Symptoms and General Pathology

All Conditions

Neoplasms

Skin and Connective Tissue Diseases

Musculoskeletal Diseases

Nervous System Diseases

Infections

Rare Diseases

Syndrome

Fatigue

Breast Neoplasms

Fatigue Syndrome, Chronic

Chronic Disease

Breast Diseases

Skin Diseases

Muscular Diseases

Encephalomyelitis

Neuroinflammatory Diseases

Neuromuscular Diseases

Disease Attributes

Chronic Graft Versus Host Disease

After treatment(6 months from inclusion) is ended a fVAS \< 50

After treatment (6 months from inclusion) with fVAS ≥ 50 mm or a rise of fVAS of ≥ 25 mm.

Healthy women matches with age

1. 50-70: women attending the mammography screening
2. 19-50: invitation in newspaper, flyers and posters

Tone Hoel Lende, PhD

Håvard Søiland, PhD

Svein Skeie, PhD

REBECCA-1 is an observational study. Clinical research is undergoing a revolutionary change. The use of electronic patient records (EHR), digital registers, smartphones etc will create "real-world data" (RWD) that provides great opportunities for advancing clinical research, but so far this opportunity has been little exploited. The REBECCA -1 study will observe and monitor fatigue in breast cancer survivors. Investigators will use self reported questionnaires (PROM-data), blood tests and objective regulations like the REBECCCA -1 smart watch that will register amount of steps every day, leaving the house, visiting friends, cafes etc. There will be three observational arms; 1.high fatigue, 2. low fatigue and 3. a healthy control arm. After the patients have finished their treatment, they will receive the REBECCA smart watch, a REBECCA app on the smart phone and a REBECCA plus device on their computer, The next offend are also invited to report their evaluation through the same apps. The observational time will be 1 year and comparison between the subjective PROM data , the objective REBECCA watch and the biological samples will be obtained.

Detailed Description:

1. Background:

   Clinical research is undergoing revolutionary changes by use of electronic patient records (EHR), digital registers and smartphones. The widespread use of portable devices have led to possibilities to collect "real-world data" (RWD) that provides great opportunities for advancing clinical research.

   Fatigue or exhaustion is one of the most common and most annoying late side effects after breast cancer treatment. Cancer Related Fatigue (CRF) may be elevated even before starting treatment and generally increases in intensity during treatment . It can also persist for years after completion of treatment in otherwise healthy cancer survivors and studies suggest that up to a third experience persistent fatigue for up to 10 years after being diagnosed with cancer. CRF is multi-dimensional and can have physical, mental and emotional manifestations, including general weakness, decreased concentration or attention, decreased motivation or interest in participating in regular activities, as well as emotional lability. Fatigue has also been shown to have a negative impact on work, social relationships, mood and daily activities and causes a significant reduction in overall quality of life during and after treatment for the patients affected. Thus, studying of RWD in CRF will be an appropriate method and design. As far as known this has not been done before.

   The biological mechanisms associated with the development of CRF may involve inflammatory processes contribute to fatigue during and especially after cancer treatment. Various cytokines may be produced during cancer treatment in response to tissue damage from radiation or chemotherapy. Inflammatory candidate biomarkers include Interleukin (IL) 1b, IL6, IL10, IL-17, IL1βRa and IL1-RII 32, 33. Heat shock Protein (HSP) 90 is another current biomarker candidate as it has been shown to reflect the severity of fatigue in patients with Crohn's disease.
2. Rationale behind the REBECCA project

   By using multi-source RWD in clinical studies, it will be possible to monitor the quality of life of patients and have a unique opportunity to map the challenges patients have in their daily lives in terms of work life participation, physical activity, social activity / relationships and their concerns. At the same time, the investigators will explore whether different immunological candidate biomarkers can provide prognostic information related to the development of fatigue in this patient group.
3. Objectives

   REBECCA-1 is an observational study in which a REBECCA smartwatch will be used to monitor the quality of life and fatigue in breast cancer patients
4. Spesific aims include:

   * Evaluating whether the use of REBECCA-collected patient information (i.e. collection of continuous RWDs and PROMs) will provide better insight into fatigue in breast cancer survivors.
   * Evaluating immunological biomarkers such as HSP90, IL1b, IL6, IL10, IL-17, IL1βRa, IL1-RII, HPX, CFB, APOA4 and Serpin-F1 and DNA methylation patterns.
5. Study design

   The REBECCA-1 sub-study: Characterize the quality of life and late effects in breast cancer patients.

