Hypertension in the elderly with cognitive impairment has been one of the global health issues. Mild cognitive impairment (MCI) is the state of transition between the normal aging process and cognitive changes of unformed dementia. Diagnosis and treatment of MCI are the keys to prevent dementia, and hypertension is one of the important influencing factors of MCI. Our preclinical experiment found that Yizhi Qingxin Decoction (YQD) could effectively reduce the blood pressure of spontaneously hypertensive rats (SHR), improve their spatial learning and memory abilities in Morris water maze, and play a neuroprotective role. The objective is to estimate the safety and efficacy of YQD (capsules) in the treatment of hypertension in the elderly with MCI (deficiency of kidney essence syndrome) through this study.Ginkgo biloba extract tablets). The conversion rate of dementia will be used as the main evaluating indicator by the CDR scale. The MoCA scale, MMSE scale, ADCS-MCI-ADL-24 scale, CGIC-KDS scale, and 24-h ambulatory blood pressure will be used as the secondary evaluating indicator. Safety will be evaluated based on specific manifestations of adverse reactions and the incidence of adverse events.According to the random number generated by the block random method, 100 participants will be randomly and equally divided into the treatment group (YQD) or the control group (The objective is to estimate the curative effect of YQD (capsules) on hypertension in the elderly with MCI (deficiency of kidney essence syndrome), and to evaluate the safety of its clinical application.Chinese Clinical Trial Registry (ICTRP member): ChiCTR2000030292. Hypertension in the elderly with cognitive impairment has been one of the global public health problems. The prevalence of hypertension in the elderly increased linearly, with more than 70% of the population over 70 years old. Mild cognitive impairment (MCI) is a transitional state between the normal aging process and cognitive changes in early dementia, and the incidence of MCI in people over 70 years old is nearly 20%. Current studies have shown that hypertension is correlated with the occurrence and development of cognitive impairment and dementia. The risk of MCI and dementia can be reduced by keeping blood pressure within the appropriate range.As the population ages, the burden of hypertension on the global population is increasing, Preventing risk factors without the use of cognitive impairment drugs is the first step in controlling MCI. Ginkgo biloba preparations have also not been shown to reduce cognitive decline in the elderly with normal or MCI. A trial with an average follow-up of 6.1 years abroad, surveyed 3069 community residents, taking 120 mg of Ginkgo biloba extract tablets (Ginaton) twice daily, with the placebo of the same appearance. In comparison, it showed no significant difference in the incidence of adverse events. But research shows that Ginkgo biloba extract has a protective effect on the decline of memory. Some in vitro studies have shown that Ginkgo biloba extract may inhibit the aggregation of amyloid protein, suggesting another mechanism to prevent or delay the cognitive decline associated with Alzheimer's disease. In summary, Ginkgo biloba extract may prevent or delay age-related changes in individuals with normal cognitive abilities, or slow down the cognitive decline in patients with MCI, and Ginkgo biloba extract tablets (Ginaton) have not found evidence of long-term use to increase the incidence of adverse events.The latest 2017 ANN guideline for MCI makes clear that there is no high-quality evidence to support drug therapy for MCI.Alpinia oxyphylla Miq, Lycii Fructus, and so on. Its efficacy is mainly based on tonifying the kidney and replenishing essence, as well as clearing the heart and liver heat.In traditional Chinese medicine, MCI can be classified into the category of “amnesia” and “dementia.” At present, it is believed that the deficiency of kidney essence is the fundamental factor of MCI. Wind, fire, phlegm, and blood stasis are the key factors for the development of the disease. Academician Ke-Ji Chen summarized Yizhi Qingxin Decoction (YQD) based on his many years of clinical experience in MCI treatment of elderly hypertension. The composition of the formula is Ginkgo biloba extract tablets (Ginaton) will be used as a positive control drug to estimate the efficacy of YQD (capsules) on hypertension in the elderly with MCI (deficiency of kidney essence syndrome) and the safety of its clinical application.Our preclinical experiment found that YQD could effectively reduce the blood pressure of spontaneously hypertensive rats (SHR), improve their spatial learning and memory abilities in Morris water maze, and play a neuroprotective role. It can inhibit aortic fibrosis and reduce serum aldosterone and angiotensin II levels in SHR. In this trial, 2This trial has been registered in the Chinese Clinical Trial Registry and meets the specification of the CIOMS international ethical guidelines for human biomedical research. The results will be reported in accordance with the CONSORT extension recommendation of the 2017 Chinese herbal formula test report.The study uses a positive-drug parallel randomized control design. Participants will fully understand the benefits and risks and sign a written informed consent before being included in this study. The personal data of participants will be kept strictly by the researchers in order to protect privacy. The enrolled participants n = 100) are randomly divided into a treatment group (n = 50) and a control group (n = 50). The two groups of participants will be measured for 24 h ambulatory blood pressure. If the blood pressure is not within the normal range, we will adjust the use of antihypertensive drugs, and check it 1 month later to make all patients reach the standard blood pressure. Both groups will receive 52 weeks of treatment and 5 follow-ups, as shown in Figure 00 are ra2.1Researchers will recruit 100 participants through advertising, outpatient, etc. A total of 100 elderly participants who meet the inclusion and fail to meet exclusion criteria will be enrolled.2.22.2.1 hypertension in the elderly diagnostic criteria: The sitting systolic blood pressure (SBP) ≥140 mm Hg and/or diastolic blood pressure (DBP) ≥90 mm Hg measured three times in different days among patients aged ≥65 years or older.Refer to the revised Guideline for the prevention and treatment of hypertension in China,2.2.2 MCI diagnostic criteria: Report by patients or informed individuals, or experienced clinicians discover cognitive impairment; objective evidence of impairment of one or more cognitive functional domains (from cognitive tests); complex instrumentality daily abilities can be slightly impaired, but the independent daily living ability is maintained; the disease has not yet reached the diagnosis of dementia.Refer to China's Guidelines for MCI,Auxiliary diagnostic criteria: The MoCA scale score <26 points; the MMSE scale score is graded according to the educational level, with 21 points ≤ primary school ≤26 points, and 24 points ≤ middle school or above  ≤ 26 points; the CDR scale score is 0 or 0.5 points.2.2.3 the sum of all the symptom scores is ≥7, which meets the diagnostic criteria of kidney deficiency syndrome.Refer to the Kidney Deficiency Syndrome Scale dialectical standard developed by Jin-Zhou Tian in 2017  or mental disorders.CT or MRI scans within the past 12 months revealed central nervous system infection, infarction, or other focal lesions; Hachinski Ischemic Scale (HIS) > 4.Other conditions are not suitable for participation, such as hypertensive emergencies, hypertensive crises, high blood pressure that has not been controlled despite medication, severe arrhythmia, the patients who occurred myocardial infarction within 3 months before participating in this trial.Patients who had regularly taken traditional Chinese medicines with similar effects, or anticholinergic drugs, anticonvulsants, antiparkinsonian, excitatory drugs, cholinergic drugs, antipsychotics, anti-anxiety drugs, or who were known to be allergic to the trial drugs before this trial.Severe liver and kidney dysfunction; severe asthma and chronic obstructive pulmonary disease; severe digestive system disease.Participants are participating in other clinical trials.Participants are deemed unable to follow the trial procedures.2.3.3Some participants’ condition constantly worsens or the participants emerge severe conditions during the trial such as acute hypertension, acute cerebral infarction, intracerebral hemorrhage, deterioration of cardiac function, acute coronary syndrome. The participant will withdraw from the trial.Some participants with cognitive function decline during the trial, will continue to take medication and be followed up. If the participant's condition turns into dementia, the participant will be transferred to conventional treatment, and this case will be terminated.A case judged by a doctor as a possible dangerous event should be stopped. To protect the participant, the participant should withdraw from the clinical trial and receive other treatments. The case is treated as invalid.If some participants emerge certain comorbidities or special physiological changes during the trial, they will not be appropriate to continue the trial.If some participants could not follow the clinical trial protocol in terms of taking drugs, receiving visits, and so on during the trial, they will be considered to discontinue participating in the trial because they may affect the authenticity of the study results.Participants with adverse events or severe adverse events.After the termination of the case, the case record form should be kept, and the final test results should be taken as the final results to analyze the efficacy and adverse reaction data.2.42.4.1Basic measures in the two groups will be included improvement of lifestyle to eliminate adverse factors for physical and mental health, such as weight control, reduction of dietary fat intake, appropriate restriction of salt, maintenance