver operating characteristic (ROC) curves to test the ability of the T-ACE-III to differentiate between dementia and non-dementia cases using clinician diagnosis as the gold standard. We generated the Youden Index to determine the best cut-off score., Results: We recruited 90 Taiwanese individuals aged 49-93 years: 24 males and 33 females had dementia and 12 males and 21 females did not. The area under the ROC curve was 0.99 for distinguishing dementia from non-dementia. The T-ACE-III had a sensitivity of 100% and specificity of 78.8% when the cut-off score was 86/87. With a cut-off value of 73/74, the specificity was 100.0%, and sensitivity 89.5%. The highest Youden Index was 0.895, indicating the best overall cut-off point to be 73/74., Conclusions: The T-ACE-III is an acceptable cognitive test with excellent psychometric properties for discriminating dementia from non-dementia in Taiwanese populations in memory clinic settings., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Background and Purpose: Sialorrhea often happens in patients with neurologic disorders, and botulinum toxin (BoNT), which inhibits acetylcholine activation, may be an effective treatment for drooling. This systematic review and meta-analysis of randomized control trials aims to evaluate the efficacy and safety of BoNT in adults and children with sialorrhea due to neurological disorders., Methods: The PubMed, Embase, and Cochrane databases were searched for relevant studies published before August 2021. The pooled estimate of outcomes was calculated using a random effect model., Results: The review included 17 studies involving 981 patients. Compared with placebo, both BoNT type A (BoNT-A) and BoNT type B (BoNT-B) alleviated drooling frequency and severity (mean difference, 95% CI; BoNT-A: -1.20, -1.89 to -0.51; BoNT-B: -1.62, -2.07 to -1.17), reduced saliva weight (BoNT-A: -1.70, -2.30 to -1.10; BoNT-B: -1.12, -1.97 to -0.27), and improved global impression of change (BoNT-A: -1.30, -1.73 to -0.86; BoNT-B: -1.58, -1.95 to -1.21) in adults 4 weeks postinjection. BoNT-B remained effective at 12 weeks. In children, BoNT-A and BoNT-B alleviated sialorrhea symptoms (BoNT-A: -1.63, -2.42 to -0.85; BoNT-B: -5.20, -6.03 to -4.37) and BoNT-A reduced saliva weight (-0.77, -1.54 to 0.00) at 4 weeks postinjection. After 12 weeks, BoNT-B remained efficacious. Most adverse effects (AEs) were mild to moderate and self-limited., Conclusions: There is moderate certainty of evidence (COE) that either BoNT-A or BoNT-B could relieve sialorrhea after 4 and 12 weeks of follow-up without significantly more severe AEs in adults. However, the COE is very low to low in children., (© 2021 European Academy of Neurology.)

Background: Poststroke cognitive impairment (PSCI) is a prevalent cause of disability in people with stroke. PSCI results from either lesion-dependent loss of cognitive function or augmentation of Alzheimer's pathology due to vascular insufficiency. The lack of prestroke cognitive assessments limits the clear understanding of the impact of PSCI on cognition., Objective: The present study aims to make a direct comparison of longitudinal cognitive assessment results to clarify the impact of ischemic stroke on PSCI and assess the cognitive decline in PSCI compared to people with Alzheimer's disease (AD)., Methods: All study participants had their Mini-Mental State Examination (MMSE) at the chronic poststroke stage (≥6 months after stroke), which was compared with prestroke or acute poststroke (<6 months after stroke) MMSE to investigate the two aspects of PSCI. A group of patients with AD was used to reference the speed of neurodegenerative cognitive deterioration. Repeated measures analysis of variance was used to compare the longitudinal change of MMSE., Results: MMSE score between acute and chronic poststroke revealed a 1.8 ± 6.49 decline per year (n=76), which was not significantly different from the AD patients who underwent cholinesterase inhibitors treatment (-1.11 ± 2.61, p=0.35, n=232). MMSE score between prestroke and chronic poststroke (n=33) revealed a significant decline (-6.52 ± 6.86, p < 0.001). In addition, their cognitive deterioration was significantly associated with sex, age, and stroke over the white matter or basal ganglia., Conclusion: Ischemic stroke substantially affects cognition with an average six-point drop in MMSE. The rate of cognitive decline in PSCI was similar to AD, and those with white matter or basal ganglia infarct were at greater risk of PSCI., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Gait disturbance and imbalance are the major symptoms of Parkinson disease (PD), with fall being the most undesirable consequence. However, few effective evidence-based treatments are available for alleviating these symptoms and preventing falls. Cholinesterase inhibitors (ChEIs) are a well-established treatment for PD dementia with possible impacts on gait, balance, and fall reduction. The present study involved a meta-analysis of randomized controlled trials (RCTs) to investigate the effects of ChEIs on gait, balance, and fall in patients with PD. We searched for studies using the PubMed, Embase, and Web of Science databases. The major outcomes were effects on gait parameters, balance, and fall. This study was registered with PROSPERO (CRD42021254733). Five RCTs were included in the present meta-analysis. ChEIs did not significantly increase gait speed in PD patients (mean difference [MD]: 0.03 m/s, 95% confidence interval [CI]: -0.02 to 0.07, p = 0.29). However, ChEI treatment significantly decreased step or stride variability during the single task (standard MD: -0.43, 95% CI = -0.79 to -0.06, p = 0.02). Regarding fall and balance, trending but nonsignificant beneficial effects were observed with ChEI treatment. In conclusion, although ChEI treatment did not significantly improve gait speed and reduce fall, it can significantly reduce step or stride variability. Considering that gait disorder is a challenging issue in patients with PD and that ChEIs are generally tolerable, the present meta-analysis may provide more evidence for the benefit of ChEIs on PD gait disturbance as an alternative treatment consideration., (© 2021. The Author(s).)