<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03840954</url>
  </required_header>
  <id_info>
    <org_study_id>20180460</org_study_id>
    <nct_id>NCT03840954</nct_id>
  </id_info>
  <brief_title>Effects of Neuromuscular Electrical Stimulation in Muscle Architecture and Functionality of Patients After Acute Stroke</brief_title>
  <official_title>Effects of Neuromuscular Electrical Stimulation in Muscle Architecture and Functionality of Patients After Acute Stroke</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Hospital de Clinicas de Porto Alegre</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Hospital de Clinicas de Porto Alegre</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Introduction: Stroke is a sudden illness, responsible for important neurological and&#xD;
      cognitive sequelae that can result in functional limitations and dependence. It is the&#xD;
      leading cause of neurological impairment in young adults and resting-related muscle loss is&#xD;
      one of the major factors involved. Early rehabilitation is essential for these patients and&#xD;
      neuromuscular electrical stimulation (NMES) has been identified as an intervention&#xD;
      alternative due to its known effects on the prevention of muscle loss in patients with&#xD;
      various pathologies. Objective: To evaluate the effects of NMES associated with conventional&#xD;
      physiotherapy compared to conventional physiotherapy on muscle thickness and functionality of&#xD;
      patients with acute stroke. Methodology: This is a randomized clinical trial, which will be&#xD;
      performed at the Emergency and Unit Unit of the Stroke of the Hospital de Clínicas of Porto&#xD;
      Alegre (HCPA). Patients with acute stroke, with up to 72 hours of hospital admission, who&#xD;
      present with lower limb force deficit due to the current stroke will be included. Patients&#xD;
      will be randomized into two groups: intervention group, who will receive the application of&#xD;
      NMES associated with conventional physiotherapy and control group, who will receive the&#xD;
      conventional physiotherapy of the HCPA. NMES training will be applied once a day (30 minutes&#xD;
      of application per session with an increase of five minutes each week and gradual reduction&#xD;
      in OFF time), five days a week until hospital discharge or up to a maximum of three weeks.&#xD;
      The following outcomes will be assessed before and after the intervention: quadriceps and&#xD;
      tibial thickness and quality of the quadriceps and tibialis anterior, muscle strength, stroke&#xD;
      severity, gait, functionality and disability.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Stroke is the leading cause of neurological impairment in young adults, and early&#xD;
      rehabilitation is essential for the recovery of these patients.&#xD;
&#xD;
      It is already known that muscle loss is one of the main factors responsible for functional&#xD;
      disability and dependence in stroke survivors, being observed already in the acute phase and&#xD;
      mainly in the lower limbs. The physiological mechanisms involved in stroke-related muscle&#xD;
      loss, such as muscle inactivity, denervation, malnutrition, inflammation and metabolic&#xD;
      disorders, among others have been reported in studies, but there is no consistent evidence&#xD;
      regarding effective therapies to avoid muscle loss.&#xD;
&#xD;
      The NMES is already widely used for the prevention of muscular loss in patients with various&#xD;
      pathologies. Studies have also reported the efficacy of NMES in patients with subacute or&#xD;
      chronic stroke. In patients with acute stroke, the literature is rather scarce. The&#xD;
      investigators are aware of only one study that evaluated the effects of NMES on muscle mass&#xD;
      loss, but the authors did not evaluate the effects of this intervention on the physical&#xD;
      performance or functionality of the patients. Thus, the investigators consider the importance&#xD;
      of further studies to know the effects of NMES on muscle loss in patients with acute stroke&#xD;
      and the need to evaluate the effects of NMES on the physical performance functionality of&#xD;
      these patients aiming at the possibility of offering an intervention option precocious and&#xD;
      effective for this population.&#xD;
&#xD;
      The objective of this study is to evaluate the effects of NMES associated with conventional&#xD;
      physiotherapy compared to conventional physiotherapy in the muscular architecture and&#xD;
      functionality of patients with acute stroke.&#xD;
&#xD;
      This is a randomized clinical trial in which the participants will be randomly divided into&#xD;
      experimental group (EG) and control group (CG), being evaluated before and after the&#xD;
      intervention.&#xD;
&#xD;
      The sample will be composed of hospitalized patients diagnosed with acute stroke at the&#xD;
      Hospital de Clínicas de Porto Alegre (HCPA).&#xD;
&#xD;
      The estimated sample is 70 patients (35 in each group). Waiting for a 0.5 cm difference in&#xD;
      muscle thickness between groups and a standard deviation of 0.68 and 2 of 0.80, with a&#xD;
      significance level of 5%, 80% power.&#xD;
&#xD;
      Randomization will be performed through data generated by a computer program that presents&#xD;
      the coded distribution. The sequence generation of the numbers to be randomized will be&#xD;
      performed by a researcher blind to the study - after selection of the patients according to&#xD;
      the eligibility criteria - keeping it confidential until the beginning of the intervention.&#xD;