of exercise.2.4.2Treatment group: YQD (capsules) 0.4 g/capsule, 3 times a day, 4 capsules once a time, oral after meals.Ginkgo biloba extract tablets (Ginaton) 40 mg/tablet, 2 times a day, 2 tablets once a time, oral after meals.Control group: 2.4.3Both participants will be measured for 24 h ambulatory blood pressure when they enter the group. If they do not reach the normal blood pressure range, their antihypertensive drugs will be adjusted. After 1 month, the blood pressure will be reviewed to make all participants reach the standard blood pressure. The course of treatment is 52 weeks, and 5 follow-ups are set up, at 4 weeks, 12 weeks, 24 weeks, 36 weeks, and 52 weeks.2.4.4Ginkgo biloba preparations, similar Chinese medicine or decoction, aniracetam, nicergoline. If combination therapy is required, the participant should be treated as an excluded case. The name of the combined medication used, the total daily dosage, the reason for taking it, and the start and end time of taking it should be recorded at the time of follow-up.During the trial, it is forbidden to add Chinese and western medicines that have the same or similar effects or affect the safety evaluation of the trial drugs, including drugs that improve cognitive function such as Compound Congrong Yizhi Capsule, other Combination therapy that must be taken for other diseases, can continue to be taken, and record name, dosage, and the number of times in the medical record for summary and report.2.52.5.1Conversion rate of dementia: The CDR scale.Efficacy determination criteria: The follow-up test CDR scale score is 0 or 0.5, which has not converted to dementia and reaches the main efficacy indicators.2.5.2Cognitive function: MoCA scale, the MMSE scale is graded according to educational level.Daily life ability: MCI daily living ability scale (ADCS-MCI-ADL-24).24-hour average blood pressure: day-average blood pressure, night-average blood pressure, 24 h blood pressure variability.Clinical Global Impression of Change-Kidney Deficiency Syndrome (CGIC-KDS): Changes in syndrome overall impression based on physician experience and caregiver supplementation.2.5.3All adverse events.General physical examination.Other tests: Blood test, urine test, fasting blood glucose, biochemical assay, electrocardiogram.2.6  for the treatment of hypertension in the elderly with MCI.2.8Expected adverse events include gastrointestinal reactions, such as abdominal discomfort, nausea or vomiting; bronchial allergic reactions, for instance, dyspnea, asthma; skin allergies, for example, rash, urticaria, pruritus; liver and kidney function abnormalities . The participants will be advised to stop taking the trial drugs when the above adverse events occur. All adverse events except the expected adverse events are treated as unexpected adverse events, recorded and reported by the adverse events reporting requirements, and timely and appropriate medical treatment by the clinical diagnosis and treatment norms.If serious adverse events occur during the trial, regardless of whether they are related to the trial drugs, we will give timely rescue treatment to ensure the safety of the participants and give an account of the ethics committee within 24 h or not later than the second working day. We will sign the report and indicate the date and complete a “serious adverse event report form,” which records the time, place, and person of the report. All adverse events will be traced to normal or nearly normal to ensure the safety of the participants.2.9All researchers can enter and conduct this trial only after finishing training and authorization from the principal researcher. The person in charge shall conduct Good Clinical Practice (GCP) and protocol training for all researchers and other persons related to the trial.2.10The block random method is adopted to enhance the equilibrium comparability between the two groups. The random code table is generated by Statistical Analysis System (SAS) software. It is divided into 2, one is stored in the designated computer in the form of the electronic document. The other one is kept in an opaque envelope for hidden distribution. The drug administrators will issue drugs according to the order of each participant's medical treatment and drug number.2.11The random sequence is generated by the data administrator and is unavailable to the researchers who will recruit participants. Data administrator will be performed by two data entry personnel independently for double entry and proofreading. They will randomly select a certain number of case report forms and compare them with the data in the database to ensure that the data is correct.2.12P is <.05, the data difference is significant.Statistical Product and Service Solutions (SPSS24.0) software will be used for statistical analysis of data. The different data types are analyzed by appropriate methods. Per-protocol set (PPS) and Full analysis set (FAS) will be implemented simultaneously for the main outcome indicators. All randomized patients who received at least one treatment and completed the post medication safety evaluation will use the safety set (SS) to evaluate the safety. The least-square mean (LSMEAN) of analysis of covariance and its 95% confidence limit, or logistic regression will determine the difference in efficacy between groups and eliminate the influence of confounding factors on efficacy. The statistical test is conducted by a bilateral difference test, if 3Alpinia oxyphylla Miq, Lycii Fructus, etc. YQD has the function of tonifying kidney essence. The deficiency of kidney essence is the fundamental factor of MCI in the theory of traditional Chinese medicine. A modern medical research has found that 5-HMF, the main active component of Alpinia oxyphylla Miq, can improve the memory impairment of mice induced by Aβ1–42, which has a potential therapeutic effect on dementia.Lycii Fructus extract can improve the cognitive function in mice of Alzheimer's disease, reduce Aβ deposition, and regulate the expression of brain neurotrophic derived factor and tyrosine kinase B.The objective of this study is to estimate the safety and efficacy of YQD (capsules) in the treatment of hypertension in the elderly with MCI (deficiency of kidney essence syndrome). The prescription composition of YQD includes  The prevalence of MCI in the elderly population (older than 65 years) ranges from 3% to 19%, and the conversion rate of dementia within 2 years ranges from 11% to 33%. The treatment of MCI falls under the category of secondary prevention of dementia. The treatment goal of MCI is to improve symptoms, and it is more important to delay or prevent further damage in cognitive ability and the onset of dementia. It is helpful to evaluate the therapeutic effect of drugs based on the outcome indicators of the conversion rate of dementia and cognitive function. The self-regulating imbalance of cerebral blood flow and cerebral perfusion caused by long-term hypertension is the main biological pathway of hypertension with cognitive impairment. Duration of hypertension could be a determining factor of cognitive decline in the elderly.,18 Early control of blood pressure is beneficial to reduce cognitive decline. The studies have shown that the increase of blood pressure variability may be related to the decline of cognitive function, which still exists in patients with good blood pressure control.–21 24-h ambulatory blood pressure monitoring can effectively provide information about blood pressure changes.MCI is considered a clinical syndrome with impaired participative and objective memory or other cognitive functions, but the function of daily life remains basically intact.The study is a positive-drug parallel randomized controlled trial, using a block randomization method to enhance the equilibrium comparability between two groups. Assignment concealment reduces selection bias. According to the inclusion and exclusion criteria, the homogeneity of research objects is improved. In the treatment group, YQD will be made into capsules to increase the compliance and convenience of elderly participants. The conversion rate of dementia  is the main efficacy indicator. The MMSE scale, MOCA scale, ADCS-MCI-ADL-24 scale, CGIC-KDS scale, and 24-h ambulatory blood pressure observation are the secondary efficacy indicators, to provide the certain reference for the efficacy evaluation of outcome. The treatment duration is 52 weeks, include 5 follow-ups during the treatment period, providing reliable results for the evaluation of prognosis and observation of adverse reactions.The methodological limitation includes failing to achieve double-blind. And this is a single-center study, with a small sample size and relatively short time for people with MCI. Therefore, there is a lack of long-term evaluation of the main outcome indicators (conversion rate of dementia), which limits the efficacy evaluation of drugs. In the future, it is necessary to carry out a multicenter randomized double-blind study to reduce methodological bias and conclusion deviation, and extend the follow-up time to further evaluate the effect of YQD on dementia prevention and cognitive function.4The study was accepted by the ethics committee of Xiyuan Hospital, Chinese Academy of Medical Sciences in February 2020 . The study will be based on the requirements of the Helsinki Declaration of the World Medical Association. Currently, the researchers are recruiting participants.The authors sincerely thank all the participants and the researchers who will participate in the trial for their assistance.KJC proposed the concept, PZ and FQX designed the trial, PZ, JM, and BQW were responsible for data collation, FQX conducted research supervision, BQW, JM, LL, and CXJ wrote the first draft, PZ, JM, and JNZ reviewed and checked the manuscript.Conceptualization: Ke-Ji Chen.Investigation: Bi-Qing Wang, Jun Mei, Ping Zhang.Methodology: Ping Zhang, Feng-Qin Xu.Project administration: Feng-Qin Xu.Writing – original draft: Bi-Qing Wang, Lu Liu, Chun-Xiao Ju.Writing – review & editing: Jun Mei, Jun-Nan Zhao, Ping Zhang.


