WO2021062398A1 - Génération de programmes de nutrition neuroprotecteurs et cardioprotecteurs personnalisés présentant une restriction calorique - Google Patents

Génération de programmes de nutrition neuroprotecteurs et cardioprotecteurs personnalisés présentant une restriction calorique Download PDF

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WO2021062398A1
WO2021062398A1 PCT/US2020/053144 US2020053144W WO2021062398A1 WO 2021062398 A1 WO2021062398 A1 WO 2021062398A1 US 2020053144 W US2020053144 W US 2020053144W WO 2021062398 A1 WO2021062398 A1 WO 2021062398A1
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patient
evaluating
neuroprotective
cerebral
metabolic state
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PCT/US2020/053144
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English (en)
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Yama AKBARI
Matine AZADIAN
Robert H. WILSON
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The Regents Of The University Of California
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Publication of WO2021062398A1 publication Critical patent/WO2021062398A1/fr
Priority to US17/534,986 priority Critical patent/US20220079840A1/en
Priority to US17/690,866 priority patent/US20220192919A1/en
Priority to US17/706,217 priority patent/US20220223257A1/en
Priority to US17/735,903 priority patent/US20220262496A1/en

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    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16H—HEALTHCARE INFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR THE HANDLING OR PROCESSING OF MEDICAL OR HEALTHCARE DATA
    • G16H50/00—ICT specially adapted for medical diagnosis, medical simulation or medical data mining; ICT specially adapted for detecting, monitoring or modelling epidemics or pandemics
    • G16H50/30—ICT specially adapted for medical diagnosis, medical simulation or medical data mining; ICT specially adapted for detecting, monitoring or modelling epidemics or pandemics for calculating health indices; for individual health risk assessment
    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16H—HEALTHCARE INFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR THE HANDLING OR PROCESSING OF MEDICAL OR HEALTHCARE DATA
    • G16H20/00—ICT specially adapted for therapies or health-improving plans, e.g. for handling prescriptions, for steering therapy or for monitoring patient compliance
    • G16H20/60—ICT specially adapted for therapies or health-improving plans, e.g. for handling prescriptions, for steering therapy or for monitoring patient compliance relating to nutrition control, e.g. diets
    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16H—HEALTHCARE INFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR THE HANDLING OR PROCESSING OF MEDICAL OR HEALTHCARE DATA
    • G16H50/00—ICT specially adapted for medical diagnosis, medical simulation or medical data mining; ICT specially adapted for detecting, monitoring or modelling epidemics or pandemics
    • G16H50/20—ICT specially adapted for medical diagnosis, medical simulation or medical data mining; ICT specially adapted for detecting, monitoring or modelling epidemics or pandemics for computer-aided diagnosis, e.g. based on medical expert systems

Definitions

  • Nutrition programs have multiple goals. A primary goal is to allow an individual to make dietary decisions which provide the individual with sufficient nutrition in order to sustain life. More advanced nutrition programs may guide the individual towards goals of weight loss or gain, muscle development, cognitive enhancement or optimization, cardiovascular enhancement or optimization, achievement of ketosis, or the adjustment of various biometric parameters such as blood pressure. Nutrition programs may be for a short term, an indefinite term, or a term with any intermediate duration. Nutrition programs may be static over the program term or may be iteratively updated based on measured changes in the individual’s condition.
  • Caloric restriction is defined as a reduction in caloric intake and can be daily, life-long, or intermittent. Many of the benefits appear to target aging, which includes prolongation of lifespan, and improvements in age-related deficits of learning and memory. In addition to its effects on aging, CR has been shown to be beneficial in various models of neurological diseases, like Alzheimer’s, Parkinson’s, and epilepsy, as well as having neuroprotective effects in various models of traumatic brain injury and stroke. Studies involving short-term overnight caloric restriction prior to global ischemic insult have not been previously investigated. Pre-clinical analysis of such phenomena can provide approaches to ameliorate recovery following focal cerebral ischemia, which on average affects over 795,000 people per year in the US alone.
  • CA Cardiac arrest
  • CPR cardiopulmonary resuscitation
  • the main information that is helpful for prognostication is the type (shockable or non- shockable rhythm) and duration of CA before resuscitation efforts have begun. For example, knowing that a patient has suffered a very prolonged CA in a non-shockable state forebodes a very poor prognosis, whereas if help and resuscitation starts within seconds or ⁇ 5 minutes after CA (especially a shockable rhythm), there is a meaningful chance of a good recovery if resuscitation is successful.
  • the main tools available for prognostication are neurological exams, brain imaging (e.g. CT, MRI), electrophysiologic testing (e.g.
  • SD Spreading depolarization
  • SD-related phenomena are seen in a multitude of conditions including migraine aura, traumatic brain injury, hypoxia, ischemia, as well as experimental manipulations such as administration of KCl directly onto the brain.
  • Ischemia-induced SD results in the morphological alteration of neurons, including damage to dendritic spines. This “wave of death” has been shown to mark the onset of cytotoxic events (e.g., glutamate release, Ca2+ influx, cytotoxic edema), however, this damage can be reversed with timely reperfusion.
  • cytotoxic events e.g., glutamate release, Ca2+ influx, cytotoxic edema
  • SD is particularly harmful to brain parenchyma and cerebral vasculature in a hypoxic/ischemic state, like that which occurs during cardiac arrest. Without intervention, CA results in terminal spreading depolarization.
  • Quantifying SD during CA and resuscitation may provide an important tool for diagnosis, prognosis, and possible therapeutic interventions during neurological injury during hypoxic-ischemic events.
  • Repolarization is a corresponding self-propagating wave of restoration of neuronal membrane potential following resuscitation and return of spontaneous circulation post- CA.
  • Repolarization marks restoration of neuronal activity within the first ⁇ 3 min post- resuscitation, and the cerebral blood flow and brain perfusion/metabolism relationship during this time may play a crucial role in diagnosis of injury and prognosis of recovery. Therefore, quantifying repolarization post-resuscitation may provide an additional important tool for diagnosis, prognosis, and possible therapeutic intervention immediately post-CA.
  • caloric restriction (75% for 14 h) prior to cardiac arrest and resuscitation (CA) leads to an increase in survivability and improvement in neurological recovery, including reduced neuro- degeneration in multiple regions of the brain.
  • the present invention has also found that overnight CR induces normoglycemia, while significantly decreasing levels of blood glucose, insulin, and glucagon production and increasing corticosterone and ketone body production. Furthermore, the observed beneficial effects of overnight CR are independent of SIRT-1 and BDNF upregulation.