   In REBECCA-1, participants will be included in 3 groups à n = 49 Two of the groups include breast cancer patients. After treatment, the patient will be assigned to one of the two study arms as described below. The third arm is a control group consisting of healthy women between 19 and 70 years.

   After undergoing treatment (surgery, chemotherapy given neoadjuvant or adjuvant and radiation), the breast cancer patients will again fill in PROM data and submit biological material and be assigned to the "CRF arm" and "Mild CRF arm", respectively.

   "Cancer Related Fatigue (CRF) arm" n = 49: The participants who after evaluation of the form VAS-fatigue have a change of f-VAS\> 25mm from the time of inclusion to evaluation after completion of treatment and / or fVAS score\> = 50 mm are stratified into the group "CRF arm".

   "Mild Cancer Related Fatigue (mild CRF) arm" n = 49: Patients with a final fVAS score \<50mm is randomized to the group "Mild CRF arm".

   All participants will be able to borrow a smartwatch during the observation period, which they must wear for 12 months (i.e. from month 6 to month 18). In addition, the participants must install a REBECCA patient app on their mobile and a plug-in on their PC in order to obtain objective RWD related to the participants' quality of life and lifestyle over the next 12 months. The data collected by means of these devices is described in the figure which shows which data is collected via the smartwatch and the mobile phone

   At all time points i.e. at diagnosis, 6, 12 and 18 months after the time of inclusion, patient reported outcome measures (PROMs), medicine list, biological samples and RWD from the smart watch system on REBECCA platform from all the participants in all three subgroups.
6. REAL WORLD DATA COLLECTION

   A. Smartwatch:

   Acceleration, pulse, Activity sessions (type of exercise (running, walking, walking, cycling Length of activity(minutes, training distance (km) and altitude meters Intensity level(number of calories, intensity B. Smartphone and mobile apps
   * GPS positions (movement pattern)
   * Answer to questionnaires
   * Photo initiated in the Rebecca app (related to meals/eating habits and environment)
   * Publicity available data from map services location and environmental. C. REBECCA. PC plug in internet from \*Social media such as Facebook, You Tube etc., D. REBECCA companion app (optional) \*answer questions about the patient's quality of life , symptoms and environment
7. Patient Reported Outcome Measures (PROMs)

   Patient-reported data (PROMs) related to lifestyle, quality of life, working conditions, sleep and medication use will also be collected in REBECCA. For this purpose, the investigators will both use standardized PROM forms (ΕORTC-QLQ-BR2340, SF-3641, ΕORTC-QLQ-C3042, HAD43, FSS44, FQ45 og VAS-fatigue34, 46, 47) and self-report form.
8. Collection and analyses of blod-, urine- and faeces samples

   All patients included in the REBECCA-1 sub-study will be asked to give blood, urine and faeces samples i.) at the time of diagnosis ii.) after the end of treatment (month 6) and iii.) at 12 and 18 months follow-up. A tissue sample will also be taken at the time of diagnosis. The blood samples will be used to investigate whether immunological biomarkers such as HSP90, IL1b, IL6, IL10, IL-17, IL1βRa, IL1-RII, HPX, CFB, APOA4 and Serpin-F1-can provide prognostic information related to the development of fatigue in breast cancer patients.