&#xD;
      Data collect:&#xD;
&#xD;
      Socio-demographic data will be collected such as: age and sex; anthropometric variables:&#xD;
      weight, height and BMI; and clinical data: stroke region, side of hemiparesis, comorbidities,&#xD;
      complications during the hospitalization period (eg pneumonia, need for decompressive&#xD;
      craniectomy), functional condition prior to the current stroke, time to start physical&#xD;
      therapy, time to onset of NMES, total time of NMES, time to reach orthostasis and time to&#xD;
      start ambulation. These data will be obtained through the review of medical records and&#xD;
      interviews with patients or relatives.&#xD;
&#xD;
      Assessments: The evaluations described below will be performed within 72 hours of hospital&#xD;
      admission and repeated at hospital discharge or within 21 days.&#xD;
&#xD;
      Assessment of muscle architecture - The assessment of muscle thickness will be performed in&#xD;
      the femoral and tibial quadriceps muscles (TA). The images will be obtained by ultrasound&#xD;
      using the Portable Ultrasound System (Vivid i®, GE) with a linear arrangement probe (60mm,&#xD;
      7.5 MHz - Vivid i®, GE). The same researcher (who will be blinded for the interventions) will&#xD;
      do all the evaluations, which will be performed with the musculature at rest.&#xD;
&#xD;
      Muscle Strength Assessment: Manual Dynamometry, Medical Research Council (MRC)&#xD;
&#xD;
      Functional and Inability Assessment: Barthel's Index Modified&#xD;
&#xD;
      Walking assessment and functional capacity: Functional Ambulation Category (FAC)&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Not yet recruiting</last_known_status>
  <start_date type="Anticipated">August 30, 2019</start_date>
  <completion_date type="Anticipated">August 30, 2022</completion_date>
  <primary_completion_date type="Anticipated">May 30, 2022</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Double (Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Quadriceps muscle thickness</measure>
    <time_frame>three weeks</time_frame>
    <description>Evaluated by muscular echography (cm)</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Thickness of the anterior tibial muscle</measure>
    <time_frame>three weeks</time_frame>
    <description>Evaluated by muscular echography (cm)</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Functionality - Barthel Index for Activities of Daily Living</measure>
    <time_frame>three weeks</time_frame>
    <description>The score ranges from 0 to 100 points (90 to 100 - independent, 60 to 89 - slightly dependent, 40 to 59 - moderately dependent, 20 to 39 - severely dependent and less than 20 - totally dependent).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Muscle strength - Medical Research Council (MRC) Scale</measure>
    <time_frame>three weeks</time_frame>
    <description>The MRC score is obtained by evaluating 12 muscle groups in the upper extremities (wrist extensors, elbow flexors and abductors of the shoulder) and lower extremities (dorsal ankle flexors, knee extensors, and hip flexors). For each muscle group will be assigned a score between 0 (complete paralysis) and 5 (normal force), and the total score can vary between 0 up to 60 points.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Functional walking - Functional Ambulation Categories</measure>
    <time_frame>three weeks</time_frame>
    <description>Evaluates the degree of assistance required for ambulation. It distinguishes six categories for ambulation ability (1 to 3 - need for physical assistance during walking, 4 - requires only supervision and 5 and 6 - independent walking).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Dynamometry - Knee extension</measure>
    <time_frame>three weeks</time_frame>
    <description>Dynamometry (kg)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Dynamometry - ankle dorsiflexion</measure>
    <time_frame>three weeks</time_frame>
    <description>Dynamometry (kg)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Sit and stand up to 30 seconds</measure>
    <time_frame>three weeks</time_frame>
    <description>Assess the maximum number of times it is possible to get up and sit down in 30 seconds</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Modified Rankin Scale</measure>
    <time_frame>three weeks</time_frame>
    <description>Evaluates the degree of disability and dependence in daily life with a score of 0: without any symptom at 6: death</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>10-meter walking test</measure>
    <time_frame>three weeks</time_frame>
    <description>Evaluates gait speed and cadence</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">70</enrollment>
  <condition>Stroke, Acute</condition>
  <condition>Neuromuscular Electrical Stimulation</condition>
  <arm_group>
    <arm_group_label>Neuromuscular Electrical Stimulation</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>The experimental group will receive the application of NMES associated with conventional physiotherapy. After the NMES application, conventional physiotherapy will be performed. The exercises performed will be according to the patient's physical condition, and the conducts will always be performed seeking the maximum possible functional performance for the patient. The conducts adopted according to the standard routine of the HCPA stroke unit are: passive, active, assisted and / or active exercises; muscle stretching; selective hip extension; trunk stabilization training in sedestation; orthostasis training and walking training.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Group Control</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>The control group will only receive conventional physiotherapy, composed of the same exercises performed in the experimental group.</description>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Neuromuscular Electrical Stimulation</intervention_name>