  • Chronic caloric restriction has been previously associated with various biological effects and purported health benefits. However, the acute or short-term effects of caloric restriction, and specifically the neuroprotective and cardioprotective effects of nutrition programs which feature short-term caloric restriction, have not been fully appreciated.
  • Short-term caloric restriction differs from chronic caloric restriction in that shorter periods don’t offer as much time to modify pathways typically affected by traditional dietary regimens of calorie restriction, which are predominantly in the chronic state. Indeed, the majority of benefits seen to date in caloric restriction are in the chronic state (whether continuous or intermittent restriction in calories) and the mechanisms often include changes in autophagy, brain-derived neurotrophic factor, or other pathways that typically require longer periods of time beyond 12-24 hours.
  • FIG.1 is a graph of arterial blood glucose of control vs. CR rats. Blood glucose was measured 10 minutes prior to CA and 10 minutes after resuscitation. CR significantly lowers and stabilizes blood glucose through the period of CA + CPR. ** P ⁇ 0.01; by one- way analysis of variance. CA, cardiac arrest; CON, control; SEM, standard error of the mean.
  • FIG.2 is a graph of fraction survival of post-CA rats. No mortalities occurred in the CR group.
  • FIG.3 shows neurological recovery of post-CA rats. NDS was measured at 4, 24, 48, and 72 h post-CA. Rats in the CR group consistently scored significantly higher at all measured timepoints. *p ⁇ 0.05 by two-way analysis of variance with post-hoc t-tests. CA, cardiac arrest; CON, control; NDS, Neurological Deficit Scale; SEM, standard error of the mean.
  • FIGs.4A-B show the burst suppression ratio (BSR) of control vs. CR rats.
  • FIG 4A shows BSR beginning at asphyxia (time 0) until approximately 4-hrs post-CA.
  • Statistical analysis revealed a significant group-time interaction when examining 30 minutes to the end of ECoG recording to exclude the dynamic period of asphyxia and CPR. p ⁇ 0.01; by repeated measures ANOVA.
  • FIGs. 5A-5E show neurodegeneration in multiple brain regions at 72h post-CA.
  • FIG.5A shows a brain atlas. The region within the red square displays the physiological locales of neurodegeneration as shown in FIG. 5B.
  • FIG.5B show brain sections stained with FJ-B; positive neurons are fluorescent (green). Images were cropped and signal intensities were adjusted linearly to be optimal for demonstration.
  • FIGs. 5C-5E the number of FJ-B positive neurons were counted from 3 brain sections per region in each animal. The number of FJ-B positive neurons were significantly higher in control rats; CR rats exhibited no FJ-B positive neurons at these regions. *p ⁇ 0.05 by unequal variances t- test. CA, cardiac arrest; FJ-B, Fluorojade-B, CON, control; SEM, standard error of the mean.
  • FIG. 6 shows capillary blood ketone (b-hydroxybutyrate) levels of control vs. CR rats.
  • FIGs. 7A-7C show arterial blood corticosterone, glucagon, and insulin levels of control vs. CR rats measured after 14-hrs of caloric restriction. CR significantly increases corticosterone levels and lowers glucagon and insulin levels. * P ⁇ 0.05; by Welch’s t-test. CR, caloric restriction; CON, control; SEM, standard error of the mean.
  • FIGs.8A-8B show BDNF and SIRT-1 in brain homogenates following 14-hrs of CR.
  • FIG. 9 shows ultra-short (overnight) CR hastens the onset of the spreading depolarization.
  • FIG. 10 illustrates the effect of overnight CR on three rats. The cerebral perfusion/metabolism ratio CBF/CMRO 2 was measured following isoflurane washout prior to and after overnight caloric restriction. The graph shows that overnight caloric restriction led to an increased CBF/CMRO 2 ratio that became closer to 1 for each of the three rats.
  • FIGs.11A-11B illustrate correlations between blood glucose levels in four wild-type aged mice imaged on the same day and both absolute CMRO 2 (PM O 2 / min) and the absolute CBF / absolute CMRO 2 ratio.
  • FIG.11A shows a negative relationship between glucose and absolute CMRO 2 .
  • FIG.11B shows a positive relationship between glucose and the absolute CBF/ absolute CMRO 2 ratio.
  • FIG 12A-12B demonstrate experimental data from representative rats that underwent CR or ad-lib diet, underwent cardiac arrest and resuscitation followed by euthanasia at 72 hours post-resuscitation.
  • rat’s hearts were isolated from both groups and histological staining was conducted to assess for early changes in cardiomyocytes. On Masson trichrome stain, lower amounts of myocardial scar tissue were found in CR rats.
  • FIG 12A shows heart sections of CR and non-CR rats at 72 hrs post-CA stained with Masson trichrome (red: cytoplasm and muscle fibers; purple: collagen; black: nuclei).
  • Masson trichrome red: cytoplasm and muscle fibers; purple: collagen; black: nuclei.
  • VAF vanadium acid fuchsin
  • Fig 12B shows heart sections of CR and non-CR rats at 72 hrs post-CA that were stained with vanadium acid fuchsin (purple) and toluidine (blue). There are more purple cardiac myocytes (arrow) in non-CR hearts versus CR hearts, indicating that non-CR cardiac myocytes are more susceptible to ischemic damage DETAILED DESCRIPTION OF THE INVENTION [0026]
  • the present invention features a system for generating a neuroprotective or cardioprotective nutrition program for a patient at-risk of cardiac arrest.
  • This risk of cardiac arrest may be cardiac or non- cardiac in origin (e.g.
  • the neuroprotective or cardioprotective nutrition program may include caloric restrictions for the patient.
  • the neuroprotective or cardioprotective nutrition program may comprise reducing the patient’s caloric intake by at least 50%.
  • the caloric intake is decreased by about 50-80%.
  • the caloric restrictions may be imposed for a period of about 10-20 hours per day. For instance, a patient that is hospitalized and at-risk of having a cardiac event may be calorically restricted for 15 hours per day by not eating during this period, or receiving only 25% of the normal amount of calories based on their age and weight (caloric restriction of 75%).
  • the system for generating a neuroprotective or cardioprotective nutrition program may include: a means for evaluating the patient’s risk of cardiac arrest; and a means for evaluating the patient’s metabolic state to determine the neuroprotective or cardioprotective potential of caloric restriction of the patient.