   DNA methylation will be examined by Full-genome methylation assays using Illumina's Human Methylation 850K platform and 8 CpG sites from our partner Mylin Torres will in addition be validated.
9. Data flow

   The REBECCA system will function as a data collection system, and will be a "stand alone" system that will have no communication with other systems in the hospital.

   i.) A smartwatch: The smartwatch to be used in REBECCA for RWD collection will be a commercial Garmin-type smartwatch.

   ii.) REBECCAs patient app (pApp): GPS data, data from third-party health apps, images and sensor data will first be uploaded to REBECCA's pApp. The data will be stored in the app on a separate memory location on the phone, which is isolated and therefore not available for the other phone apps. .

   iii.) REBECCAs PC plug-in: patients will install this on their PC. They will be given a description of how to do this. The connection between the patient ID and REBECCA's browser plug-in will also take place here via a unique code, generated in the pApp on the mobile, which the patient enters into the browser. The user ID is stored so that the patient does not have to log in every time they reopen the browser. The REBECCA's PC plug-in utilizes the browser's local storage space to store information that is critical to its functionality, while the data from the patient's online activity is directly transferred and stored on the REBECCA server for subsequent processing.

   iv.) REBECCAs companion app (cApp): Family members or close friends who will contribute information to REBECCA will report this data in REBECCA's companion app, which they will install on their mobile. .

   v.) RedCap server at HelseVest IKT: Deidentified clinical data and PROM data will be stored in the RedCap server at HelseVest IKT before being transferred pseudonymously and encrypted to the remotely managed REBECCA server.
10. Data storage, privacy and data security

    Data security and privacy are a high priority in REBECCA and will of course be in line with both Norwegian and European laws. The law firm TimeLex, located in Belgium, is responsible for creating an operational data security and ethical framework that the study will follow. This means that all precautions will be taken in REBECCA to respect the privacy of study participants in accordance with European Parliament and Council Regulation (EU) 2016/679 of 27 April 2016 regarding the protection of individuals with regard to the processing of personal data and the free movement of such data , and repealing Directive 95/46 / EC (General Data Protection Regulation) (GDPR))50. TimeLex, will identify and describe the ethical guidelines that apply to the various REBECCA participating countries, and the list of necessary measures will apply to the entire ethical operation of the REBECCA project.
11. Expected impact of the REBECCA project

REBECCA aims to use "real-world data" combined with an advanced data management platform and innovative methods for modeling causal data, to close the gap between clinical research and clinical practice in the treatment of cancer patients. The REBECCA project will initially focus on breast cancer, but will also demonstrate the REBECCA system's transmission to other cancers such as prostate cancer. REBECCA's technological and methodological advances will also be relevant for other clinical research domains that want to investigate the causal relationship between several clinical factors (lifestyle and environmental factors, and comorbidities), through analysis of registry and biobank data and observational data from patients' real life / everyday life.

12 Among REBECCAs milestones are:

A. Development of new approaches to measurement, and a better understanding, of indicators related to the patient's health status and quality of life.

B. Development of methods for statistical and causal analysis of "real-world data".

C. Clinical studies in cancer-related fatigue / fagitue, cancer-induced peripheral neuropathy and cancer-related osteoporosis.

D. Examination of patient monitoring in clinical trials, as a tool to improve the quality of life of cancer patients.

E. Generation and reuse of data sets that will enable the investigation of new medical issues as well as the design, implementation and delivery of an AI-enhanced data collection and management system for comprehensive monitoring of breast cancer survivors' health status and quality of life.

F. To offer new tools and data to clinicians that lead to improved follow-up of cancer patients.

G. Improved patient experience and quality of life due to detailed monitoring and a more personal follow-up.

Digital health (eHealth) has come more into focus during the COVID-19 pandemic. The REBECCA system will be able to contribute to development, increased use and increased competence in eHealth at Stavanger University Hospital by offering digital data collection, digital solutions for patient monitoring, digital solutions for early detection of comorbidities, use of artificial intelligence models as analysis tools, better utilization of health data from health registers and research biobanks as well as offering health care in new ways etc.

microRNA, circulating tumor DNA, metylation of DNA

Breast Cancer affects women in 99% of all cases

Monitoring of Chronic Conditions in Breast Cancer

REsearch on BrEast Cancer Induced Chronic Conditions Supported by Causal Analysis of Multi-source Data

Visual Analogue Scale (fVAS), which is a score from 0 to 100 mm marked on a 100 mm line on a paper.

fVAS (score from 0 to 100 mm marked on a 100 mm line on paper)

We may measure number of steps each day, papttern of movement and sleep quality

Helse Stavanger HF

Blood and Lymph Conditions

Immune System Diseases

Lymphoma

Neoplasms by Histologic Type

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Lymphosarcoma

Six months after the intervention period (T3), the participants randomized to usual care will be offered a modified version of the intervention in line with their personally expressed needs.