Supplemental Digital Content is available in the text. P<0.0001). Heart rate increased during LBNP, reaching significance at −50 mmHg (P<0.0001). There was no change in mean arterial pressure during LBNP (P=0.3). All participants showed similar reductions in CBF  and CO  during LBNP. There was no difference in resting CBF between the groups (P=0.36). In summary, during reductions in CO induced by hypovolemic stress, mean arterial pressure is maintained but CBF declines indicating that CBF is dependent on CO in middle-aged normotensive and hypertensive volunteers. Hypertension is not associated with impairments in the CBF response to reduced CO.Hypertension is associated with raised cerebral vascular resistance and cerebrovascular remodeling. It is currently unclear whether the cerebral circulation can maintain cerebral blood flow (CBF) during reductions in cardiac output (CO) in hypertensive patients thereby avoiding hypoperfusion of the brain. We hypothesized that hypertension would impair the ability to effectively regulate CBF during simulated hypovolemia. In the present study, 39 participants  underwent lower body negative pressure (LBNP) at −20, −40, and −50 mmHg to decrease central blood volume. Phase-contrast MR angiography was used to measure flow in the basilar and internal carotid arteries, as well as the ascending aorta. CBF and CO decreased during LBNP ( A reduction in CBF has also been observed with antihypertensive treatment,8 and lower CBF has been measured in treated controlled versus untreated hypertensive patients.4 However, the effect of antihypertensive medication on CBF control is poorly understood.9In a large-scale longitudinal study in 575 patients with manifest arterial disease, Muller et alonline-only Data Supplement), several studies report reduced CBF velocity (a surrogate measure of blood flow) in the middle cerebral artery, assessed by transcranial Doppler ultrasonography (TCD) in healthy volunteers.13 Studies examining the dynamic regulation of CBF in hypertension in response to changes in BP show mixed results, with some showing preserved ability to regulate flow compared with normotensive individuals15 and others showing an impairment of regulation.17 Given that hypertension is associated with structural changes in response to increased transmural pressure, such as arterial stiffening and atherosclerosis,20 it remains unclear whether the arterial remodeling may contribute to the altered CBF regulation. Any impairment in the regulation of CBF and lower perfusion at rest may risk oxygen deprivation and ischemia in hypertensive patients.In response to a BP challenge such as lower body negative pressure (LBNP), which simulates hypovolemia  or uncontrolled BP (uncontrolled hypertensives), to assess whether these groups respond differently to reductions in CO. We hypothesized that patients with hypertension would have a larger reduction in CBF in response to a decrease in CO induced by LBNP. We also hypothesized that because uHTNs are likely to have more adverse arterial remodeling versus cHTN,23 this group would have a larger decline in CBF during a reduction in CO.In healthy volunteers, regulation of CBF is crucially dependent on alterations in cardiac output (CO).https://data.bris.ac.uk/data/.This study was approved by the UK National Research Ethics Committee (reference: 15/SW/0176) and the Institutional Research and Innovation Department at the University Hospitals Bristol NHS Foundation Trust. All methods conformed to the Declaration of Helsinki, as well as local and UK national guidelines. Data and analysis is available on request from A total of 39 eligible men and women were recruited for the study, of which 13 were normotensive, 13 were hypertensive with BP controlled by medication (cHTN), and 13 were uncontrolled hypertensives . Participants were age matched and grouped based on daytime ambulatory BP averaged over at least 14 measurements, in accordance with 2018 European Guidelines for diagnosis of hypertension. The normotensive and cHTN groups were defined as a daytime ambulatory BP of <135/85 mmHg. uHTN was defined as a daytime ambulatory BP of >135/85 mmHg, either without or despite being prescribed antihypertensive medication. The uHTN group was included to investigate the effect of raised resting BP.online-only Data Supplement.All participants gave written informed consent. Participant screening procedures and eligibility is detailed in the online-only Data Supplement). A broad polyurethane skirt was wrapped around the waist and secured over the box providing an airtight seal. The participants were positioned with their feet flat against the end of the box to prevent the participant being pulled further into the box by the suction. A commercially available vacuum cleaner with continuous variable power (Sebo Airbelt K1 1800 W) was attached to the box. The negative pressure achieved inside the box was monitored with an MR safe pressure gauge (SM Gauge) continuously indicating the pressure within the box (relative to atmospheric).A magnetic resonance (MR) imaging compatible polycarbonate box was fitted to encompass the lower torso and legs  every 1.5 to 2 minutes during each phase-contrast acquisition. An average of the measurements was taken for each level of LBNP. A nasal cannula was connected to a calibrated capnograph  to measure the percentage of expired end-tidal COAll MR images were acquired during free breathing at 1.5T .online-only Data Supplement.ECG-gated phase-contrast MR angiography was used to measure (1) CBF in the basilar and internal carotid arteries, in the transverse plane perpendicular to the internal carotid arteries at the level of the basilar artery, followed by (2) flow in the ascending aorta in the transverse plane, at the level of the main pulmonary trunk . All flow imaging was performed at isocenter. Examples of flow data in the intracranial arteries and the aorta are shown in Figure S1 in the The time-of-flight angiogram was covering the superior vertebral arteries and the entirety of the Circle of Willis. Time-of-flight images were used primarily to position the phase-contrast images for the intracerebral flow measurements. However, a 3-slice localizer with slice thickness of 5 mm was used for the repositioning of the flow slices during LBNP to ensure a consistent positioning regardless of movement of the subject due to suction. An example angiogram is shown in Figure S1.A 3-dimensional T1-weighted scan (T1-MPRAGE) was acquired in the transverse plane.online-only Data Supplement.MR image analysis is outlined in the 24 Abstract) in resting CBF between the uHTN and normotensive groups with a 2-sided α of 0.05.We calculated that a sample size of 11 in each group provides a power of 80% to find a 17% difference (estimated based ononline-only Data Supplement.Inter- and intraobserver variability data are available in the  (pulse pressure). Total peripheral resistance (TPR) was estimated as Mean arterial BP (MAP) was calculated as MAP=diastolic BP (DBP)+ Cerebrovascular conductance was calculated as:Analyses were completed in Prism v7 (GraphPad Software) unless otherwise stated.10 transformation.Normality of distribution in the data was assessed by D’Agostino-Pearson. CO did not pass the test of normality and was transformed by a logonline-only Data Supplement.Mean differences between the groups during LBNP were analyzed using mixed-model ANOVA and compared using Tukey multiple comparisons with respect to resting values. Mean differences between the groups at rest were analyzed by a 1-way ANOVA and Bonferroni correction for multiple comparison. Analysis by sex is presented in the A 3-way ANOVA with factors artery, LBNP, and group was performed to assess potential interactions between the arteries and groups during LBNP .online-only Data Supplement. The data are reported as mean and SD. α was set at 0.05.Vascular remodeling and structural incidents related to vascular disease are included in the 2 was not reliably recorded because of technical difficulties.9 These participants were removed from the CO2 analysis. Incidence of stenosis can be found in Table S1 presented in the online-only Data Supplement. Only mild stenosis was observed. Interestingly, 4 of the normotensives showed stenosis versus 3 in uHTN and 0 in cHTN.All participants completed the experimental protocol. One participant who, due to presyncopal symptoms, was unable to tolerate LBNP of −50 mmHg, had incomplete data for aortic flow and was excluded from all assessments of CO. In 9 participants, end-tidal COP=0.0076; ambulatory SBP, P<0.0001; ambulatory DBP, P=0.0019) but not clinic DBP (P=0.05). There was no difference in BP between normotensive and cHTN .The participant demographics are summarized in the Table. There were no differences in the average age, body mass index, or sex ratio between groups. Clinic and ambulatory BPs were higher in the uHTN compared with normotensive and cHTN  with no difference between the groups . There was no change in MAP with LBNP , nor an interaction of the change in MAP between groups and LBNP . Overall, SBP was significantly lowered by LBNP , at −50 mmHg LBNP only when compared with rest (P=0.013). There was no interaction effect between LBNP and group on SBP . DBP increased with LBNP , at −40 mmHg (P=0.01) and −50 mmHg (P=0.01). DBP was significantly different between groups , and there was an interaction of DBP between LBNP and group . DBP significantly increased in the normotensive group at −50 mmHg (P=0.0024) and in the cHTN group (P=0.034) but not the uHTN (P=0.9). Between-group Dunnett post hoc comparisons showed a significant difference for DBP between the normotensive and uHTN only (P=0.01).Figure P<0.0001). There was no interaction between the change in TPR during LBNP and group . There was a reduction in end-tidal CO2 with LBNP . Compared with rest, the reduction was 0.08% at −20 mmHg (P=0.3), 0.2% at −40 mmHg (P=0.0009) and 0.3% at -50 mmHg (P<0.0001). Regarding end-tidal CO2, there was no difference between groups  or interaction between LBNP and group . However, a change from nasal to oral breathing was observed at −50 mmHg LBNP. Unfortunately, we did not measure breathing rate, and as such, no data are available on the minute ventilation.LBNP increased TPR , with no difference between the groups  or interaction between LBNP and group . CO was reduced compared with rest at −20 (P<0.0001), −40 (P<0.0001), and −50 mmHg (P<0.0001) in all participants  and blood flow velocity  were reduced by LBNP. Post hoc tests revealed a significant reduction in normalized CBF at −40 (P<0.0001) and −50 mmHg (P<0.0001) but not at −20 mmHg (P=0.13). There was no interaction between LBNP and group .Figure P<0.0001) with no interaction between LBNP and artery (P=0.64) or between LBNP, artery, and group .LBNP reduced CBF in all 3 intracranial arteries measured , with no difference between the groups  or interaction between LBNP and group . Cerebrovascular conductance was reduced at −40 (P=0.0004) and −50 mmHg (P<0.0001) but not at −20 mmHg (P=0.053). No correlation was observed between the change in end-tidal CO2 and the change in tCBF .There was a reduction in cerebrovascular conductance during LBNP  in the percentage of the CO that was distributed to the brain . This difference amounted to 0.75% at −20 mmHg (P=0.12), 1.35% at −40 mmHg (P=0.0015), and 1.15% at −50 mmHg (P=0.0081). There was no difference between the groups  and no interaction between the change in the percentage of the CO going to the brain during LBNP and group .On average, tCBF reduced by −3.9% at −20 mmHg, −8.2% at −40 mmHg, and by −14.6% at −50 mmHg LBNP from resting values. There was an increase  in >100 participants but acquired only 9 reconstructed phases over the cardiac cycle. Therefore, while Warnert et al4 had good spatial resolution and thus reliable measurements of vessel diameter, 9 frames per cardiac cycle equates to an effective temporal resolution of ≈111 ms (assuming a HR of 60 beats per minute), which will inescapably lead to undersampling.35 By contrast, the present study acquired phase-contrast flow with 100 reconstructed phases over the cardiac cycle, equating to an effective temporal resolution of ≈10 ms. The 10-fold higher temporal resolution of the current study allows for a more detailed and reliable characterization of flow throughout the cardiac cycle. Lastly, the current study sample comprised middle-aged subjects who may show less pronounced differences in resting CBF, when compared with an older demographic with more advanced vascular disease.3Previous reports have pointed to a lower resting CBF in patients with hypertension.36 The present study does not support this theory given that the percentage of the CO going to the brain increased  with LBNP. Second, based on the principles of Poiseuille law, the perfusion of any organ depends on the arterial pressure and vascular resistance. In the present study, the lower flow and conductance observed in response to a reduced CO may have been compensated for by vasoconstriction of the cerebral circulation  thereby maintaining perfusion pressure. Third, as the regulation of CBF is critical for maintaining constant nutrient and oxygen supply to the brain, a brain-specific theory for the regulation of blood flow, referred to as the selfish brain hypothesis, has been proposed. According to this theory, the body prioritizes CBF and adjusts peripheral BP to adjust flow to the brain to maintain constant perfusion.37 The theory further proposes that hypertension is caused by a reduction in brain stem perfusion driving up BP to normalize the perfusion. Eventually, the BP becomes insufficient to compensate for the lowered perfusion, leading to a permanently lowered CBF.4Three main theories on how the body maintains optimal brain blood flow are relevant and should be considered. First, proportional blood distribution states that blood flow to each organ is a fixed percentage of the CO, and each organ’s share is based on their metabolic demand.The current study suggests that irrespective of high BP, the brain is able to tolerate a reduction in tCBF when CO falls at rest. The fact that CBF fell by −14.6% at −50 mmHg LBNP supports this idea. However, this claim may be challenged by the increase seen in the percentage of the CO going to the brain, suggestive of a degree of priority given to brain perfusion. Indeed, we saw an increase of ≈1% at −50 mmHg LBNP. This supports the selfish brain hypothesis in that CBF is given priority through an increase in the proportional distribution ably assisted by increasing peripheral vascular resistance to maintain arterial pressure. However, at −40 mmHg where CBF was reduced by an average of −8.2%, an equivalent increase in the percentage of the CO going to the brain was observed , suggesting a reserve would still be available at this level given the steady decline in CO, unchanged MAP, and HR. Furthermore, we did not measure blood flow to any other organ and, therefore, do not have information on whether the redistribution of blood flow may be unique to the brain.Reductions in CBF caused by conditions that lower CO in populations with already low resting CBF and extensive microvascular disease may put the cerebral circulation at risk of hypoperfusion and ischemic events.38 the lower CBF must still be able to meet the metabolic demands. It is, therefore, of interest to know whether a cognitive task would increase CBF under conditions of LBNP or whether the performance on such a task would suffer. Under resting conditions, it may be assumed that sufficient CBF was available to meet demand. This can be achieved either through a change in the extraction fraction of metabolic substrate from the blood during perfusion, for example, by the slowing of blood flow as seen in the present study, or by an abundance of blood flow at rest. Importantly, these mechanisms are likely to be dependent on the perfusion pressure to maintain the substrate exchange across the blood-brain barrier. Future studies should focus on measuring the perfusion of the brain with respect to oxygen extraction during a hypovolemic challenge to better understand whether lowering of CBF has functional consequences.Given that MAP was unchanged during LBNP, this may suggest that, so long as perfusion pressure can be maintained, a reduction in CBF as a consequence of reduced preload is tolerated. As the brain has a limited capacity for metabolic substrate storage,In summary, the study shows that in middle-aged men and women, tCBF decreases when CO decreases. Since MAP was maintained during LBNP, this suggests that cerebral perfusion pressure was unchanged despite a reduction in tCBF. There was no difference in the decline in CBF between normotensive and hypertension groups, indicating that hypertension does not impact the regulation of CBF during simulated hypovolemia.We would like to acknowledge the support received from the Bristol Heart Institute radiographers to conduct this study. Further, we wish to acknowledge the research nurses who have helped with the recruitment and eligibility screening of the participants. Finally, we wish to thank the participants who volunteered their time to take part in this study.This study was supported by the Wellcome Trust and the Bristol National Institute for Health Research (NIHR) Biomedical Research Centre. The views expressed are those of the authors and not necessarily those of the National Health Service, NIHR, or the Department of Health and Social Care.None.


