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Background: Perinatal asphyxia, more appropriately known as hypoxic-ischemic encephalopathy (HIE), is a condition characterized by clinical and laboratory evidence of acute or sub-acute brain injury resulting from systemic hypoxemia and/or reduced cerebral blood flow. HIE is a common and devastating clinical condition in resource-poor countries with poor treatment outcome. This paper describes the protocol for an ongoing study that aims to evaluate the neuroprotective effects of Erythropoietin (EPO) as compared to routine care in the management of moderate to severe HIE among term infants.Methods: This study is a double-blind randomized controlled trial that will be conducted in the neonatal wards of the Lagos University Teaching Hospital (LUTH), Lagos, Nigeria, over a two-year period after ethical approvals and consents. One hundred and twenty-eight term newborns (≥ 37 weeks gestation) diagnosed with moderate/ severe HIE at admission will be allocated by randomization to receive either EPO or normal saline. All the participants will be offered standard care according to the unit protocol for HIE. Baseline investigations and close monitoring of the babies are done until discharge. Participants are followed up for 2 years to monitor their outcome (death or neurological development) using standard instruments.Discussion: Previous trials had shown that EPO confers neuroprotective benefits and improve neurological and behavioral outcome in infants with HIE both singly or as an adjuvant to therapeutic hypothermia. This study hypothesized that administering EPO to newborns with moderate /severe HIE can positively influence their clinical and neurological outcomes and will provide evidence to either support or disprove the usefulness of Erythropoietin as a sole agent in the treatment of HIE, especially in resource-limited environment with the highest burden of the disease.Trial Registration: The study has been registered with the Pan African Clinical trials registry on the 2nd of December 2018, with registration number PACTR201812814507775. [ABSTRACT FROM AUTHOR]

Background: Parkinson disease (PD) is a debilitating and chronic neurodegenerative disease resulting in ambulation difficulties. Natural walking activity often declines early in disease progression despite the relative stability of motor impairments. In this study, we propose a paradigm shift with a "connected behavioral approach" that targets real-world walking using cognitive-behavioral training and mobile health (mHealth) technology.Methods/design: The Walking and mHealth to Increase Participation in Parkinson Disease (WHIP-PD) study is a twelve-month, dual site, two-arm, randomized controlled trial recruiting 148 participants with early to mid-stage PD. Participants will be randomly assigned to connected behavioral or active control conditions. Both conditions will include a customized program of goal-oriented walking, walking-enhancing strengthening exercises, and eight in-person visits with a physical therapist. Participants in the connected behavioral condition also will (1) receive cognitive-behavioral training to promote self-efficacy for routine walking behavior and (2) use a mHealth software application to manage their program and communicate remotely with their physical therapist. Active control participants will receive no cognitive-behavioral training and manage their program on paper. Evaluations will occur at baseline, three-, six-, and twelve-months and include walking assessments, self-efficacy questionnaires, and seven days of activity monitoring. Primary outcomes will include the change between baseline and twelve months in overall amount of walking activity (mean number of steps per day) and amount of moderate intensity walking activity (mean number of minutes per day in which > 100 steps were accumulated). Secondary outcomes will include change in walking capacity as measured by the six-minute walk test and ten-meter walk test. We also will examine if self-efficacy mediates change in amount of walking activity and if change in amount of walking activity mediates change in walking capacity.Discussion: We expect this study to show the connected behavioral approach will be more effective than the active control condition in increasing the amount and intensity of real-world walking activity and improving walking capacity. Determining effective physical activity interventions for persons with PD is important for preserving mobility and essential for maintaining quality of life. Clinical trials registration NCT03517371, May 7, 2018.Trial Registration: ClinicalTrials.gov: NCT03517371. Date of registration: May 7, 2018. Protocol version: Original. [ABSTRACT FROM AUTHOR]