  • a means for evaluating the patient’s risk of cardiac arrest may be used to determine the neuroprotective or cardioprotective potential of caloric restriction of the patient.
  • combination of the patient’s risk of cardiac arrest and neuroprotective or cardioprotective potential of caloric restriction may allow for generation of a patient- specific neuroprotective or cardioprotective nutrition program.
  • the means for evaluating the metabolic state of the patient may be configured to evaluate a cerebral metabolic state, a non-cerebral metabolic state, or a combination thereof.
  • the term “non-cerebral metabolic state” refers to a metabolic state that is measured in a portion of the body other than the brain.
  • a non-cerebral metabolic state may be evaluated via measurement of a peripheral limb, another tissue or organ (such as the heart or lungs), or multiple portions of the patient’s body.
  • the system may be configured to allow for comparison of a cerebral metabolic state and a non-cerebral metabolic state so as to assess autoregulation.
  • the system may use any of a variety of means to evaluate the patient’s risk of cardiac arrest. In some embodiments, it may be determined that the patient is at risk of cardiac arrest because they have already had a cardiac event, either recently or some time ago. In that case, the means to evaluate the patient’s risk of cardiac arrest may be the patient’s medical history records. [0029] Similarly, the system may use any of a variety of means to evaluate the patient’s metabolic state. This evaluation may focus on a comprehensive metabolic state of the entire body, a local metabolic state (such as a cerebral metabolic state or the metabolic state of another tissue), or a relationship between the metabolism (or flow/metabolism ratio) of the brain and that of other tissues (i.e. an autoregulation ratio).
  • a local metabolic state such as a cerebral metabolic state or the metabolic state of another tissue
  • a relationship between the metabolism (or flow/metabolism ratio) of the brain and that of other tissues i.e. an autoregulation ratio.
  • the system may use optical devices to measure cerebral blood flow and oxygenation (e.g., laser Doppler flowmetry or diffuse correlation spectroscopy to measure blood flow and near-infrared spectroscopy, time-resolved spectroscopy, or frequency- domain spectroscopy to measure brain tissue concentrations of oxygenated and deoxygenated hemoglobin.
  • optical devices e.g., laser Doppler flowmetry or diffuse correlation spectroscopy to measure blood flow and near-infrared spectroscopy, time-resolved spectroscopy, or frequency- domain spectroscopy to measure brain tissue concentrations of oxygenated and deoxygenated hemoglobin.
  • CMRO 2 absolute or relative cerebral metabolic rate of oxygen
  • CBF/CMRO 2 flow-metabolism ratio
  • a threshold may be placed on the value or values of one or more of these metrics to distinguish a patient for which caloric restriction is expected to have significant neuroprotective or cardioprotective effects from a patient for which caloric restriction is not expected to provide notable neuroprotection or cardioprotection.
  • one or more of these metrics may be treated as continuous independent variables in a mathematical model (e.g., a linear regression) to predict the amount of caloric restriction (e.g., 25%, 50%, or 75% of baseline caloric intake) recommended for the patient to have a significant chance of obtaining neuroprotection or cardioprotection.
  • the combination of the patient’s risk of hypoxia or ischemia to the brain or other body parts that may lead to a cessation of brain or bodily blood flow and metabolism, (e.g. cardiac arrest) and the neuroprotective or cardioprotective potential of caloric restriction may allow for generation of the neuroprotective nutrition program.
  • the combination of the patient’s risk of cardiac arrest and the neuroprotective or cardioprotective potential of caloric restriction may allow for generation of the neuroprotective or cardioprotective nutrition program.
  • This algorithm can be trained (using an initial data set) to obtain the values of k 1 and k 2 .
  • the combination of data on oxygen or glucose supply and metabolic rate may allow for evaluation of the neuroprotective or cardioprotective potential of caloric restriction of the patient.
  • the data can be represented by a coordinate in a multi-dimensional space (e.g., the coordinate (O 2 , Glu, CMRO 2 ) in a 3-dimensional space, where the x-axis represents oxygen supply, the y-axis represents glucose supply, and the z-axis represents cerebral metabolic rate of oxygen).
  • the present invention features a neuroprotective or cardioprotective nutrition program for a patient.
  • the neuroprotective or cardioprotective nutrition program may include a neuroprotective dietary limit.
  • the neuroprotective or cardioprotective dietary limit may be a caloric limit or may exclude or limit certain foods or food groups.
  • the neuroprotective or cardioprotective nutrition program may include a set ratio of macronutrients such as carbohydrates, fats, proteins, sugars, or other energy-providing nutrients such as ketone bodies or nutrients that feed into the anaerobic glycolysis and/or aerobic citric acid cycle.
  • macronutrients such as carbohydrates, fats, proteins, sugars, or other energy-providing nutrients such as ketone bodies or nutrients that feed into the anaerobic glycolysis and/or aerobic citric acid cycle.
  • the caloric limit may cap consumption at about 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2100, 2200, 2300, 2400, 2500, 2600, 2700, 2800, 2900, 3000, 3100, 3200, 3300, 3400 or 3500 kilocalories per half-hour, hour, meal, morning, afternoon, 12-hour period, 24-hour period, 36-hour period, 48-hour period, or 72-hour period.
  • the neuroprotective or cardioprotective nutrition program may be for a period of less than 72 hours. In other embodiments, the neuroprotective or cardioprotective nutrition program may be for a period of less than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 26, 28, 30, 32, 34, 36, 40, 44, 48, 60, 70, 80, 90 or 100 hours, or may be for a period of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more days, weeks, or months.
  • means for evaluating the patient’s risk of hypoxia and/or ischemia (e.g. cardiac arrest) to the brain and body include means for evaluating clinical signs and symptoms (e.g.
  • an oxygen saturation monitor e.g. pulse oximetry
  • a blood pressure monitor e.g. a heart rate monitor, a heart rhythm monitor (e.g. an electrocardiogram device)
  • a serum laboratory profile e.g. cardiac enzymes, blood sugar, inflammatory markers, lactate, renal function labs, coagulopathy labs, platelet function assays, etc
  • a coronary catherization or angiogram device e.g. a chest x-ray device, an echocardiogram device, a computed tomography (CT) device, a magnetic resonance imaging (MRI) device, a diffuse optical spectroscopy device, a near infrared spectroscopy (NIRS) device, a perfusion monitoring device, a laser Doppler flowmetry device, a nuclear scan device, a genetic test, or a combination thereof.