Together, these data suggest that the kynurenine/tryptophan ratio predicts angiotensin receptor blocker responsiveness in patients with diabetic kidney disease.Albuminuria is a measurement and determinant factor for diabetic kidney disease (DKD). Angiotensin receptor blocker (ARB) is recommended for albuminuria in DKD with variable response. To find surrogate markers to predict the therapeutic effect of ARB, we carried out a prospective study to correlate plasma metabolites and the progression of renal function/albuminuria in DKD patients. A total of 56 type 2 diabetic patients with various stages of chronic kidney disease and albuminuria were recruited. ARB was prescribed once albuminuria was established. Urinary albumin-to-creatinine ratio (UACR) was determined before and six months after ARB treatment, with a ≥30% reduction of UACR considered an ARB responder. Plasma levels of 145 metabolites were measured before ARB treatment; only those associated with albuminuria were selected and compared between ARB responders and non-responders. Both lower tryptophan (Trp ≤ 46.75 μmol/L) levels and a higher kynurenine/tryptophan ratio (KTR ≥ 68.5 × 10 Diabetic kidney disease (DKD) is defined as a decline in renal filtration and/or the development of albuminuria, which occurs in approximately 40% of diabetic patients and is the leading cause of chronic kidney disease (CKD) worldwide . The natMany randomized control trials in recent decades have proven that the reduction of albuminuria may slow the progression of nephropathy ,6,7,8. BPrevious metabolomics studies have revealed potential pathways and surrogate prognostic markers associated with the development and progression of DKD ,11. Neven = 48) or without (n = 8) albuminuria were enrolled from April 2017 to May 2018. The presence of albuminuria was assessed by at least two measurements of the urinary albumin-to-creatinine ratio in a random spot urine collection. While normoalbuminuria means a UACR < 30 mg/g, microalbuminuria and macroalbuminuria are defined as when UACR ranges between 30–300 mg/g and UACR ≥ 300 mg/g, respectively [With informed consent approved by the Ethics Committee on Research of the institutional review board , T2DM patients aged from 35 to 75 years, regularly followed-up at the out-patient department of a tertiary hospital, were screened. Patients with acute inflammatory diseases, severe systemic disease, and/or ACEi/ARB vulnerability were excluded. Eventually, 56 patients with various stages of CKD with  was used for the metabolomics analyses of the samples. The assay was performed in Waters Acquity Xevo TQ-S instrument according to manufacturer’s instruction. The metabolomics dataset contained 20 acylcarnitine, 21 amino acids, 8 biogenic amines, 14 sphingomyelins, and 82 glycerophospholipids.Continuous variables were presented as mean ± standard deviation (SD) and range, categorical variables were presented as number and percentage. The comparisons of the characteristics were calculated by a one-way ANOVA for continuous variables with normal distribution; a Kruskal–Wallis ANOVA was used for continuous variables without normal distribution, and a Chi-Squared test was used for categorical variables.p value < 0.05 was considered statistically significant.An independent sample t-test was used for continuous variables with normal distribution and a Mann–Whitney U-test for continuous variables without normal distribution to analyze the difference between ARB responders and non-responders in both MAU and mau groups. The receiver operating characteristic (ROC) curve and Youden Index were carried out to identify the most predictive value of Trp and KTR for albuminuria and KTR for predicting ARB responsiveness in MAU. The adjusting confounding factors about KTR between responders and non-responders in the MAU group was determined by multivariate binary logistic regression. Analysis was performed using SPSS statistical software . A n = 34), microalbuminuria , and normoalbuminuria  according to their initial urinary albumin-to-creatinine ratio (UACR) before the enrollment. Despite that patients with MAU were significantly younger, the other parameters, such as body mass index (BMI), glycated hemoglobin (HbA1c), duration of diabetes, and blood pressure before ARB treatment were comparable among the three groups. Meanwhile, the use of oral anti-diabetic drugs and anti-hypertensive drugs were all similar among the three groups.p < 0.001). The average baseline estimated glomerular filtration rate (eGFR) was similar  among the three groups, with 11.8%, 64.7%, 23.5%; 28.6%, 64.3%, 7.1% and 12.5%, 87.5%, 0% of the patients allocated in CKD stage II, III, and IV–V, respectively.The average UACR was 1831.0 ± 1640.5 in MAU, 146.5 ± 85.9 in mau, and 10.6 ± 6.4 mg/g in control groups, respectively, with statistical significance , tryptophan (Trp), tyrosine (Tyr), ornithine (Orn), phenylalanine (Phe); 3 glycerophospholipid, PC ae C44:3, lysoPC a C24:0, lysoPC a C26:1; and 1 sphingolipid, SM C26:0, showed significant differences among the three groups . In contp = 0.025) to predict ARB responsiveness in the MAU, but not in the mau  for albuminuria, and KTR ≥ 54.7 × 10−3  for ARB responsiveness, respectively  and KTR ≥ 68.5 × 10ectively .The clinical diagnosis of DKD is on the basis of a patient with long-standing diabetes with albuminuria and/or reduced eGFR in the absence of signs or symptoms of other primary causes of kidney damage . Lines oTo reach this goal, we correlated the change of metabolites in T2DM patients with various stages of CKD in this study, and we found a trend of decreased metabolites , except Orn and Phe, showing significant association with the severity of albuminuria. Several amino acids, including Orn, were reported to be positively correlated with UACR . Here, wPlasma levels of Phe are regulated by phenylalanine hydroxylase (PAH); factors such as stress, sepsis, or any causes of hepatic dysfunction may influence the activity of PAH ,24. In a+ T cells produce IFN-γ in order to respond to advanced glycation end products and thus exacerbate inflammation in the diabetic kidney [−3) and the severity of albuminuria. Similarly, Zhao et al. also reported that plasma KTR could be applied as a reliable biomarker for the assessment of renal function in patients with hypertension [However, IDO is potently induced by proinflammatory cytokines and acts locally to modulate Trp levels in response to inflammation ,28. Therc kidney . Corresprtension .The renin–angiotensin system blockages are valid of renoprotection beyond blood pressure control . Althoug−3) might be regarded as a potential prognostic marker for improvement of albuminuria, especially in patients with macroalbuminuria. Impressively, although the MAU group was significantly younger, KTR remained at a significant difference after adjusting for confounding factors such as age, gender, SBP, eGFR, HbA1c, duration of DM, and the use of SGLT2 inhibitor  of these patients had more than 30% UACR reduction. Among the 27 responders, 20 were initially MAU and seven were mau; in addition, five of the MAU patients regressed from macroalbuminuria to microalbuminuria after ARB treatment. Subsequently, the aforementioned metabolites associated with albuminuria were analyzed and only KTR was found to be associated with ARB responsiveness, albeit only in the MAU, but not in the mau group. A higher level of KTR . Meanwhile, a higher KTR ≥ 54.7 × 10−3 may predict ARB responsiveness in the MAU group. We conclude that tryptophan and/or kynurenine could play an important role in diabetic nephropathy and can be used to evaluate the response of ARB treatment in macroalbuminuria patients.Despite the mechanism remaining obscured, extensive albuminuria may be associated with lower levels of plasma Trp (≤46.75 μmol/L) and a higher ratio of kynurenine versus tryptophan (KTR ≥ 68.5 × 10


Hypertension is 1 of the major global public health challenges, which means that patients with hypertension need more measures to control their blood pressure. Currently, smart phones and applications are developing rapidly, and mobile health applications are used to manage hypertension, but evidences related to effectiveness are limited.The purpose was to assess the impact of m-Health apps on blood pressure control, medication adherence.480 participants were randomly assigned to the intervention and control groups. The intervention group used the “Yan Fu” app to manage their blood pressure, and the control group did not use any m-Health apps. The outcomes were changes in blood pressure, the percentage of participants with their blood pressure under control and medication adherence.P > .05). Participants in the 2 groups all had lower systolic blood pressure and diastolic blood pressure than they did at baseline, and the intervention group demonstrated a significantly greater systolic blood pressure and diastolic blood pressure reduction than the control group (P < .05). Additionally, the percentage of participants with controlled blood pressure was higher in the intervention group (P < .05). The medication adherence of the intervention group was much higher than that of the control group (P < .05).At the end of the study, the baseline characteristics between the 2 groups had no statistically differences (M-Health apps are effective for hypertension management, it can favor the medication adherence and blood pressure control. Perhaps m-Health apps can be promoted in the blood pressure control.Trial Registration: This study was registered in the Chinese Clinical Trial Registry under the number ChiCTR-IOR-17012069. Many patients don’t control their blood pressure well because of poor medication adherence, therapeutic inertia and lack of patient engagement.Unfortunately, traditional hypertension management measurements are less efficient because of the barriers of communication between physicians and