The interdisciplinary complex intervention lasts 12 weeks and includes the 4 following components;

Patient-education: a 2-hours group-based digital session, including information about fatigue, training theory, psychological strategies and nutrition, all in relation to chronic fatigue (CF).

Physical exercise program: two weekly sessions with aerobic exercise and resistance training. The participants are instructed to do the same program in the unsupervised sessions as in the supervised sessions. After the first 12 weeks exercise period, the participant and the physiotherapist makes an individually tailored plan for exercise and follow-up the next 12 weeks.

Cognitive behavioral program: 6 group-based online sessions lead by two psychologists, based on elements from cognitive behavioral therapy to reduce and/or manage CF. Each session lasts for 135 minutes.

Nutritional counselling: 3 individual sessions by a clinical dietitian. Each session lasts for 30-60 minutes.

Interdisciplinary complex intervention

The present study is a randomized controlled trial (RCT) with an overall objective to examine the effect of an interdisciplinary complex intervention on the level of fatigue in lymphoma survivors with chronic fatigue. Secondary aims are to examine the effects of the intervention on daily functioning, work status/ability, physical fitness and QoL among the survivors, on QoL of their relatives and on the societal costs.The intervention will last for 12+12 weeks and include four components; patient education, supervised physical exercise, cognitive behavioral program and nutritional counselling. Outcomes will be assessed at baseline,post-intervention (12 weeks after baseline) and at 3-month, 6-month, 12-month and 24-month follow-up after completed intervention.

Chronic fatigue (CF) is a subjective experience of substantial lack of energy, exhaustion and cognitive difficulties lasting for six months or longer. CF is one of the most common and distressing late effects after cancer, affecting 15-35 % of survivors, often for years beyond treatment. Despite the high prevalence and the huge negative consequences of CF on daily functioning and QoL and the economic and societal costs, effective treatment of CF and standardized follow-up care are currently lacking.

Today, there is no curative treatment of CF. However, several modifiable behavioral factors including emotional distress, physical inactivity, sleep disturbances and unhealthy diets are found to be associated with CF. So far, most of the interventions aiming to reduce fatigue during and shortly after cancer treatment have targeted only one of these factors at a time, with small to moderate effect sizes. No prior study has examined if CF in cancer survivors is better treated by a complex intervention targeting combinations of these factors, an approach which seems logical due to the complexity of the symptom.

The project is a two-armed RCT in which chronically fatigued lymphoma survivors are randomized to an interdisciplinary complex intervention or to usual care. Eligible participants will receive written information about the study by mail. Survivors who perceive themselves as having physical and mental fatigue, and who are willing to participate, will be asked to fill out and return the Chalder Fatigue Questionnaire (FQ) to the study coordinator. Those who have chronic fatigue as measured by the FQ will be invited to a medical screening by an oncologist in the project group, for evaluation of inclusion.

The interdisciplinary complex intervention will last for 12 + 12 weeks and include four components; patient education, physical exercise (and follow-up), cognitive behavioral program and nutritional counselling, organized in a systematic way, i.e. a standardized patient care pathway.

All outcomes will be assessed in all participants at four points; pre-intervention (baseline) (T0), post-intervention (12 weeks after baseline) (T1) and at 3-month (T2) and 6-month (T3) after T1. Moreover, selected patient reported outcomes will be assessed in all participants at 12-month (T4) and 24-month (T5) after T1.

A Complex Intervention for Chronically Fatigued Lymphoma Survivors

A Complex Intervention for a Complex Symptom - a Randomized Controlled Trial in Chronically Fatigued Lymphoma Survivors

The Fatigue Questionnaire consists of 11 questions, distributed on a physical fatigue scale (7 items) and mental fatigue scale (4 items) Each item is scored from 0 to 3. This provides a physical fatigue score from 0 to 21, mental fatigue score from 0 to 12, and total score from 0 to 33. Higher score implies more fatigue.