  • CT computed tomography
  • MRI magnetic resonance imaging
  • NIRS near infrared spectroscopy
  • Non-limiting examples of means for evaluating a metabolic state of the patient include: an optical hemodynamic monitor, a blood sugar test using a rapid handheld glucometer, or an indicator of ketosis level, the latter of which can be tested by serum or urine samples including with rapid bedside testing.
  • the means for evaluating a metabolic state of the patient may be configured to measure absolute or relative values of one or more of the following parameters: cerebral metabolic rate of oxygen (CMRO2), cerebral metabolic rate of glucose, cerebral blood flow (CBF), flow-metabolism ratio (CBF/CMRO2) tissue concentration of deoxy-hemoglobin (ctHb), tissue concentration of oxygenated hemoglobin (ctHbO2), tissue oxygenation (StO2), tissue water content, tissue lipid content, tissue reduced scattering coefficient, tissue scattering amplitude, tissue scattering slope, tissue reflectance, or a combination thereof.
  • CMRO2 cerebral metabolic rate of oxygen
  • CBF cerebral blood flow
  • CBF/CMRO2 flow-metabolism ratio
  • ctHbO2 tissue concentration of oxygenated hemoglobin
  • StO2 tissue oxygenation
  • tissue water content tissue lipid content
  • tissue reduced scattering coefficient tissue scattering amplitude
  • tissue scattering slope tissue reflectance, or a combination thereof.
  • the patient’s cerebral or non-cerebral metabolic state may be evaluated based on most recent meal times, corticosterone levels, glucagon levels, insulin levels, ketone levels, or a combination thereof.
  • the means for evaluating the patient’s cerebral or non-cerebral metabolic state may measure one or more analytes from a biological sample (such as blood, tissue, saliva, sweat, cerebral spinal fluid, respiratory gas sample, or a urine sample) taken from the patient.
  • a biological sample such as blood, tissue, saliva, sweat, cerebral spinal fluid, respiratory gas sample, or a urine sample
  • the means for evaluating the patient’s cerebral or non- cerebral metabolic state may be a wearable device. This wearable device may consist of a miniaturized light source and detector and associated optics (e.g.
  • MEMS/MOEMS technology built into a patch or elastic band that attaches to the head, limb, or another part of the body.
  • This device may detect the backscattered light at one or more wavelengths and modulation frequencies to obtain tissue optical properties such as absolute or relative blood flow, hemoglobin concentration, oxygenation, and cerebral metabolic rate of oxygen (or ratios of these parameters). If any of these properties (or a combination thereof) crosses a certain threshold, an indicator on the wearable device (e.g., a light or an alarm) may be activated to alert the patient and clinicians about this hemodynamic change.
  • This technology may be used as a feedback mechanism to inform a personalized caloric restriction program to optimize neuroprotection or cardioprotection for each patient.
  • the means for evaluating the patient’s metabolic state features a system for quantitative intracranial measurement of cerebral blood flow, oxygenation, metabolism, autoregulation, or a combination thereof.
  • the system for evaluating the patient’s metabolic state may comprise: a device body; one or more light sources; one or more detectors, a microprocessor, and a memory component.
  • the light sources and the detectors may extend from the device body and be configured to be positioned in proximity to a head of a subject.
  • the light sources and the detectors may extend from the device body so as to pass through the hair of the subject and contact the skin surface at a plurality of points in a measurement area.
  • the light sources and detectors may not extend from the device body, but instead be integrated within an end of the device body.
  • the microprocessor may be operatively connected to the one or more light sources, the one or more detectors, or a combination thereof.
  • the memory component may be operatively connected to the microprocessor, and the microprocessor may be capable of executing instructions held or stored in the memory component.
  • one or more of the light sources may be configured to emit a coherent light signal.
  • the system may be configured to detect and decouple one or more backscattered signals via the detectors.
  • the memory component may comprise instructions for decoupling components of the one or more backscattered signals.
  • the system may be configured to: differentiate between components of the one or more backscattered signals which are due to different layers of the head; measure or determine a dynamic perfusion metric; measure or determine a tissue absorption coefficient; measure or determine a tissue reduced scattering coefficient; calculate a value of an absolute perfusion metric, using the dynamic perfusion metric, the tissue absorption coefficient, and the tissue reduced scattering coefficient; calculate a value of an absolute metabolic metric, using the absolute perfusion metric, the tissue absorption coefficient, and the tissue reduced scattering coefficient; and calculate a quantitative value of cerebral autoregulation, using the absolute values of the perfusion metric and the metabolic metric.
  • the instructions for decoupling components of the one or more backscattered signals may comprise differentiating between components of the one or more backscattered signals that are due to different layers of the head; determining a dynamic perfusion metric using the one or more backscattered signals; determining a tissue absorption coefficient using the one or more backscattered signals; determining a tissue reduced scattering coefficient using the one or more backscattered signals; calculating a value of an absolute perfusion metric, using the dynamic perfusion metric, the tissue absorption coefficient, and the tissue reduced scattering coefficient; calculating a value of an absolute metabolic metric, using the absolute perfusion metric, the tissue absorption coefficient, and the tissue reduced scattering coefficient; calculating a quantitative value of cerebral autoregulation, using the absolute values of the perfusion metric and the metabolic metric; or a combination thereof, thereby providing for quantitative intracranial measurement of cerebral blood flow, oxygenation, metabolism, and autoregulation
  • tissue absorption coefficient and “tissue reduced scattering
  • the present invention may feature a system for evaluating the neuroprotective or cardioprotective potential of caloric restriction of a patient.
  • the system may include: a means for evaluating oxygen or glucose supply to the patient’s brain; and a means for evaluating the patient’s cerebral metabolic rate of oxygen or glucose.
  • the combination of data on oxygen or glucose supply and cerebral metabolic rate may allow for evaluation of the neuroprotective or cardioprotective potential of caloric restriction of the patient.
  • the system may additionally include a means for evaluating a non-cerebral metabolic rate of oxygen or glucose. Comparison of the cerebral and non-cerebral metabolic rates of oxygen or glucose may allow for an assessment of the patient’s state of autoregulation.
  • a threshold may be placed on one or more parameters relating these different metabolic rates (e.g., the ratio of cerebral metabolic rate of oxygen to non-cerebral metabolic rate of oxygen) to determine whether a patient is expected to receive significant neuroprotective or cardioprotective effects from caloric restriction.