patients and a lack of detailed management. The Healthy China 2020 Strategic Research Report indicates that we need to transform our medical model. Mobile-Health is a new health mode recently. It can overcome the disadvantages of the traditional medical mode. Nowadays many applications based on mobile health are applied to the hypertension management. The functions of these apps are hypertension education, monitoring blood pressure and tools to promote medication adherence. However, the effectiveness of mobile health applications is not clear. We need to explore the effectiveness of mobile health applications on hypertension management.Hypertension is a leading risk factor for cardiovascular and cerebrovascular diseases.22.1This study was a multicenter, randomized, controlled trial. This clinical trial was approved by the Ethics Committee of the Second Affiliated Hospital of Chongqing Medical University. This clinical trial was registered in the Chinese Clinical Trial Registry under the number ChiCTR-IOR-17012069. Informed consent was obtained from each patient and the study protocol conforms to the ethical guidelines of the 1975 Declaration of Helsinki as reflected in a priori approval by the institution's human research committee.The trial was carried out in 38 hospitals in Chongqing. All the investigators in charge of the study underwent standard training. Patients aged 18 to 79 diagnosed with primary hypertension according to the diagnostic criteria in the 2010 Chinese Guidelines for Hypertension Prevention and Treatment were recruited. A detailed list of the inclusion and exclusion criteria is shown in Table 2.2The participants in the intervention group downloaded the “Yan Fu” app and registered with their real name. The basic functions of the app are shown in Table 2.32.3.1The primary outcomes of this clinical trial were systolic blood pressure (SBP) and diastolic blood pressure (DBP) changes in all participants. The mean SBP and DBP at the baseline and end of this trial were calculated from the first and last 3 days’ BP respectively. The other outcome was the change in percentage of participants in the 2 groups with controlled blood pressure. According to the 2010 Guidelines for Hypertension Prevention and Treatment in China, hypertensive patients with chronic kidney disease or diabetes should have a blood pressure under 130/80. Patients with hypertension who are aged 65 years or older should have a target blood pressure of less than 150/90, and other general patients should have a target blood pressure of less than 140/90. Only both the diastolic and SBP reach the set standards, the blood pressure is categorized as controlled.2.3.2 MMS-8 score less than 6 was categorized as low adherence; a score of 6–8 was categorized as medium adherence, and a score of 8 was categorized as high adherence. The details of the MMS-8 scores are shown in Table The Modified Morisky Scale 8 (MMS-8), which was comprised of 8 questions, was used to measure medication adherence.2.4t tests were used to compare the 2 samples. The qualitative findings of the study are described using frequency and percentage frequency. Chi-squared test were used to compare the qualitative datas of the trial between the 2 groups. The MMS-8 scores for medication adherence were measured via a nonparametric Wilcoxon signed-rank test. P < .05 was considered to be statistically significant.SPSS 24.0 statistical software was used for data analysis. Quantitative datas fitted normal distribution were described using the mean and standard deviation, and Student 33.1From November 2017 to November 2018,480 participants were enrolled. At last,443 participants completed trial, and 37 participants lost to follow up, of which 7 were out of contact and 30 withdrew from our study. There were 218 participants in the control group (Group A) and 225 participants in the intervention group (Group B) The baseline characteristics of the 2 groups are shown in Table 3.2P = .00. Significant differences were also observed in the mean decreases of DBP between the intervention group (-7.04 ± 6.135mm Hg) and the control group  and the control group (-5.92 ± 6.945 mm Hg), P = .00) (Table P = .011)  Table . The int3.3At 6th month, The medication adherence were both improved in the 2 groupsTable . 8 parti4 But few m-health apps have been tested in clinical trials, so the effectiveness of the apps in hypertension lacks reliable datas. A systematic review in 2012 analyzed 147 m-health apps which targeted medication adherence, the results showed that there were no effective data to prove that these apps could improve medication adherence. Although there had some studies exploring the effectiveness of apps. Kim et al evaluated the use of a wireless self-monitoring program which had functions of reminders for monitoring, information about the disease condition, and general health behavior recommendations, results showed that the wireless self-monitoring program could improve patients’ behaviors and blood control, but no differences were observed with respect to medication adherence. MedISAFE-BP trial is a randomized trial for Americans to evaluate the effect of m-health apps. Morawski et al found that MedISAFE-BP app could help blood pressure control and improve medication adherence, but the follow-up period was only 12 weeks. Jha et al carried out a multicenter,cluster randomised,12-month, controlled trial to expolre the effectiveness of mWellcare in India, the conclusion was that mWellcare was effective for blood pressure control. Also, a clinical trial in Iran showed that BPMAP-APP was good for blood pressure control and medication adherence. Above all, we could know that there were not enough datas to prove the effectiveness of apps for hypertension, also some clinical trials had different views. Trials about Chinese was little, we know that there are different characteristics and race diversities between Chinese and other countries, so we can’t extend the conclusion that apps are effective for blood pressure control and medication adherence to Chinese directly. Our trial was a multicenter, randomized, controlled study for Chinese. In this trial, participants with primary hypertension who used the “Yan Fu” app had significantly greater reductions in both SBP and DBP than participants in the control group. The intervention group also had a higher percentage of participants with controlled blood pressure than the control group, which meant that the “Yan Fu” app was effective for hypertension management. Also, from the results we could conclude that the use of the app can improve medication adherence. We analyzed that the app could help control blood pressure mainly through improving medication adherence. Actually 1 of the reasons why the rate of blood pressure control is low can be attributed to low medication adherence. Maybe the reason of medication nonadherence can be divided into unintentional or intentional, though the cause of medication nonadherence varies among patients. Unintentional nonadherence involves failing to do for some reasons such as forgetting. The “YanFu” app have the functions of reminder, monitoring blood pressure,counseling,education so that users could remember to take medicine in time and pay more attention to the disease. In our trial the participants monitored blood pressure with home blood pressure monitors, which could minimize the “white-coat effect” of artificially elevated blood pressure in clinic compared to previous hypertension trials. Also, Studies have shown that a 5 mm Hg reduction in SBP could cause clinically meaningful decreases in the incidence of stroke and coronary heart diseases. So maybe we could extend the follow-up period to explore whether apps can reduce the disability rate and mortality of hypertension.Hypertension is a growing public health problem worldwide, the rate of blood pressure control is still unsatisfactory. Many m-health applications are applied to the management of hypertension, The developers claim apps can improve the medication adherence and control the blood pressure. Some researches show that there may be as many as 1.7 billion mhealth users globally by 2018.5There were several limitations:(1)It was difficult to observe the effect of the smartphone application on long-term outcomes such as major adverse cardiac and cerebrovascular events and lead to discrepancies in results because of the follow-up period was too short;(2)the measurement of medication adherence was too subjective which may impact the reliability of the results.6The use of m-Health apps could help to reduce blood pressure and improve blood pressure control and medication adherence, which can play an important role in reducing the economic and social burden of hypertension in humans. In the future, we may promote the use of m-Health applications to manage hypertension and even other chronic diseases.The application and the sphygmomanometers was provided by Shanghai O2O Care Company for free. We thank Xuejun Wang who is the president of the company, the APP study group which was constituted by 38 hospitals in Chongqing and the patients. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.Article drafting: Ke Gong, Yu-Ling Yan, Qiang She.Collaborators: Zhong-lin Xu, Guang-yan Mei, Hui Zhang, Yin-pin Zhou, Chun-hui Hou, Ting-rong Liu, Hong-dong Xia, Fang-qiong Li, Yong-yue Tian, Xue-mei Liao, Ze-hui Ao, Xiao-hua Pang, Wei Zhang, Xiao-ke Wang, Song-tao Zhang, Zhen-yun Wu, Dong Ma, Qiang Li, Chun-lin Xiong, Yue-long Yuan, Jun-lan Li, Qing-bin Liao, Shi-quan Fu, Ming-chen Li, Chang-qing Yu, Wen-li Wu, Chun Yang, Jun Chen, Jing Chen, He-ping Qin, Hong-bin Cheng, Heng-hua Dai, Sha-sha Zeng, Hong-jun Liu, Feng Yan, Qing Zhang, Fang He.Data collection and analysis: Ke Gong, Yu-Ling Yan, Yue Han, Ya Zou, Xin-yu Zou, Hong Huang, APP Study Group, Qiang She.Study design: Ke Gong, Yu Li, Jun Du, Jing Wang, Qiang She.