Background: Ischemic stroke is a leading cause of morbidity and mortality. Thrombolytic therapy improves disability and survival rates; however, to be effective, it must be given within 4.5 h of onset. Moreover, thrombolytic therapy is frequently contraindicated. Therefore, alternative therapeutic options are required. In China, cinepazide maleate injection has been shown to improve the cerebral collateral circulation and further reduce disability in stroke patients; however, very few studies investigating this therapy have been conducted to date. Therefore, this study aimed to further confirm the efficacy and safety of cinepazide maleate injection in patients with acute ischemic stroke.Methods: Patients with acute ischemic stroke were administered an intravenous infusion of 320 mg cinepazide maleate or placebo once daily for 14 days. All patients were also administered basic therapy (citicoline sodium). The primary efficacy endpoint was the proportion of patients with a modified Rankin scale (mRS) ≤2 on day 90. Secondary efficacy endpoints included Barthel Index ≥95. Safety was evaluated by recording all adverse events (AEs), monitoring laboratory parameters and vital signs, and electrocardiogram.Results: In total, 937 patients with an acute ischemic stroke were included, with a mean (standard deviation, SD) National Institutes of Health Stroke Scale score of 8.8 (2.4) and a mean (SD) stroke onset of 30.9 (11.4) hours prior. Following treatment for 90 days, the proportion of patients with an mRS score ≤ 2 was significantly higher in the cinepazide maleate group than in the control group (60.9% vs. 50.1%; p = 0.0004). Moreover, the proportion of patients with a Barthel Index of ≥95 on day 90 was also significantly higher in the cinepazide maleate group than in the control group (53.4% vs. 46.7%; p = 0.0230). There were no statistically significant differences in safety parameters between the cinepazide maleate and control groups.Conclusions: The results of this study show that cinepazide maleate injection is superior to placebo in improving neurological function and activities of daily living, reducing disability, and promoting functional recovery in patients with acute ischemic stroke. Cinepazide maleate injection was safe and well tolerated with no unexpected AEs reported.Trial Registration: Chinese Clinical Trial Registry CTR20160292 and ChiCTR1900023827 . Retrospectively registered June 13, 2019. [ABSTRACT FROM AUTHOR]

Background: Hyperhomocysteinemia (HHCY) is a risk factor for cardiovascular and cerebrovascular diseases. The C677T 5, 10-methylenetetrahydrofolate reductase (MTHFR) gene polymorphism increases homocysteine (HCY) levels. This study analyzed the relationship between C677T MTHFR polymorphism and the therapeutic effect of lowering HCY in stroke patients with HHCY.Methods: Baseline data were collected from stroke patients with HHCY for this prospective cohort study. The C677T MTHFR genotype was detected by polymerase chain reaction-restriction fragment length polymorphism and the therapeutic effect to reduce HCY was compared.Results: Of 200 stroke patients 162 (81.0%) completed follow-up and were evaluated. Most of them responded well to treatment (103 cases, 63.5%), but 59 (36.4%) patients were in the poor efficacy group. There was a significant difference in terms of age (P < 0.001), hypertension (P = 0.041), hyperuricemia (P = 0.042), HCY after treatment (P < 0.001), and MTHFR genotype (P < 0.001) between the poor efficacy and effective groups, with increased frequency of the TT genotype in the poor efficacy group. Logistic regression showed that the T allele was associated with poor efficacy (OR = 0.733, 95%CI: 0.693, 0.862, P < 0.001). In the codominant model the TT genotype was associated with poor outcome (OR = 0.862, 95%CI: 0.767, 0.970, P = 0.017) and this was also the case in the recessive model (OR = 0.585, 95%CI: 0.462, 0.741, P < 0.001) but there was no association between CT and TT in the dominant model.Conclusions: The T allele and TT genotype of the MTHFR C677T polymorphism was associated with poor HCY reduction treatment efficacy in stroke patients with HHCY.Trial Registration: The registration number of the clinical trial is ChiCTR1800020048. Registration date: December 12, 2018. [ABSTRACT FROM AUTHOR]