  • One or more parameters relating these metabolic rates may also be treated as a continuous independent variable in a mathematical model (e.g., a linear regression model) to predict the optimal amount of caloric restriction (e.g., 25%, 50%, or 75% of baseline caloric intake) recommended for a specific patient to have a significant chance of obtaining neuroprotection or cardioprotection.
  • the present invention features a method for generating a neuroprotective or cardioprotective nutrition program for a patient.
  • the method may comprise: evaluating the patient’s risk of cardiac arrest; evaluating the patient’s cerebral or non-cerebral metabolic state; and generating a neuroprotective or cardioprotective nutrition program for the patient based on combination of the patient’s risk of cardiac arrest and cerebral or non-cerebral metabolic state.
  • the method may comprise re-evaluating the patient’s cerebral or non- cerebral metabolic state after a time period and amending the neuroprotective or cardioprotective nutrition program based on a change in the cerebral or non-cerebral metabolic state, for example, in an iterative manner.
  • the present invention features a system for improving neurological outcome in a patient during or after cardiac arrest.
  • the system may comprise: a means for evaluating the patient’s metabolic state (e.g. cerebral or non-cerebral metabolic state); and a means for inducing spreading depolarization of the patient.
  • the system may allow for inducement of spreading depolarization of the patient at a specific time during or after cardiac arrest, based on the patient’s cerebral or non-cerebral metabolic state.
  • Non- limiting examples of means for inducing spreading depolarization include: a therapeutic configured to place the patient in a state that mimics a caloric restricted state, a therapeutic treatment configured to increase ketone levels, a therapeutic treatment configured to lower glucagon and insulin levels, chemical stimulation, physical stimulation, electrical stimulation, magnetic stimulation, optical stimulation, soundwave-induced stimulation, or a combination thereof.
  • the means for inducing spreading depolarization may comprise imposing caloric restrictions on the patient prior to the cardiac arrest.
  • the system may be configured to induce spreading depolarization at an earlier time or a later time depending on the patient’s cerebral or non-cerebral metabolic state.
  • the system may additionally comprise a means for inducing repolarization in the patient at a specific time after reperfusion, re- oxygenation, or resuscitation. In some embodiments, this time may depend on the metabolic state of the patient.
  • the means for inducing repolarization may be configured to modify the patient’s blood pressure, cerebral blood flow, cerebral metabolism, or a combination thereof, via chemical stimulation, physical stimulation, electrical stimulation, magnetic stimulation, optical stimulation, soundwave- induced stimulation, or a combination thereof.
  • the present invention features a system for evaluating the neuroprotective or cardioprotective potential of caloric restriction of a patient.
  • the system may comprise: a means for evaluating the patient’s risk of cardiac arrest; and a means for evaluating the patient’s cerebral or non-cerebral metabolic state.
  • the combination of the patient’s risk of cardiac arrest and cerebral or non-cerebral metabolic state may allow for evaluation of the neuroprotective or cardioprotective potential of caloric restriction of the patient.
  • the present invention features a system for guiding neuroprotective or cardioprotective caloric restriction of a patient.
  • the system may comprise: a means for evaluating the patient’s risk of cardiac arrest; and a means for iteratively evaluating the patient’s metabolic state (e.g. cerebral or non-cerebral metabolic state).
  • Combination of the patient’s risk of cardiac arrest and metabolic state may allow for guided neuroprotective or cardioprotective caloric restriction of the patient.
  • the effects e.g. neuroprotective or cardioprotective effects
  • the program of caloric restriction may be adjusted accordingly so as to optimize health and provide for neuroprotection or cardioprotection of the patient.
  • the present invention features a method of determining a neuroprotective or cardioprotective dietary limit for a patient.
  • the method may comprise: evaluating the patient’s risk of cardiac arrest; evaluating the patient’s cerebral or non-cerebral metabolic state; and determining a neuroprotective or cardioprotective dietary limit for the patient based on combination of the patient’s risk of cardiac arrest and metabolic state.
  • the present invention features a method of acute caloric restriction for neurological protection of a patient.
  • the method may include: determining that the patient is at risk of cardiac arrest; determining that caloric restriction of the patient has a neuroprotective or cardioprotective potential; and imposing caloric restrictions on the patient for a period of time.
  • the period of caloric restriction may be less than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 20, 22, 24, 28, 32, 36, 40, 44, 48, 60 or 72 hours.
  • the caloric restrictions may provide for neurological protection of the patient.
  • the present invention features a method of guiding caloric intake for neurological protection of a patient.
  • the method may comprise: evaluating the patient’s cerebral or non-cerebral metabolic state; determining that the patient is at risk of neurological damage due to cardiac arrest, based on the metabolic state; and imposing caloric restrictions on the patient.
  • the caloric restrictions provide for neurological protection of the patient.
  • the present invention features a method of improving survival and neurological outcome in a patient at-risk of cardiac arrest, comprising imposing caloric restrictions on the patient for a period of less than about 72 hours.
  • the caloric restrictions may be based on a value or a change in value of the one or more metabolic metrics. These metabolic metrics may be measured via an optical probe.
  • the caloric restrictions of the present invention may comprise reducing the patient’s caloric intake by at least 5, 10, 15, 20, 25, 30, 35, 40, 45 50, 55, 60, 65, 70, 75, 80, 85, 90 or more percent for a period of hours, days, weeks, months, or years.
  • the caloric restrictions may necessitate the use of a nutrition program to ensure that the patient receives adequate nutrition while following a caloric restriction regime and staying within a caloric limit.
  • the caloric restrictions may be imposed for a period of about 10-20 hours per day.
  • the caloric restrictions may also include specific changes in the nutrients to optimize potential neuroprotective or cardioprotective features in the diet, including but not limited to specific nutrients that promote a state of ketosis. Overall, the nutrition may be consumed by mouth if able to eat or by tube ending in the stomach or intestines (as needed by patients unable to eat) or intravenously (as hospitalized patients frequently need).
  • the invention may feature a method of improving survival and neurological outcome in a patient at-risk of cardiac arrest.
  • the invention may feature a method of improving neurological survival and outcome in a patient during hypoxia or ischemia to the brain or other body parts.
  • the method may comprise administering to the patient a therapeutic treatment that places the patient in a state that mimics a caloric restricted state. This method may also be used during cardiac arrest.
  • the therapeutic treatment may comprise administering ketones to increase ketone levels.
  • the therapeutic treatment can lower glucagon and insulin levels.