Several studies had suggested that complex body stature could be a risk factor of hypertension.  We aim to correlate body mass index (BMI), waist-hip ratio (WHR), and waist-height ratio (WHtR) of rural dwellers in Afikpo community, Ebonyi State, Nigeria, with blood pressure parameters. Furthermore, we aim to ascertain how each of the anthropometric variables affects blood pressure in men and women, respectively.  A sample of 400  adults aged 18–89 years were selected for the correlation cross-sectional study. Data for weight, height, waist, and hip circumferences were collected by means of anthropometric measurement protocol with the aid of a calibrated flexible tape and health scale and mercury sphygmomanometer for measurement of blood pressure. A participant was classified as being hypertensive if systolic blood pressure (SBP) was >140 mmHg and diastolic blood pressure (DBP) >90 mmHg. Pulse pressure was recorded as the numeric difference of SBP and DBP. P < 0.01). The prevalence of hypertension failed to correlate with sex among participants in the study . Variation in SBP and DBP of both sexes was dependent on BMI, WHtR, and waist and hip circumference, but not on WHR. The SBP of both sexes and female pulse pressure did correlate with age (P < 0.001). Waist circumference, BMI, and WHtR correctly predicted the variations in SBP, DBP, and pulse pressure.  The result revealed that male BMI and WHR were higher than those of females while female WHtR was higher than that of males ( The strength of association of BMI, WHtR, and waist girth with SBP and DBP of both sexes was robust and similar, but inconsistent with WHR. Thus, a simple estimation of the trio-anthropometric predictors could serve as a means for routine check or preliminary diagnosis of a patient with hypertension. The skirmish with hypertension and third world health challenges has been one of the foremost global concerns. The symptomatic management of high blood pressure in most developing nations without clinical knowledge has worsened the identification of its causes thereby increasing the prevalence of hypertension especially, in sub-Saharan region of Africa. Its complications constitute approximately 25% of emergency medical admissions in urban hospitals in Nigeria –4. PulsePrevious studies have investigated extensively the systematic reviews of the various prevalence studies of hypertension in rural and urban Nigeria , 9. ThesGiven the importance and role of anthropometric features in predicting and controlling hypertension in various Nigerian populations , 9, it iA sample of 400 subjects  were selected for the study. A convenience sampling technique was adopted specifically for the purpose of the quantitative study which gives a 5% margin of error and 95% level of confidence and accounts for subjects that are more readily accessible in the population. Subjects involved in this cross-sectional design were rural dwellers of the Afikpo community, Ebonyi State, Nigeria (age range: 18–89 years). A limited number of rural dwellers in our locality seek medical checkups. Therefore, those who showed no signs of ill-health and go about their routine activities were adjudged to be healthy. A town crier announced the aims and objectives of the study to the rural dwellers using our local dialect and assembled them at the village square for blood pressure and anthropometric data collection. The study was considered and approved by the ethics committee of the Alex Ekwueme Federal University Ndufu Alike. Only those who gave informed verbal consent and who showed neither signs of ill-health nor use of hypertensive drugs were allowed to participate in this study.2 (kg/m2), WHR was calculated as waist girth/hip girth while WHtR was calculated as waist girth/height. The systolic blood pressure (SBP) and diastolic blood pressure (DBP) of each participant were measured using a portable digital mercury sphygmomanometer . The subject sat in an upright position on a chair with the feet on the floor and arm of interest resting on a table to enable the elbow placed at the heart level. A cuff was tied round the arm slightly above the medial and lateral epicondyle, making sure the inflatable part of the cuff surround 80% of the arm on bare skin. The stethoscope was placed on the cubital fossa and the readings of both the systolic and diastolic pressure were taken. Pulse pressure was recorded as the numeric difference of SBP and DBP. The authors were actively involved during data collection together with the trained research assistants, which included some nurses of the rural health posts.Standard anthropometric measurement protocol was adopted for this study. Weight and height were measured with the aid of a health scale (model RGZ-160). The subject was made to stand still without support, with their weight evenly distributed on the health scale, looking at the Frankfurt plane, while the weight and height were recorded. Weight and height were recorded to the nearest 0.1 kg and 0.1 m, respectively . The wait-test . A chi-square test was performed to test the null hypothesis that the prevalence of hypertension does not depend on sex. Thereafter, a correlation between blood pressure and anthropometric parameters was analyzed using Pearson's Product Moment Correlation. Since the strength of association of BMI, WHtR, and waist circumference with the blood pressure parameters of both sexes was robust and similar as shown in Descriptive statistics of male and female anthropometric and blood pressure parameters of the participants were carried out, and the significance of the mean difference between men and women was assessed by two-sample The statistical analysis of this study is shown in Tables 1P < 0.05). The mean difference of SBP, DBP, and pulse pressure in both sexes was not significant (P < 0.05).χ2 = 0.567; P < 0.05).P < 0.001).  SBP = 150.399–0.261 (BMI)–0.558 (waist girth)–0.018 (WHtR).  DBP = 68.946 + 0.247 (BMI) + 0.184 (waist girth)–0.031 (WHtR).Male prediction equations:  SBP = 130.791–0.163 (BMI)–0.495 (Waist girth) + 0.823 (WHtR).  DBP = 76.714 + 0.131 (BMI)–0.519 (Waist girth) + 0.840 (WHtR).Female prediction equations:SBP and DBP of both sexes are predictable with the following equations:The regression analysis  shows thP < 0.05).Hypertension  in cardiovascular disorders is an independent predictor of mortality. Indeed, it is often not detected on time and thereby described as a “silent killer” , 15. TheNotably, the incidence of male or female hypertension was 26% or 22%, respectively, using a blood pressure benchmark of 140/90 mmHg. Although the difference was not statistically significant, it was lower when compared with the results of several studies . The reaUltimately, elevation in SBP alone leads to an increase in the value of pulse pressure, and the amount of pressure in the arteries when the heart contracts. With aging, there is a reduction in the quantity and elasticity of elastic fibres in the arterial wall leading to arterial stiffness and loss of arterial adjustment to changes in heart stroke volume –19. ArdeThe study established a relationship between body stature and blood pressure. Similarly, the authors in –22 reporConversely, previous authors –28 stateFurthermore, the study established a prediction equation for male and female pulse pressure, using the trio-anthropometric parameters. The trio-anthropometric parameters could predict 49% and 74% pulse pressure of the male and female participants, respectively. It implied that the variation in male and female pulse pressure might depend on the interactions of BMI, WG, and WHtR. This may be largely due to susceptibility of blood pressure variables; SBP and female pulse pressure to age and body stature and by extension justifies the consideration of a gender factor in the regression analysis.We ensured that the research assistants recruited in this study were trained adequately, before embarking on the study and also anthropometric data were sourced by repeated measurements using a standard anthropometric protocol. The sample size adopted for the population cross-sectional study was setback due to the withdrawal and noncompliance of some participants, especially, females at some stages of the study, because the available facility provided limited privacy. Furthermore, a limited number of rural dwellers in our locality seek medical checkups. Therefore, those who showed no signs of ill-health and go about their routine activities were adjudged to be healthy. Although the study did not consider the dietary intake and physical activities of each of the participants, it excluded the impact of the upgrade of lifestyles, ethnicity, and environment, since they are predominantly farmers and consume locally made dry gin as a beverage and stable agricultural products. These factors no doubt are indicators for the incident of hypertension in previous studies , 30. AgaThe study provided a clear understanding of how appreciable increment in BMI, WG, and WHtR could lead to hypertension and variation in SBP, DBP, and pulse pressure, using correlation base analysis. Precisely, it revealed that an appreciable increase in female waist and hip girth with the advancement in age could increase pulse pressure and lead to hypertension. Furthermore, it suggested that SBP, DBP, and pulse pressure of both sexes were similar to each other and not mutually exclusive.A simple estimation of the trio-anthropometric parameters could serve as a preliminary diagnosis of a patient with hypertension. However, further study is urgently needed to understand how other indicators of hypertension interact with body stature and possibly facilitate a model of intervention. It will add to available means of a routine check of hypertension and reduce significantly the prevalence of its associated mortality.