Background: Patients with Alzheimer's disease dementia (ADD) are thought to exhibit taste disorders; however, this has not been extensively studied. We investigated gustatory functions and factors affecting taste in patients with ADD or mild cognitive impairment (MCI) and in non-demented controls (NDCs) and evaluated associations between cognitive impairment and gustatory functions.Methods: We recruited 29 patients with ADD, 43 with MCI, and 14 with NDCs. We obtained medical and medication history, measured salivary secretion volumes, and performed cognitive function tests, blood tests, whole-mouth gustatory tests, and dietary and gustatory questionnaires.Results: Patients with ADD showed significantly higher recognition threshold values than NDCs (p < 0.05). Many individuals did not recognize umami at the maximum concentration, and this happened more frequently in patients with ADD or MCI than in NDCs. Evaluation items other than cognitive function tests did not show significant differences among the groups, but many individuals had decreased salivation, low serum zinc levels, and were on multiple medications. We found a significant correlation between recognition threshold and age (r = 0.229, p < 0.05) and cognitive function test score (r = 0.268, p < 0.05).Conclusions: Patients with ADD showed impairment of gustatory function. Gustatory impairment in patients with MCI could not be confirmed. However, many individuals with MCI did not recognize umami, either. Our results suggest that taste disorders in elderly people with cognitive decline occur independently of factors affecting taste such as salivation, zinc levels, or prescription drugs.Trial Registration: The study was registered in the UMIN Clinical Trials Registry on February 10, 2017, with reference number UMIN000026087. [ABSTRACT FROM AUTHOR]

Background: Mild Cognitive Impairment (MCI) carries a high risk of progression to Alzheimer's disease (AD) dementia. Previous clinical trials testing whether cholinesterase inhibitors can slow the rate of progression from MCI to AD dementia have yielded disappointing results. However, recent studies of the effects of repetitive transcranial magnetic stimulation (rTMS) in AD have demonstrated improvements in cognitive function. Because few rTMS trials have been conducted in MCI, we designed a trial to test the short-term efficacy of rTMS in MCI. Yet, in both MCI and AD, we know little about what site of stimulation would be ideal for improving cognitive function. Therefore, two cortical sites will be investigated in this trial: (1) the dorsolateral prefrontal cortex (DLPFC), which has been well studied for treatment of major depressive disorder; and (2) the lateral parietal cortex (LPC), a novel site with connectivity to AD-relevant limbic regions.Methods/design: In this single-site trial, we plan to enroll 99 participants with single or multi-domain amnestic MCI. We will randomize participants to one of three groups: (1) Active DLPFC rTMS; (2) Active LPC rTMS; and (3) Sham rTMS (evenly split between DLPFC and LPC locations). After completing 20 bilateral rTMS treatment sessions, participants will be followed for 6 months to test short-term efficacy and track durability of effects. The primary efficacy measure is the California Verbal Learning Test-II (CVLT-II), assessed 1 week after intervention. Secondary analyses will examine effects of rTMS on other cognitive measures, symptoms of depression, and brain function with respect to the site of stimulation. Finally, selected biomarkers will be analyzed to explore predictors of response and mechanisms of action.Discussion: The primary aim of this trial is to test the short-term efficacy of rTMS in MCI. Additionally, the project will provide information on the durability of cognitive effects and potentially distinct effects of stimulating DLPFC versus LPC regions. Future efforts would be directed toward better understanding therapeutic mechanisms and optimizing rTMS for treatment of MCI. Ultimately, if rTMS can be utilized to slow the rate of progression to AD dementia, this will be a significant advancement in the field.Trial Registration: Clinical Trials NCT03331796. Registered 6 November 2017, https://clinicaltrials.gov/ct2/show/NCT03331796. All items from the World Health Organization Trial Registration Data Set are listed in Appendix A.Protocol Version: This report is based on version 1, approved by the DSMB on 30 November, 2017 and amended on 14 August, 2018 and 19 September, 2019. [ABSTRACT FROM AUTHOR]