  • the present invention features a method of improving survival and neurological outcome in a patient during cardiac arrest.
  • the method may comprise inducing ketosis in said patient.
  • the method may comprise administering to the patient a therapeutic treatment that increases ketone levels.
  • the patient is administered ketones immediately after cardiac arrest, or ketones may be administered in patients at high risk of cardiac arrest.
  • the method may comprise administering to the patient a therapeutic treatment that lowers glucagon and insulin levels.
  • the methods described herein can induce early onset spreading depolarization in the patient during cardiac arrest. In some embodiments, the methods described herein can also induce early repolarization in the patient being resuscitated from cardiac arrest.
  • a method of inducing early onset spreading depolarization in a patient during cardiac arrest may comprise imposing caloric restrictions on the patient or administering treatment that mimics a caloric restricted state prior to the cardiac arrest. Without wishing to limit the present invention to a particular theory or mechanism, imposing caloric restrictions or mimicking a caloric restricted state may increase ketone levels and/or lower glucagon and insulin levels.
  • the method of inducing early onset spreading depolarization in a patient during cardiac arrest may comprise inducing ketosis in said patient. Ketosis may be induced by administering to the patient a therapeutic treatment that increases ketone levels.
  • the method may comprise administering to the patient a therapeutic treatment that lowers glucagon and insulin levels.
  • a method of inducing early repolarization in a patient being resuscitated from cardiac arrest may comprise administering to the patient a therapeutic treatment that increases ketone levels and/or a therapeutic treatment that lowers glucagon and insulin levels.
  • the treatment may be administered during or immediately after cardiac arrest or during or immediately after resuscitation.
  • a patient may be injected with ketones during CPR, which is performed after spreading depolarization has taken place but before spreading repolarization is about to take place, to induce earlier spreading repolarization.
  • the methods described herein may further comprise inducing spreading depolarization in the patient during or immediately after cardiac arrest and/or inducing repolarization in the patient during or immediately after resuscitation by some other means.
  • spreading depolarization and/or repolarization may be induced by chemical stimulation, physical stimulation, electrical stimulation, magnetic stimulation, optical stimulation, soundwave-induced stimulation, or a combination thereof.
  • the present invention provides a method of prognosticating neurological outcome in a patient after cardiac arrest. The method may comprise receiving metabolic information and determining and measuring a metabolic state from said metabolic information. The metabolic state may indicative of the severity and prognosticate outcome of the neurological condition of the brain.
  • the metabolic information may comprise the most recent meal times prior to cardiac arrest, corticosterone levels, glucagon and insulin levels, and/or ketone levels.
  • the levels are measured from a biological sample, such as blood, tissue, saliva, sweat, cerebral spinal fluid, respiratory gas sample, or urine, taken during or after cardiac arrest.
  • the prognostication method may include detecting a presence, lack or delay of spreading depolarization and repolarization.
  • the present invention features a method of improving survival and neurological outcome in a patient during cardiac arrest.
  • the method may comprise determining a metabolic state of the patient, where the metabolic state indicates severity of a neurological condition of the patient, and depending on the metabolic state, inducing spreading depolarization at a specific time during or after cardiac arrest.
  • the step of determining a metabolic state of the patient includes receiving metabolic information on the patient.
  • the metabolic information may comprise one or more of most recent meal times prior to cardiac arrest, corticosterone levels, glucagon and insulin levels, and ketone levels. The levels may be measured from a biological sample taken during or after cardiac arrest.
  • the patient may be in a fasted or non-fasted metabolic state.
  • spreading depolarization may be induced at an earlier time or a later time after cardiac arrest.
  • the method may further include inducing repolarization in the patient at a specific time after resuscitation, where said time depends on the metabolic state of the patient.
  • the step of inducing spreading depolarization and/or repolarization may comprise administering to the patient a therapeutic treatment that places the patient in a state that mimics a caloric restricted state, administering to the patient a therapeutic treatment that increases ketone levels, administering to the patient a therapeutic treatment that lowers glucagon and insulin levels, chemical stimulation, physical stimulation, electrical stimulation, magnetic stimulation, optical stimulation, soundwave-induced stimulation, or a combination thereof.
  • Example 1 Effects of Caloric Restriction in Rat Model
  • rats that were calorically restricted (75%) overnight for 14 h and assessed for changes in outcome.
  • levels of glucose, insulin, glucagon, corticosterone, and ketone bodies were measured in the blood, in addition to SIRT-1 and BDNF expression in the brain.
  • Animal preparation [0062] Adult male Wistar rats weighing 300-370g were used. The animals were housed under standard conditions (23 ⁇ 2°C, 60–70% relative humidity, 12 h light and dark cycles; free access to food and water). Animals typically arrived 2 weeks prior to experiments and were handled daily for 5 min to promote habituation and reduction of stress levels. To enable monitoring of electrocorticography (ECoG), one week prior to the experiment, each rat had two electrodes (1.57 mm in diameter) implanted on the dura (2 mm anterior and 2.5 mm lateral to bregma), corresponding to the left and right M1 motor cortices of the frontal lobes.
  • EoG electrocorticography
  • Average daily food intake was calculated as weight of standard laboratory chow pellets consumed per day per rat.
  • CR rats were calorically restricted overnight, starting at 6:00pm, approximately 14-hrs prior to surgical procedures at 8:00am on the following morning and 18-hrs prior to cardiac arrest at 12:00pm.
  • Capillary blood ketone (b- hydroxybutyrate) levels were measured the morning after caloric restriction prior to surgical procedures with a blood glucose and ketone monitoring system. Rats in the CR group were allowed to resume ad libitum feeding during the recovery period following surgical and cardiac arrest procedures. Both groups had ad libitum access to water.
  • Cardiac arrest experiment [0066] On the day of CA, rats were endotracheally intubated, connected to a mechanical ventilator, and maintained under 2% isoflurane anesthesia carried by 50% O 2 and 50% N 2 gas during the surgical preparations leading up to CA. The femoral artery and vein were cannulated to monitor blood pressure and heart rate and to allow for the intravenous (i.v.) administration of medications. While under mechanical ventilation, positive end expiratory pressure was maintained at 3 cmH2O and body temperature was monitored with a rectal probe and maintained at 37°C. CA was induced via an 8-minute duration of controlled asphyxia followed by cardiopulmonary resuscitation (CPR) until return of spontaneous circulation (ROSC).