Numerous recent publications have explored Brain Computer Interfaces (BCI) systems as rehabilitation tools to help subacute and chronic stroke patients recover upper extremity movement. Recent work has shown that BCI therapy can lead to better outcomes than conventional therapy. BCI combined with other techniques such as Functional Electrical Stimulation (FES) and Virtual Reality (VR) allows to the user restore the neurological function by inducing the neural plasticity through improved real-time detection of motor imagery (MI) as patients perform therapy tasks.Fifty-one stroke patients with upper extremity hemiparesis were recruited for this study. All participants performed 25 sessions with the MI BCI and assessment visits to track the functional changes before and after the therapy.P < 0.001, reduction of the spasticity in the wrist and fingers assessed by Modified Ashworth Scale (MAS), ΔMAS-wrist = -0.72 points (SD = 0.83), P < 0.001, ΔMAS-fingers = -0.63 points (SD = 0.82), P < 0.001. Other significant improvements in the grasp ability were detected in the healthy hand. All these functional improvements achieved during the BCI therapy persisted 6 months after the therapy ended. Results also showed that patients with Motor Imagery accuracy (MI) above 80% increase 3.16 points more in the FMA than patients below this threshold . The functional improvement was not related with the stroke severity or with the stroke stage.The results of this study demonstrated a significant increase in the motor function of the paretic arm assessed by Fugl-Meyer Assessment (FMA-UE), ΔFMA-UE = 4.68 points, The BCI treatment used here was effective in promoting long lasting functional improvements in the upper extremity in stroke survivors with severe, moderate and mild impairment. This functional improvement can be explained by improved neuroplasticity in the central nervous system. Stroke is the second largest cause of death worldwide and one of the most common causes of disability . Stroke Hence, there is a need for improved approaches to support motor rehabilitation therapy for stroke patients, especially those in the chronic stages. Some approaches to support therapy have been gaining attention, such as robotic devices  or VirtuBrain Computer Interfaces (BCI) use neural activity to directly control external devices with real-time feedback. Some BCI systems synchronize neural activity with feedback devices to create closed-loop multi-modal feedback aimed at bolstering Hebbian plasticity and thereby helping to restore lost motor functions . NumerouThere are different methods to record brain function, but most commonly used tool in BCI systems is the electroencephalography (EEG), which has been employed to record the activity modulations associated with MI tasks. MI has been shown to activate the primary motor cortex (M1) and related motor areas and elicits Event Related Desynchronization (ERD) and Event Related Synchronization (ERS), which reflect power changes in the mu band. Several studies have shown that stroke patients can elicit ERD/ERS during MI of their paralyzed hand and during passive movement provided by robotic assistive devices . FurtherBCI systems can be combined with different types of external devices to assist the execution and learning of movements. In the approach for movement restoration, stroke survivors perform MI exercises while wearing an EEG cap. The decoded brain oscillations can be used to move a VR avatar and/or trigger another feedback mechanism to reproduce the imagined movement with the paretic limb, such as a functional electrical stimulation (FES). Hence, rewarding feedback only occurs if the patient imagines the desired movement. This feedback loop is most effective with “closed-loop” feedback, meaning that feedback is presented in real-time, ideally through informative, clear feedback that supports effective co-adaptation between the end-user and the system.The combination of MI-based BCIs with FES or VR has shown promising results in stroke survivors. The FES combined with other therapies seems effective for upper limb motor rehabilitation after stroke , and couThe objective of this study is to explore the effectiveness of a specific approach toward BCI therapy to help patients with impaired upper extremity movement due to stroke. The BCI system used in this study is called recoveriX , 2017. TThe study was approved by the Ethikkommission des Landes Oberösterreich in Austria (#D-42-17) and each participant provided written informed consent before the pre-assessment. No adverse events were reported during the entire study period. The following inclusion criteria were applied to all participants: (1) able to understand written and spoken instructions, (2) stable neurological status, (3) willing to participate in the study and to understand and sign the informed consent, (4) able to attend recording sessions. The following inclusion were also applied to participants with stroke: (1) residual hemiparesis; (2) the stroke occurred at least 4 days before the first assessment; and (3) functional restriction in the upper extremities.Each participant received 3 months of BCI-supported MI training with 2 weekly sessions, 25 sessions in total. Two pre-assessments (Pre1 and Pre2) and three post-assessments  were performed by two certified physiotherapists and were evaluated by the research team. Pre1 and Pre2 were scheduled 1 month and a few days before the intervention (respectively), while Post1, Post2, and Post3 were carried out a few days, 1 month, and 6 months after the intervention (respectively) see .SD = 16.65). The time since the stroke ranged from 3 to 377 months . The participants were classified in four groups based on their stroke diagnosis: Cortical, Subcortical, Cortical + Subcortical and Unknown. The most common type of stroke was Subcortical with 20 patients (39.2%), followed by Cortical + Subcortical with 12 patients (23.5%) and Cortical with 5 patients (9.8%). 14 patients where categorized as Unknown (27.5%).Fifty-one stroke patients were enrolled on this study, 28 males and 23 females. The mean age was 60.52 years (Forty-five patients were in the chronic phase (88.2%), and six were in the subacute phase (11.8%). Thirty-four patients had a stroke in the right hemisphere (66.7%), and the stroke was in the left hemisphere in 17 patients (33.3%). A series of functional and behavioral scales were administered in pre- and post-assessments. The primary outcome measure was the upper extremity section of the Fugl-Meyer assessment . The score reflects impairment in upper limb functions, with lower scores corresponding to greater impairment, and is often used to assess the damage resulting from stroke and progress during therapy . The graAll patients answered a Self-Rated questionnaire (SRQ) with five parts: Pain (0–70 points); Function (0–70 points); Memory and thinking (0–70 points); Ability to be mobile at home and in the community (0–90 points); and Stroke recovery (0–10 points). Each of these parts has descriptions of different tasks. The patient estimates the difficulty in performing the task on a scale from 0–10, where 0 means “unable to do,” and 10 means “no difficulty.” The scale is different for the Pain part, where 0 means “none” and 10 means “extreme.”Patients were seated in a comfortable chair in front of an LCD screen with both arms resting on a desk. Patients wore EEG caps with 16 active electrodes . EEG electrode positions were FC5, FC1, FCz, FC2, FC6, C5, C3, C1, Cz, C2, C4, C6, CP5, CP1, CP2, and CP6 according to the international 10/20 system. A reference electrode was placed on the right earlobe and a ground electrode at FPz see .One pair of FES pads were placed on the skin over both the left and right wrist extensors. The two FES devices  were set to a frequency of 50 Hz and a rectangular pulse width of 300 μs. The stimulation amplitude (in mA) was adjusted to find the optimal movement produced by electrical stimulation in both the healthy and affected limbs without inducing pain or spasms.All participants were instructed to imagine the dorsiflexion wrist movement according to the system indications. This is a type of mental imagery (MI) task. One session was composed by 240 MI repetitions on both hands, divided in 3 runs of 80 trials. Each session lasted about one hour, including time for preparation and cleaning.The MI tasks were presented in pseudo random order with randomized inter-trial intervals. X. This matrix is a set of spatial patterns that may reflect regional cortical activation during hand MI. The decomposition of a trial is written as Z = WX. This transformation projects the variance of X onto the rows of Z and results in 16 new time series. The columns of A = W–1 are a set of CSPs and can be considered as time-invariant EEG distributions. The variance for left trials is largest in the first row of Z and decreases with the subsequent rows. The opposite occurs in a trial with right trials. The variances were extracted as reliable features of the newly calculated 16 time series for the binary classification (left vs. right).EEG signals were sent to a biosignal amplifier and were bandpass filtered (4th order Butterworth filter) between 8 and 30 Hz. Then, common spatial patterns (CSP) were applied to transform the data to a new matrix with minimal variance of one class and maximal variance of the other class . Each clXT, only the first and last two rows  of W were used to process new input X. Then, the variance (VARp) of the times series was calculated for a time window T. After normalizing and log-transforming, four feature vectors were obtained via Eq. 1.According to Mueller-Gerking’s work, the optimal number of CSPs should be four  . Using aA linear discriminant analysis (LDA) classified each trial as either left or right MI. When the input signals were correctly classified according to the assigned task, the feedback devices were triggered. This online classification and control of the FES and avatar were updated every 25 ms.We estimated offline classification accuracy via a 10-fold cross validation. This refers to partitioning a sample of movements into 10 complementary subsets and validating the analysis on one subset  and training the CSPs and classifier on the other subsets .The accuracy was calculated  for all trials in the testing pool within a 4.5 s time window beginning 1.5 s after the attention beep and ending with the end of the trial. For each step and each trial, the classification result is either 100 or 0%. The accuracy of all trials of the test pool is then averaged for each single step, resulting in accuracy levels ranging between 0 and 100%. After averaging all ten repetitions of the cross validation, the maximum value during the feedback phase was noted as the session accuracy.The software used for the statistical analysis was MATLAB R2017b. We designated the mean of Pre1 and Pre2 as the baseline value for each outcome measure [PRE = (Pre1 + Pre2)/2]. Post-assessment was the outcome measure after completion of the 25 training sessions. The primary and secondary outcomes were statistically analyzed after a normal distribution was determined with the Shapiro-Wilk test. The significance threshold was set to α = 0.05. The statistical test was chosen according to the normality of the sample, the homogeneity of variance  and sample size. Descriptive statistics will be showed as mean and the standard deviation (SD), or the median with the inter-quartile rate (IQR) of 0.25 and 0.75.t-test or a Wilcoxon signed rank test was used to investigate the outcome of changes between two different assessments in the same group of patients. We used the unpaired t-test or Mann-Whitney U test to compare the results of two different groups based on the mean accuracy obtained during the BCI training.A two-tailed paired sample For multiple comparisons, p-values were corrected using the False Discovery Rate (FDR) described by t-test or Wilcoxon signed rank test) between PRE values and Post1 values. The second step was analyzing the long-term effects 1 month after therapy by comparing Post1 vs. Post2, and 6 months after the therapy by comparing Post1 vs. Post3.First, we analyzed the functional improvement after the BCI therapy using paired comparison . The functional baseline in the upper extremity assessed by the FMA-UE was 19 points [9.63–33.88] on a scale with a maximum score of 66 points. The Wilcoxon signed rank test shows that there is a significant improvement in FMA-UE after the therapy . Changes after therapy were not significant ΔFMA-LE = 0 [−0.38 to 1], P < 0.001, and the mean delta was 6.29 points (SD = 7.25). The basal values of the BBT of the paretic hand was 0 blocks [0–6], and this scale did not show significant changes