Background: The Paul Coverdell National Acute Stroke Registry (PCNASR) is a U.S. based national registry designed to monitor and improve the quality of acute stroke care delivered by hospitals. The registry monitors care through specific performance measures, the accuracy of which depends in part on the reliability of the individual data elements used to construct them. This study describes the inter-rater reliability of data elements collected in Michigan's state-based prototype of the PCNASR. Methods: Over a 6-month period, 15 hospitals participating in the Michigan PCNASR prototype submitted data on 2566 acute stroke admissions. Trained hospital staff prospectively identified acute stroke admissions, abstracted chart information, and submitted data to the registry. At each hospital 8 randomly selected cases were re-abstracted by an experienced research nurse. Interrater reliability was estimated by the kappa statistic for nominal variables, and intraclass correlation coefficient (ICC) for ordinal and continuous variables. Factors that can negatively impact the kappa statistic (i.e., trait prevalence and rater bias) were also evaluated. Results: A total of 104 charts were available for re-abstraction. Excellent reliability (kappa or ICC > 0.75) was observed for many registry variables including age, gender, black race, hemorrhagic stroke, discharge medications, and modified Rankin Score. Agreement was at least moderate (i.e., 0.75 > kappa ≥; 0.40) for ischemic stroke, TIA, white race, non-ambulance arrival, hospital transfer and direct admit. However, several variables had poor reliability (kappa < 0.40) including stroke onset time, stroke team consultation, time of initial brain imaging, and discharge destination. There were marked systematic differences between hospital abstractors and the audit abstractor (i.e., rater bias) for many of the data elements recorded in the emergency department. Conclusion: The excellent reliability of many of the data elements supports the use of the PCNASR to monitor and improve care. However, the poor reliability for several variables, particularly time-related events in the emergency department, indicates the need for concerted efforts to improve the quality of data collection. Specific recommendations include improvements to data definitions, abstractor training, and the development of ED-based real-time data collection systems. [ABSTRACT FROM AUTHOR]

Background: Studies report rates of mild cognitive impairment (MCI) in spinal cord injury (SCI) range between 10 and 60%. This broad estimate of MCI in SCI is most likely a result of: (i) inconsistent operationalization of MCI; (ii) heterogeneity among individuals with SCI; (iii) failure to account for MCI subtypes, thereby adding to the heterogeneity of samples; and, (iv) poor control for traumatic brain injury (TBI) that obscures differentiation of MCI attributable to TBI versus other factors. There is a paucity of longitudinal studies following the course of MCI in SCI, and none that account for multiple predictors of MCI, including interactions among predictors.Methods: An inception cohort longitudinal study will assess approximately 100 individuals aged 17-80 years with acute SCI, with measures taken at three timepoints (baseline, 3 months post-baseline, and 12 months post-injury). Data relevant to medical care received within the first 24-48 h of presentation to the emergency department will be analysed, as will measures of cognition, injury characteristics, medical history, personal factors, psychological status, psychosocial functioning, and quality of life. Latent class mixture modelling will determine trajectories for the primary outcome of interest, cognitive functioning and its subtypes, and secondary outcomes of interest such as depression. Multiple regression analyses will identify predictors of MCI and its subtypes.Discussion: The prospective design will reveal change in cognitive functioning across time and unveil different outcome trajectories; thus addressing the lack of knowledge on trajectories of MCI and MCI subtypes in SCI. Through subtyping MCI, we hope to yield groups of cognitively impaired individuals with SCI that are potentially more homogenous and thereby stable and predictable. This is the first study to capture emergency department and acute care diagnostic evidence of mild TBI, which has been poorly controlled in previous studies. Our study will also be the first to distinguish the contribution of TBI from other factors to the development of MCI in individuals with SCI.Trial Registration: The study was prospectively registered with the Australian and New Zealand Clinical Trial Registry ( ACTRN12619001702101 ) on 3rd December 2019. [ABSTRACT FROM AUTHOR]

Background: Parkinson's disease (PD) causes motor and nonmotor disorders in patients. Unlike aerobic training, potential adaptations from the practice of dance are less understood in PD, particularly compared with better known exercise modes. This study aimed to verify and compare the effects of a Brazilian dance program, inspired by Samba and Forrró rhythms, and a walking program on functional mobility and spatiotemporal gait parameters in patients with PD.Methods: Eighteen participants with PD were divided into a dance group (DG) and a walking group (WG) and were assessed before and after an intervention period of 24 1-h sessions, performed twice per week for 12 weeks. The timed-up-and-go test (TUG) and walking kinematics at self-selected speed (SSS) and fast speed (FS) were determined. The generalized estimating equation method was used to compare the DG and WG pre- and post-intervention and to evaluate the group*time interaction (α <  0.05).Results: Both groups demonstrated a significant improvement in TUG test at SSS (p = 0.02; effect size [ES] = 0.42) and FS (p = 0.02; ES = 0.24). In general, spatiotemporal parameters remained unchanged, except at SSS, in which the DG increased the stride frequency (p = 0.011; ES = 0.72). At FS, the swing time demonstrated a significant group*time interaction (p <  0.001; ES = 1.10), in which the two groups exhibited different behaviors: DG decreased (p = 0.015) and WG increased (p = 0.012).Conclusions: Functional mobility improved similarly in both groups. The results suggest that a 12-week program of Brazilian dance was sufficient to produce improvements in functional mobility and gait in individuals with PD.Trial Registration: This study is registered with the International Clinical Trial Registry under number NCT03370315 . Registered December 28, 2017 - Retrospectively registered. [ABSTRACT FROM AUTHOR]