  • CPR cardiopulmonary resuscitation
  • ROSC return of spontaneous circulation
  • NDS Neurological Deficit Scale
  • Brain tissue collection [0072] At 72h following CA, survived rats were anesthetized with sodium pentobarbital and perfused transcardially with 0.9% NaCl solution, followed by 0.1 M phosphate buffered saline, pH 7.4. Brains were separated at the mid-sagittal plane into left and right hemispheres. The left hemisphere was post-fixed in 4% PFA for 24 hrs at 4°C and cryoprotected in 30% sucrose for 4 days. It was then frozen in optimal cutting temperature (OCT) embedding medium and stored in -80°C until sectioned.
  • OCT optimal cutting temperature
  • the right hemisphere was flash frozen in dry ice and stored in -80°C until homogenization for western blot analysis
  • Histologic analysis [0074] Left brain hemispheres frozen in OCT were coronally sectioned at 30 mm using a cryostat (Microtome HM 505N). Sections were stored in serial order in a 96-well plate in 1 x PBS with sodium azide at 4°C. Fluorojade-B staining was used to scan and identify neuronal degeneration at 72h post-CA.
  • the antibodies used were: anti-rabbit IgG (Cat #NA 934-1ml; 1:5000 dilution), mouse anti-beta tubulin (Cat# E7), IRDye 800cw donkey anti-rabbit (Cat #32212; 1:10,000 dilution).
  • BDNF mouse anti-beta tubulin
  • IRDye 800cw donkey anti-rabbit Cat #32212; 1:10,000 dilution
  • BDNF analysis the primary antibody used was rabbit anti-BDNF N- 20 (Cat #SC-546; 1:1000 dilution).
  • SIRT-1 analysis the primary antibody used was rabbit SIRT-1 (Cat # 07-131; 1:500 dilution).
  • the immunoreactive bands were detected using a detection reagent according to the manufacturer’s instructions. Bands were analyzed with image analysis software.
  • CR improves neurological recovery
  • NDS scores were measured at 4, 24, 48, and 72 h post-ROSC.
  • Table 1 NDS testing assesses arousal, brainstem reflexes, basic motor strength, gait, and primitive behaviors.
  • rats have perfect NDS scores of 70, whereas post-CA all rats exhibit deficits in NDS.
  • FIG. 3 the CR group exhibited significantly higher NDS scores in comparison to the control group at every assessed timepoint post-CA.
  • BSR Burst suppression ratio
  • burst suppression is generally associated with poor prognosis after cardiac arrest, it has been reported previously that early increased bursting in rats after asphyxial cardiac arrest is linked to a good outcome. Also, a study in humans reported that a faster recovery of EEG from a bursting pattern to a continuous pattern after cardiac arrest can improve prognostication of a good neurological outcome. Yet another study in humans showed patients with good outcomes had a significantly lower BSR during the first 48 hrs after cardiac arrest than patients with poor outcomes. These results revealed a similar pattern in the BSR when comparing the CR and control groups during the first four hours after CA.
  • CR leads to higher corticosterone and lower glucagon and insulin
  • corticosterone, glucagon, and insulin levels were assessed in arterial blood collected after 14-hrs of caloric restriction.
  • Blood levels of glucagon, on the contrary, were significantly lower in the CR group in comparison to the control group ([n 9]; p ⁇ 0.05).
  • CR does not change expression of SIRT1 and BDNF
  • Caloric restriction is known to upregulate brain-derived neurotrophic factor (BDNF) and sirtuin 1 (SIRT1) pathways in the brain, particularly following subacute periods of dietary restriction.
  • BDNF brain-derived neurotrophic factor
  • SIRT1 sirtuin 1
  • Example 2 Generation of Neuroprotective Nutrition Program
  • a 67-year-old male patient presents to the emergency department complaining of chest pains.
  • the attending physician examines the patient by conducting a physical exam, including auscultation while checking his vital signs, electrocardiogram, chest x-ray, bedside echocardiogram, and blood tests results that include cardiac enzymes in addition to standard blood tests and any prior medical records suggestive of coronary artery disease and potential cardiac ischemia.
  • the physician determines that the patient is at high risk of cardiac arrest.
  • the physician evaluates the cerebral metabolic state of the patient by using a portable optical device which measures CBF and CMRO 2 . Because the CBF/CMRO 2 ratio is 0.5 (which is significantly less than 1), the physician determines that a neuroprotective nutrition program for the patient should include acute caloric restriction of 75% for a period of 20 hours.
  • the physician generates a neuroprotective nutrition program for the patient which includes a caloric limit of 500 kilocalories for the next 20 hours.
  • the physician re-evaluates the cerebral metabolic state of the patient and determines that the CBF/CMRO 2 ratio has increased to 0.9.
  • Example 3 Inducement of Early Spreading Depolarization via Ketone Injection
  • a 55-year-old female patient presents to the emergency department complaining of chest pains. While in the hospital, the patient experiences cardiac arrest. During the cardiac arrest, the patient’s cerebral metabolic state is monitored via a portable optical/EEG device. During entry into cardiac arrest, it is seen that the patient’s brain metabolism (measured by absolute CMRO 2 ) is low (e.g., ⁇ 3 ml O 2 /min/100g).
  • Example 4 Iterative Generation of a Neuroprotective Nutrition Program Via a Wearable Device [00107] A 48-year-old male patient with a history of coronary artery disease presents to his primary care physician with shortness of breath and a rapid and irregular heartbeat.
  • the physician prescribes use of a wearable device to generate a neuroprotective nutrition program for the patient based on monitoring of the patient’s metabolic state.
  • the patient wears the wrist-mounted device for 12 hours a day and receives hourly automatic updates to a digital nutrition program on his phone based on his metabolic rates of glucose and oxygen consumption.
  • This device uses a multivariate linear regression algorithm (see [0028]) to make updated personalized calculations of the patient’s recommended percentage of caloric restriction each day, based on the patient’s metabolic rates of glucose and oxygen consumption and other risk factors.
  • the patient makes dietary decisions based on the digital nutrition program.
  • Example 5 Applications to hypoxic-ischemic states originating from non- cardiac sources that can lead to cardiac arrest
  • a 70-year old female is admitted with shortness of breath. She has no history of prior medical conditions and just returned from a long overseas trip. On workup in the emergency room, she is found to be hypoxic with pulse oximeter around 90% oxygen saturation and tachycardic. CT angiography of the lungs demonstrate a pulmonary embolism and the source is found to be a deep venous thrombosis in her right leg. She is started on intravenous anticoagulation medications and admitted to the intensive care unit, later becoming more hypoxic requiring intubation and mechanical ventilation.