    <description>The application of NMES will be performed with the patient positioned in the supine position in the bed. Self-adhesive electrodes will be positioned at the motor points of the quadriceps and anterior tibial muscles respectively. A symmetrical biphasic pulsed current with a frequency of 80 Hz, a pulse width of 500 μs and an intensity at the motor threshold will be applied up to the maximum tolerated by the patient. ON and OFF time and total session time will be used according to protocol with progressive increase of the total intervention time and reduction of OFF time of the NMES. The device used will be the Neurodyn II model, manufactured by IBRAMED.&#xD;
Patients will receive NMES for as long as they remain hospitalized or for up to 3 weeks.</description>
    <arm_group_label>Neuromuscular Electrical Stimulation</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Clinical diagnosis of ischemic or hemorrhagic stroke performed by a neurologist based&#xD;
             on clinical and neuroimaging characteristics;&#xD;
&#xD;
          -  To present motor sequelae in the lower limb due to stroke.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Previous motor deficits&#xD;
&#xD;
          -  Complete recovery of motor deficits before the initial evaluation;&#xD;
&#xD;
          -  Conditions that prevent neuromuscular electrical stimulation such as skin lesions at&#xD;
             the site of electrode placement, pacemaker and therapy intolerance.&#xD;
&#xD;
          -  Time greater than 72 hours since hospitalization.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>85 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Graciele Sbruzzi, doctor</last_name>
    <role>Study Director</role>
    <affiliation>Federal University of Rio Grande do Sul</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Graciele Sbruzzi, doctor</last_name>
    <phone>+55(51)33577334</phone>
    <email>gsbruzzi@hcpa.edu.br</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Débora Schmidt</last_name>
    <phone>+55(51)33577334</phone>
    <email>dschmidt@hcpa.edu.br</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>HCPA</name>
      <address>
        <city>Porto Alegre</city>
        <state>Rio Grande Do Sul</state>
        <zip>90035903</zip>
        <country>Brazil</country>
      </address>
    </facility>
    <contact>
      <last_name>Graciele Sbruzzi, Doctor</last_name>
      <phone>+55(51)33597334</phone>
      <email>gsbruzzi@hcpa.edu.br</email>
    </contact>
    <contact_backup>
      <last_name>Débora Schmidt</last_name>
      <phone>+55(51)33597334</phone>
      <email>dschmidt@hcpa.edu.br</email>
    </contact_backup>
  </location>
  <location_countries>
    <country>Brazil</country>
  </location_countries>
  <verification_date>June 2019</verification_date>
  <study_first_submitted>February 12, 2019</study_first_submitted>
  <study_first_submitted_qc>February 12, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">February 15, 2019</study_first_posted>
  <last_update_submitted>June 27, 2019</last_update_submitted>
  <last_update_submitted_qc>June 27, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">July 1, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Stroke</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03840954
org study id: 20180460
nct id: NCT03840954
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Introduction: Stroke is a sudden illness, responsible for important neurological and
      cognitive sequelae that can result in functional limitations and dependence. It is the
      leading cause of neurological impairment in young adults and resting-related muscle loss is
      one of the major factors involved. Early rehabilitation is essential for these patients and
      neuromuscular electrical stimulation (NMES) has been identified as an intervention
      alternative due to its known effects on the prevention of muscle loss in patients with
      various pathologies. Objective: To evaluate the effects of NMES associated with conventional
      physiotherapy compared to conventional physiotherapy on muscle thickness and functionality of
      patients with acute stroke. Methodology: This is a randomized clinical trial, which will be
      performed at the Emergency and Unit Unit of the Stroke of the Hospital de Clínicas of Porto
      Alegre (HCPA). Patients with acute stroke, with up to 72 hours of hospital admission, who
      present with lower limb force deficit due to the current stroke will be included. Patients
      will be randomized into two groups: intervention group, who will receive the application of
      NMES associated with conventional physiotherapy and control group, who will receive the
      conventional physiotherapy of the HCPA. NMES training will be applied once a day (30 minutes
      of application per session with an increase of five minutes each week and gradual reduction
      in OFF time), five days a week until hospital discharge or up to a maximum of three weeks.
      The following outcomes will be assessed before and after the intervention: quadriceps and
      tibial thickness and quality of the quadriceps and tibialis anterior, muscle strength, stroke
      severity, gait, functionality and disability.
Stroke is the leading cause of neurological impairment in young adults, and early
      rehabilitation is essential for the recovery of these patients.