Background: The relevance of regular moderate to intense exercise for ameliorating psychomotor symptoms in persons with multiple sclerosis (pwMS) is becoming increasingly evident. Over the last two decades, emerging evidence from clinical studies and animal models indicate immune regulatory mechanisms in both periphery and the central nervous system that may underlie these beneficial effects. The integrity of the blood-brain barrier as the main structural interface between periphery and brain seems to play an important role in MS. Reducing the secretion of proteolytic matrix metalloproteinases (MMP), i.e. MMP-2, as disruptors of blood-brain barrier integrity could have profound implications for MS.Methods: In this two-armed randomized controlled trial 64 participants with relapsing-remitting MS (RRMS) (EDSS 0-4.0) will be allocated to either an intervention group or a passive wait list control group. The intervention group will perform 60 min of combined functional resistance and endurance exercises 3x per week over a period of 12 weeks in a community-based and publicly available setting. Changes in serum concentration of MMP-2 will be the primary outcome. Secondary outcomes are numbers of immune cell subsets, soluble (anti-) inflammatory factors, physical capacity, cognitive performance, physical activity behavior, gait performance, and patient-reported outcomes. All outcome measures will be assessed at baseline and after week 12 with an additional blood sampling before, during and immediately after a single training session in week 6.Discussion: To our knowledge, this will be the first RCT to investigate both the acute and chronic effects of a community-based intense functional resistance and endurance exercise regimen in persons with RRMS. Combining analysis of biological and cognitive or psychological outcomes may provide a better understanding of the MS-specific symptomology.Trial Registration: DRKS00017091; 05th of April, 2019; International Clinical Trials Registry Platform. [ABSTRACT FROM AUTHOR]

Background: Our understanding of the etiology, pathophysiology, phenotypic diversity, and progression of Parkinson's disease has stagnated. Consequently, patients do not receive the best care, leading to unnecessary disability, and to mounting costs for society. The Personalized Parkinson Project (PPP) proposes an unbiased approach to biomarker development with multiple biomarkers measured longitudinally. Our main aims are: (a) to perform a set of hypothesis-driven analyses on the comprehensive dataset, correlating established and novel biomarkers to the rate of disease progression and to treatment response; and (b) to create a widely accessible dataset for discovery of novel biomarkers and new targets for therapeutic interventions in Parkinson's disease.Methods/design: This is a prospective, longitudinal, single-center cohort study. The cohort will comprise 650 persons with Parkinson's disease. The inclusion criteria are purposely broad: age ≥ 18 years; and disease duration ≤5 years. Participants are followed for 2 years, with three annual assessments at the study center. Outcomes include a clinical assessment (including motor and neuro-psychological tests), collection of biospecimens (stool, whole blood, and cerebrospinal fluid), magnetic resonance imaging (both structural and functional), and ECG recordings (both 12-lead and Holter). Additionally, collection of physiological and environmental data in daily life over 2 years will be enabled through the Verily Study Watch. All data are stored with polymorphic encryptions and pseudonyms, to guarantee the participants' privacy on the one hand, and to enable data sharing on the other. The data and biospecimens will become available for scientists to address Parkinson's disease-related research questions.Discussion: The PPP has several distinguishing elements: all assessments are done in a single center; inclusion of "real life" subjects; deep and repeated multi-dimensional phenotyping; and continuous monitoring with a wearable device for 2 years. Also, the PPP is powered by privacy and security by design, allowing for data sharing with scientists worldwide respecting participants' privacy. The data are expected to open the way for important new insights, including identification of biomarkers to predict differences in prognosis and treatment response between patients. Our long-term aim is to improve existing treatments, develop new therapeutic approaches, and offer Parkinson's disease patients a more personalized disease management approach.Trial Registration: Clinical Trials NCT03364894 . Registered December 6, 2017 (retrospectively registered). [ABSTRACT FROM AUTHOR]