  • her cerebral and global metabolic state is assessed using a bedside portable device measuring CBF and CMRO 2 . Since her CBF/CMRO2 ratio is found to be suboptimal at 0.7, the medical team optimizes her nutrition to maximize neuroprotection and cardioprotection. Acute caloric restriction is instated at 90% for the next 24 hours to limit her calorie intake to 200 kilocalories, and this takes into account both enteral nutrition through a nasogastric tube as well as dextrose infusion through her intravenous catheters.
  • Causes of worsening global ischemia and severe shock can be cardiac or non-cardiac in origin.
  • Cardiac causes can include myocardial infarction caused by coronary artery disease, cardiac arrhythmia caused by genetic predisposition or environmental insults.
  • Pulmonary causes can be due to hypoxia resulting from massive pulmonary embolism, acute respiratory distress syndrome (e.g. ARDS), severe pneumonia due to infection or aspiration, severe pulmonary edema, or other causes.
  • Hypercoagulable states and inflammatory states can have a major impact on these causes, and this can include COVID-19 related causes that can frequently cause hypoxia or hypercoagulability that can lead to cardiac arrest.
  • circulatory shock can be due to severe sepsis (e.g.
  • septic shock cardiac shock not necessary caused by acute coronary syndrome (e.g. severe heart failure such as Takotsubo disease), hemorrhagic shock (e.g. trauma or related incident causing internal or external haemorrhage), neurogenic shock (e.g. impending brain death due to acute brain injury leading to severe cerebral edema and brain herniation), spinal shock (e.g. due trauma or other cause), hypovolemic shock (e.g. due to severe dehydration), or other types of conditions alone or in a combination thereof of any of these conditions that can lead to a state of hypoxia and/or ischemia to specific regions of the body, including or excluding the brain.
  • acute coronary syndrome e.g. severe heart failure such as Takotsubo disease
  • hemorrhagic shock e.g. trauma or related incident causing internal or external haemorrhage
  • neurogenic shock e.g. impending brain death due to acute brain injury leading to severe cerebral edema and brain herniation
  • spinal shock
  • the risk of cardiac arrest may stem from a risk of any of the conditions above and the means for evaluating risk of cardiac arrest may include a means for evaluating any of the conditions above.
  • descriptions of the inventions described herein using the phrase “comprising” includes embodiments that could be described as “consisting essentially of” or “consisting of”, and as such the written description requirement for claiming one or more embodiments of the present invention using the phrase “consisting essentially of” or “consisting of” is met.

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Abstract

L'invention concerne des systèmes et des procédés pour générer des programmes de nutrition neuroprotecteurs et cardioprotecteurs. Ces programmes de nutrition neuroprotecteurs et cardioprotecteurs sont particulièrement applicables à des patients présentant un risque d'arrêt cardiaque (par exemple dû à l'hypoxie ou à l'ischémie du cerveau ou d'autres parties du corps). Les programmes peuvent présenter une restriction calorique, par exemple, une restriction calorique à court terme. Les programmes peuvent être générés ou modifiés de manière itérative sur la base de l'état hémodynamique et métabolique du cerveau, des membres ou d'autres tissus ou organes du patient. Une rétroaction dynamique concernant l'état hémodynamique et métabolique du patient peut être fournie par des techniques comprenant, entre autres, une technologie optique pour mesurer quantitativement et de manière non invasive le flux sanguin, l'oxygénation, le taux métabolique d'oxygène et le rapport perfusion/métabolisme dans le cerveau, les membres ou d'autres tissus ou organes. Les systèmes décrits ici peuvent également induire une dépolarisation par étalement et une repolarisation à des moments spécifiques pendant ou après un arrêt cardiaque sur la base de l'état métabolique cérébral du patient.
PCT/US2020/053144 2018-09-21 2020-09-28 Génération de programmes de nutrition neuroprotecteurs et cardioprotecteurs personnalisés présentant une restriction calorique WO2021062398A1 (fr)

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US17/534,986 US20220079840A1 (en) 2018-09-21 2021-11-24 Real-time methods to enable precision-guided cpr to improve neurological outcome and predict brain damage after ischemic injury and reperfusion
US17/690,866 US20220192919A1 (en) 2018-09-21 2022-03-09 Real-time methods to enable precision-guided cpr to improve neurological outcome and predict brain damage after ischemic injury and reperfusion
US17/706,217 US20220223257A1 (en) 2018-09-21 2022-03-28 Generation of personalized neuroprotective and cardioprotective nutrition programs featuring caloric restriction
US17/735,903 US20220262496A1 (en) 2018-09-21 2022-05-03 Generation of personalized neuroprotective and cardioprotective nutrition programs featuring caloric restriction

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US17/277,616 Continuation-In-Part US20220032074A1 (en) 2018-09-21 2019-09-23 Spreading depolarization and repolarization as biomarkers of neurological recovery after cardiac arrest
US17/690,866 Continuation-In-Part US20220192919A1 (en) 2018-09-21 2022-03-09 Real-time methods to enable precision-guided cpr to improve neurological outcome and predict brain damage after ischemic injury and reperfusion

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US17/534,986 Continuation-In-Part US20220079840A1 (en) 2018-09-21 2021-11-24 Real-time methods to enable precision-guided cpr to improve neurological outcome and predict brain damage after ischemic injury and reperfusion
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US20180044278A1 (en) * 2015-02-09 2018-02-15 Board Of Supervisors Of Louisiana State University And Agricultural And Mechanical College Compounds, compositions, and methods for the treatment of inflammatory, degenerative, and neurodegenerative diseases
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US20080177572A1 (en) * 2006-09-29 2008-07-24 Fuhrman Joel H Methods for Developing and Conducting a Nutritional Treatment Program
US20130261183A1 (en) * 2010-10-14 2013-10-03 Urvashi Bhagat Optimized nutritional formulations, methods for selection of tailored diets therefrom, and methods of use thereof
US20140088996A1 (en) * 2012-09-21 2014-03-27 Md Revolution, Inc. Systems and methods for developing and implementing personalized health and wellness programs
US20180044278A1 (en) * 2015-02-09 2018-02-15 Board Of Supervisors Of Louisiana State University And Agricultural And Mechanical College Compounds, compositions, and methods for the treatment of inflammatory, degenerative, and neurodegenerative diseases
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