      It is already known that muscle loss is one of the main factors responsible for functional
      disability and dependence in stroke survivors, being observed already in the acute phase and
      mainly in the lower limbs. The physiological mechanisms involved in stroke-related muscle
      loss, such as muscle inactivity, denervation, malnutrition, inflammation and metabolic
      disorders, among others have been reported in studies, but there is no consistent evidence
      regarding effective therapies to avoid muscle loss.

      The NMES is already widely used for the prevention of muscular loss in patients with various
      pathologies. Studies have also reported the efficacy of NMES in patients with subacute or
      chronic stroke. In patients with acute stroke, the literature is rather scarce. The
      investigators are aware of only one study that evaluated the effects of NMES on muscle mass
      loss, but the authors did not evaluate the effects of this intervention on the physical
      performance or functionality of the patients. Thus, the investigators consider the importance
      of further studies to know the effects of NMES on muscle loss in patients with acute stroke
      and the need to evaluate the effects of NMES on the physical performance functionality of
      these patients aiming at the possibility of offering an intervention option precocious and
      effective for this population.

      The objective of this study is to evaluate the effects of NMES associated with conventional
      physiotherapy compared to conventional physiotherapy in the muscular architecture and
      functionality of patients with acute stroke.

      This is a randomized clinical trial in which the participants will be randomly divided into
      experimental group (EG) and control group (CG), being evaluated before and after the
      intervention.

      The sample will be composed of hospitalized patients diagnosed with acute stroke at the
      Hospital de Clínicas de Porto Alegre (HCPA).

      The estimated sample is 70 patients (35 in each group). Waiting for a 0.5 cm difference in
      muscle thickness between groups and a standard deviation of 0.68 and 2 of 0.80, with a
      significance level of 5%, 80% power.

      Randomization will be performed through data generated by a computer program that presents
      the coded distribution. The sequence generation of the numbers to be randomized will be
      performed by a researcher blind to the study - after selection of the patients according to
      the eligibility criteria - keeping it confidential until the beginning of the intervention.

      Data collect:

      Socio-demographic data will be collected such as: age and sex; anthropometric variables:
      weight, height and BMI; and clinical data: stroke region, side of hemiparesis, comorbidities,
      complications during the hospitalization period (eg pneumonia, need for decompressive
      craniectomy), functional condition prior to the current stroke, time to start physical
      therapy, time to onset of NMES, total time of NMES, time to reach orthostasis and time to
      start ambulation. These data will be obtained through the review of medical records and
      interviews with patients or relatives.

      Assessments: The evaluations described below will be performed within 72 hours of hospital
      admission and repeated at hospital discharge or within 21 days.

      Assessment of muscle architecture - The assessment of muscle thickness will be performed in
      the femoral and tibial quadriceps muscles (TA). The images will be obtained by ultrasound
      using the Portable Ultrasound System (Vivid i®, GE) with a linear arrangement probe (60mm,
      7.5 MHz - Vivid i®, GE). The same researcher (who will be blinded for the interventions) will
      do all the evaluations, which will be performed with the musculature at rest.