Background: Complex brain arteriovenous malformations (bAVMs) in ≥3 Spetzler-Martin grades have long been challenges among cerebrovascular diseases. None of the traditional methods, such as microsurgical operation, endovascular intervention, or stereotactic radiotherapy, can completely eliminate complex bAVMs without a risk of neural function deterioration. The multistaged hybrid operation solved part of the challenge but remained risky in the installment procedures and intervals. The one-staged hybrid operation was applied in the surgical treatment of cerebrovascular diseases and proved to be a potentially safe and effective method for curing complex bAVMs. However, lacking the support of high-level evidence, its advantages remain unclear. This study was proposed to validate the benefits and risks of one-staged hybrid operation in the treatment of complex bAVMs, as well as its indications, key technologies, and workflows.Methods: The study is being conducted from Jan 2016 to Dec 2020 with 20 cooperation centers. It consists of 2 sets. The registry set is designed as a prospective real-world registry. The trial set is designed as a prospective pragmatic clinical trial, specifically for the patients with perforating arterial feeders. The two sets share a common grouping: the traditional operation group and the one-staged hybrid operation group. The assignment is based on the clinical condition in the registry set and is randomized in the trial set. End points will be evaluated at scheduled time points. The safety and efficiency of one-staged hybrid operation in treating complex bAVMs will be validated.Discussion: The study is designed for a real-world exploration of benefits and risks of one-staged hybrid operation in the treatment of complex bAVMs. The two-set design reduces the compromise of clinical practice due to the study and improves the statistical power and research quality with a practical sample size. In the study, advantages of the one-staged hybrid operation will be evaluated and compared to those of traditional operation. A spanning development of neurosurgical operation might be facilitated by the study, which means a higher cure rate and lower disability rate in patients with complex bAVMs.Trial Registration: The study was retrospectively registered in ClinicalTrials.gov ( NCT03774017 ) on 11th Dec, 2018. [ABSTRACT FROM AUTHOR]

Background: To evaluate whether a shorter time of lying supine without a pillow and fasting for solids and liquids (LSFSL) after a lumbar puncture (LP) is associated with a higher risk of post-lumbar puncture headache (PLPH) and post-lumbar puncture lower back pain (PLPBP) in a randomized, assessor-blinded, controlled trial.Methods: Paediatric patients who underwent their first LP after hospital admission were randomly allocated to either the group with half an hour of LSFSL (0.5 h LSFSL) or 4 h of LSFSL (4 h LSFSL) immediately after LP. The primary outcome is PLPH after LP. The incidence of PLPH, PLPBP, and vomiting; vital signs (respiratory rate, heart rate, blood pressure); and other post-procedure conditions after LP were measured as the outcomes. The Non-inferiority test and Wilcoxon rank-sum test were used to analyse the outcome data.Results: In total, 400 patients (201 in the 0.5-h LSFSL group and 199 in the 4-h LSFSL group) were included in this trial. Twelve (5.97%) of 201 patients experienced PLPH in the 0.5 h LSFSL group versus 13 (6.53%) of 199 patients in the 4 h LSFSL group (difference 0.56, 95% CI -4.18 to 5.31; p = 0·0108 for the non-inferiority test). Fourteen (6.97%) of 201 patients experienced PLPBP in the 0.5 h LSFSL group versus 17 (8.54%) of 199 patients in the 4 h LSFSL group (difference 1.57, 95% CI -3.66 to 6.82; p = 0.007 for the non-inferiority test). The changes in heart rate (HR), respiratory rate (RP) and systolic blood pressure (SBP) before and after the LP were not different between the 0.5-h LSFSL group and the 4-h LSFSL group. No other adverse events were reported.Conclusions: Compared with 4 h of LSFSL after LP, 0.5 h of LSFSL was not associated with a higher risk of PLPH, PLPBP or other adverse events. In conclusion, 0.5 h of LSFSL is sufficient for children undergoing LP.Trial Registration: Clinical trial NCT02590718 . The date of registration was 08/25/2015. [ABSTRACT FROM AUTHOR]