in the BBT after the therapy, ΔBBT-paretic = 0 [0–1.5], P = 0.129.The values of the BBT in the healthy hand before the therapy was 51.25 blocks [43–64]. This scale showed a significant change after the therapy, ΔBBT-healthy = 6.25 [1.5–9], P = 0.010, and the mean change was −2.05 s (SD = 3.5). In the paretic hand, only 9 patients could perform the 9HPT test at the beginning, and the mean needed time to do the test was 190 s [154.13–364.59]. There were no significant changes after the therapy, Δ9HPT-paretic = −52.00 [−172.01 to 26.5], P = 1.000.Patients needed 23.00 s on average [19.79–28.5] to perform the 9HPT with the healthy hand before the therapy. After the therapy, there was a significant reduction of the time needed to perform the test, Δ9HPT-healthy = −1.55 [−3.5 to −0.43], P < 0.001, and the mean delta was −0.63 (SD = 0.82), and the wrist, ΔMAS-wrist = −0.5 [−1.44 to 0], P < 0.001, and the mean change was −0.72 (SD = 0.83).Before the therapy, the patients reported some degrees of spasticity with 2.5 points [0.63–3.5] in the wrist and 2.5 points [1– 3.5] in the fingers. After the therapy, the MAS scale showed a significant reduction of the spasticity in the fingers, ΔMAS-fingers = −0.5 [−1 to 0], P = 0.163. In the paretic hand, the tremor before the therapy was very high, 12 points [6–12], and the change after the therapy was not significant, ΔFTRS-Paretic = 0 [−1.5 to 0], P = 0.090.The degree of tremor did not show a significant change using the FTRS. The tremor in the healthy hand before the therapy was very low, 0 points [0–0.5], and consequently the change after the therapy was not significant, ΔFTRS-Healthy = 0 [0–0], P = 0.090, ΔTPDT-healthy-index = −0.5 [−1 to 0], P = 0.057. The sensitivity in the paretic thumb before therapy was 4.5 mm [4–5.5], and was 3.75 mm [3–5] in the index of the paretic hand. The changes on this scale were also not significant for the paretic hand, ΔTPDT-paretic-thumb = −1 mm [−2 to −0.25], P = 0.090, ΔTPDT-paretic-index = 0 mm [−1 to 1], P = 1.000.The sensory acuity in the healthy hand before the therapy was 3.5 mm [2.88–4] in the thumb, and 3.5 mm [3–4] in the index. The changes after therapy were not significant in the healthy hand, ΔTPDT-healthy-thumb = −0.5 [−1 to 0], P = 0.083.The baseline values of the BI were 90 points [70–95] up to 100. The BI showed no significant changes after the therapy, ΔBI = 0 [0–5], P = 1.000. The other cognitive scale, SCWT, had the following baseline values: 73.75 words [54–100.5] for the Word card; 73 words [59–94] for the Color card; and 22.25 words [10.5–34.5] for the Color-Word card. No significant changes were detected on this test, ΔWord = 4.25 words [−2 to 10], P = 1.000, ΔColor = 3.75 words [1–8] P = 0.768, and ΔColor_Word = 6.75 words [2–8], P = 0.083.The baseline cognitive assessment using MOCA was 27 points [21.5–28], and the values after the therapy did not change significantly ΔMOCA = 2 points [1–5], P = 1.000, ΔFunction = 0 points [−0.38 to 4.13] with P = 1.000, ΔMemory = 0 points [−3–5.25] with P = 1.000, ΔMobility = 1 point [−1.38 to 7] with P = 0.768 and ΔRecovery = 1 point [0–2] with P = 0.090.Finally, the baseline values of the SRQ were: Pain = 30.5 points [19.75–37.13], Function = 4 points [0–13.88], Memory = 60.5 points [45.75–70], Mobility = 71 points [38.38–80], Recovery = 5 points [4.13–6.38]. No significant changes were detected on this questionnaire after the therapy; ΔPain = 0 points [−7.28 to 3.5] with The analysis of the long-term effects based on comparisons between the Post2 and Post3 assessments did not show significant results. P = 1.000. The changes 6 months after the therapy are also not significant, 1 point [−3 to 2], P = 1.000. The primary measure, FMA-UE, did not show significant changes in Post2. The median change between Post1 and Post2 was 0 points [−2 to −-2], SD = 5.51). For patients that were below 80% median MI accuracy, the median improvement in FMA-UE was 2 points [0.5–6.38], and the mean was 2.93 points (SD = 3.62).Patients with median MI accuracy above of 80% increased their FMA-UE score by 6.5 points [3–12], and the mean was 6.97 points , P = 0.003] than the other patients. The unpaired First, we present the improvement within groups to assess whether all groups improved significantly after the BCI therapy. SD = 5.18), P = 0.006. The delta between Post1 and Post2 was 0 points [−1.5 to 1], P = 1.000, and the delta between Post1 and Post3 was 1 point [−2 to 2], P = 1.000.In the Severe group (35 patients), the PRE vs. Post1 median change was 2 points [0.5–8], and the mean change was 3.70 points . The change between Post1 and Post2 was 0 points [−1.5 to 2], P = 1.000, and the delta between Post1 and Post3 was −2 points [−8 to 0.75], P = 1.000.The Moderate group (9 patients) showed a significant improvement between PRE and Post1 of 7.5 points [5.13–9.75], P = 0.015, and the mean improvement was 5.29 points (SD = 2.41). The median change between Post1 and Post2 was −2 points [−3 to 1.75], P = 1.000, and the delta between Post1 and Post3 was 1 point [−3 to 5.25], P = 1.000.Finally, the Mild group (7 patients) also showed significant differences between PRE and Post1. The median difference was 6 points [4.13–6.75], F = 3.025 and P = 0.058.The comparison between groups using a One-Way ANOVA with the data PRE vs. Post1 showed non-significant differences between groups, The objective of this study was to analyze the effects of the MI BCI therapy for upper extremity motor rehabilitation in stroke survivors. Fifty-one stroke patients with hemiparesis in the upper extremity completed the study and were categorized according to their stroke location, level of impairment determined by the baseline FMA-UE, and time since stroke.SD = 4.92). This mean change is above the Clinically Important Difference (CID) (SD = 4.30). 5 patients decreased at least 1 point in FMA score, and the mean decrease in this group was −2.9 points (SD = 2.04). The FMA score did not change in the remaining 3 patients.The primary measure, FMA-UE, assessed upper limb functionality and showed that patients improved upper extremity motor function significantly by 4.68 points (ce (CID) . These BThis motor improvement was preceded by the reduction of the spasticity in the fingers and the wrist. Usually, the patients verbally reported a reduction of the spasticity in the affected hand during the therapy. This fact seems be related with performance in the other motor tests like BBT and 9HPT. Another important finding is that the spasticity did not increase some months after therapy ended. This will be discussed later.The spasticity reduction and the significant improvement in the upper extremity function may explain the improvement in grasp ability. Thirty five patients (68.6%) improved their BBT scores with the healthy hand, and 13 (25.5%) improved with the paretic hand. Two patients could not perform the BBT before the therapy due to the severity of the motor impairment, but both patients could move at least one block after the therapy. In the 9HPT, 38 out of 49 patients (77.5%) improved coordination and speed in the healthy hand. Performing this test with the paretic hand was challenging for most patients. Only 9 patients could perform the 9HPT before the therapy, and 8 of them reduced the needed time to complete the 9HPT. One patient was unable to perform the 9HPT with the paretic hand prior to therapy, but after the therapy, this patient could complete this test in 324 s.As mentioned above, these results show some significant improvements in the performance of the healthy hand. It is well known that coordinated movements require interactions between two hemispheres and primary motor areas. The reduction of the time in the 9HPT of the healthy hand, and the improvement in the BBT, could result from improved inter-hemisphere interactions. Other studies suggest that bimanual coordination between paretic and non-paretic hands is highly associated with motor recovery .Nevertheless, the motor system improvements were not evident in other scales. The FMA improvements should correspond to increases in scores for daily living activities in Post1, Post2, and Post3. This expected functional improvement was not apparent in the Post1 or in the long-term analysis of BI, probably because the roof effect of this scale. The BI score decreased in 3 patients, while 23 patients reported positive changes in the BI after the therapy and 25 patients did not show changes in this parameter. Similarly, motor changes are usually accompanied by changes in the sensory system, but sensitivity did not change significantly. After alpha correction, the TPDT changes are not significant. All these inconsistent results (no improvement in daily living activities or sensitivity) might be explained with our selection of scales in this study. Maybe the measure of the daily living activities or the sensitivity is not accurate enough. This could explain who only 26 patients could perform the TPDT in the paretic hand.The feedback that patients received was related to the maximum MI accuracy. Patients that were more focused during the therapy might be able to attain better MI accuracy and use the BCI system more effectively. We analyzed the relation between BCI performance and the functional improvement assessed by the primary measure, FMA-UE. One of the patient’s main tasks is learn how perform MI most effectively, and the role of the healthy hand may be important. Patients might relearn MI by imagining or performing the movement with the healthy side and applying the same mental strategies in the paretic side. This approach may be most effective when the feedback is equally applied to both sides.We also analyzed the functional improvement based on stroke severity, shown in Functional improvement was not correlated with stroke stage either. Patients in the chronic stage could improve motor function in the paretic side, which is not commonly accepted. These results support other work indicating that a BCI can play an important role in cortical reorganization that underlies functional improvement . The impSome limitations and opportunities for future research should be mentioned. First, this study did not employ a control group, which limits direct comparisons between the approach used here and conventional rehabilitation approaches. Randomized clinical trials that consider different treatment arms and compare BCI versus non-BCI therapies should further elucidate the best approaches to rehabilitation. Prior studies have already shown that BCI therapy can yield greater functional improvement than conventional therapy. The objective of this investigation was instead to explore the effects of the approach used here to assess whether results are similar to other studies and may have clinical value. Second, not all patients could perform all the tests both before and after the therapy. This limitation led to statistical analyses with a low sample size because we disregarded those subjects who could not do the test. Third, this study used the term “long-term,” but we have not yet explored effects beyond 6 months after therapy ends. Further research could explore whether the approach used here, and related approaches, yield benefits that persist even longer. Fourth, while we used a broad range of scales, different scales and assessment methods could yield different results. Fifth, emerging qEEG approaches  or othersebastian@gtec.at and CG, guger@gtec.at.The datasets generated for this article are not readily available because patients’ data need to be treated according to current data protection laws and ethical guidelines. Requests to access the datasets should be directed to MS-R, The studies involving human participants were reviewed and approved by the Ethikkommission des Landes Oberösterreich, Austria. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.MS-R and WC participated in the data acquisition, performed the analysis, and did the main contribution to the manuscript writing. RO supervised the whole process, data acquisition, analysis, and manuscript revision. NM participated to the data acquisition. TV and KK participated in the manuscript revision, supervised the whole process, and provided clinical input. BZA provided the scientific input and contributed to the manuscript writing. CG supervised the whole project and reviewed the manuscript. All authors contributed to the article and approved the submitted version.MS-R, WC, RO, and NM were employed at g.tec medical engineering. CG was CEO of g.tec medical engineering, who developed and sells the BCI system used on this study. The remaining 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. The reviewer YZ declared a past co-authorship with one of the authors BZA to the handling editor.