      Muscle Strength Assessment: Manual Dynamometry, Medical Research Council (MRC)

      Functional and Inability Assessment: Barthel's Index Modified

      Walking assessment and functional capacity: Functional Ambulation Category (FAC)
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Double (Investigator, Outcomes Assessor)
measure: Quadriceps muscle thickness
time frame: three weeks
description: Evaluated by muscular echography (cm)
measure: Thickness of the anterior tibial muscle
time frame: three weeks
description: Evaluated by muscular echography (cm)
measure: Functionality - Barthel Index for Activities of Daily Living
time frame: three weeks
description: The score ranges from 0 to 100 points (90 to 100 - independent, 60 to 89 - slightly dependent, 40 to 59 - moderately dependent, 20 to 39 - severely dependent and less than 20 - totally dependent).
measure: Muscle strength - Medical Research Council (MRC) Scale
time frame: three weeks
description: The MRC score is obtained by evaluating 12 muscle groups in the upper extremities (wrist extensors, elbow flexors and abductors of the shoulder) and lower extremities (dorsal ankle flexors, knee extensors, and hip flexors). For each muscle group will be assigned a score between 0 (complete paralysis) and 5 (normal force), and the total score can vary between 0 up to 60 points.
measure: Functional walking - Functional Ambulation Categories
time frame: three weeks
description: Evaluates the degree of assistance required for ambulation. It distinguishes six categories for ambulation ability (1 to 3 - need for physical assistance during walking, 4 - requires only supervision and 5 and 6 - independent walking).
measure: Dynamometry - Knee extension
time frame: three weeks
description: Dynamometry (kg)
measure: Dynamometry - ankle dorsiflexion
time frame: three weeks
description: Dynamometry (kg)
measure: Sit and stand up to 30 seconds
time frame: three weeks
description: Assess the maximum number of times it is possible to get up and sit down in 30 seconds
measure: Modified Rankin Scale
time frame: three weeks
description: Evaluates the degree of disability and dependence in daily life with a score of 0: without any symptom at 6: death
measure: 10-meter walking test
time frame: three weeks
description: Evaluates gait speed and cadence
arm group label: Neuromuscular Electrical Stimulation
arm group type: Experimental
description: The experimental group will receive the application of NMES associated with conventional physiotherapy. After the NMES application, conventional physiotherapy will be performed. The exercises performed will be according to the patient's physical condition, and the conducts will always be performed seeking the maximum possible functional performance for the patient. The conducts adopted according to the standard routine of the HCPA stroke unit are: passive, active, assisted and / or active exercises; muscle stretching; selective hip extension; trunk stabilization training in sedestation; orthostasis training and walking training.
arm group label: Group Control
arm group type: No Intervention
description: The control group will only receive conventional physiotherapy, composed of the same exercises performed in the experimental group.
intervention type: Other
intervention name: Neuromuscular Electrical Stimulation
description: The application of NMES will be performed with the patient positioned in the supine position in the bed. Self-adhesive electrodes will be positioned at the motor points of the quadriceps and anterior tibial muscles respectively. A symmetrical biphasic pulsed current with a frequency of 80 Hz, a pulse width of 500 μs and an intensity at the motor threshold will be applied up to the maximum tolerated by the patient. ON and OFF time and total session time will be used according to protocol with progressive increase of the total intervention time and reduction of OFF time of the NMES. The device used will be the Neurodyn II model, manufactured by IBRAMED.
Patients will receive NMES for as long as they remain hospitalized or for up to 3 weeks.
arm group label: Neuromuscular Electrical Stimulation
criteria: 
gender: All
minimum age: 18 Years
maximum age: 85 Years
healthy volunteers: No
last name: Graciele Sbruzzi, doctor
role: Study Director
affiliation: Federal University of Rio Grande do Sul
last name: Graciele Sbruzzi, doctor
phone: +55(51)33577334
email: gsbruzzi@hcpa.edu.br
last name: Débora Schmidt
phone: +55(51)33577334
email: dschmidt@hcpa.edu.br
facility: 
contact: 
contact backup: 
country: Brazil
responsible party type: Sponsor
mesh term: Stroke
sharing ipd: No