The Fatigue Questionnaire consists of 11 questions, distributed on a physical fatigue scale (7 items) and mental fatigue scale (4 items) Each item is scored from 0 to 3, providing a total score from 0 to 33. Higher score implies more fatigue.

The questionnaire includes five functioning scales (physical, role, cognitive, emotional and social).All of the scales range in score from 0 to 100.

A high score for a functional scale represents a high / healthy level of functioning.

The questionnaire includes a global health status / quality of life (QoL) scale, which range in score from 0 to 100. A high score for the global health status / QoL represents a high QoL.

Participants are asked to report their current work status

Current work ability is rated compared with the lifetime best on a scale from 0 to 10. Higher score implies higher work ability.

Assessed by rating work ability in relation to the physical demands of the job, by the following response alternatives: very good, rather good, moderate, rather poor or very poor

Assessed by rating work ability in relation to the psychological demands of the job, by the following response alternatives: very good, rather good, moderate, rather poor or very poor

In cases where participants do not have the opportunity to travel for physical fitness tests, cardiorespiratory fitness will be assessed by an indirect treadmill test (modified Balke protocol) at their local physiotherapist. Time to exhaustion will be used as an indicator of cardiorespiratory fitness.

The one-repetition maximum (1RM) test (the maximal workload that can be lifted once)) in leg press.

The maximum number of push-ups that can be performed in one set

Each of the 9 items is scored from 0-3, providing a total score from 0 to 27. A higher score implies higher level of depressive symptoms.

Each of the 7 items is scored from 0-3, providing a total score from 0-21. A higher score implies higher level of anxiety symptoms.

Each item is scored from 0-3, providing a total score from 0-21. A higher score implies higher level of anxiety symptoms.

The scale consists of 4 items, each scored from 1 (totally disagree) to 7 (totally agree). A sum score from 0 to 7 is calculated based on the mean score of the items, with increasing score implying higher exercise competence.

The scale consists of 5 items, each scored from 1 (totally disagree) to 7 (totally agree). A sum score from 5 to 35 is calculated, with increasing score implying higher satisfaction with life.

The scale consists of 5 items, each scored from 1 (totally disagree) to 7 (totally agree). A sum score from 5 to 35 is calculated, with increasing score implying higher sense of vitality.

DIGIKOST-FFQ is a food frequency questionnaire aiming to benchmark against the Norwegian food-based dietary guidelines.

EQ-5D consists of five dimensions (mobility, self-care, usual activities, pain \& discomfort, anxiety \& depression), each of which has five severity levels that are described by statements appropriate to that dimension.

RAND-36 comprises 36 items that assess eight health concepts: physical functioning, role limitations caused by physical health problems, role limitations caused by emotional problems, social functioning, emotional well-being, energy/fatigue, pain, and general health perceptions. Physical and mental health summary scores are also derived from the eight RAND-36 scales.All questions are scored on a scale from 0 to 100, with 100 representing the highest level of functioning possible.

Combining information about health-related QoL will give quality-adjusted life-years, while valuation of resource use using standard principles of health economic evaluation will provide estimates of costs

Questions assessing benefits of the intervention

Questions assessing daily use of information, strategies and advices learned in the intervention program

University of Oslo

Norwegian School of Sport Sciences

UiT The Arctic University of Norway

Norwegian University of Science and Technology

Diakonhjemmet Hospital

University of Alberta

St. Olavs Hospital

Oslo University Hospital

Principal Investigator

Behaviors and Mental Disorders

Anxiety Disorders

Depression

Depressive Disorder

Subjects will move for 1 hour in time to the Congolese rhythm called Zebola.

Movement to rhythm

Kenneth Wilson, MD

Pre-agricultural societies almost universally used healing ceremonies that involved reverence, rhythm and dance in the presence of a healer. It is believed that we are "wired" for such experiences and they foster an integrative mode of consciousness similar to that of mindfulness based stress reduction, which has been shown to have therapeutic effects in a variety of conditions. Collaborator Ava Lavonne Vinesett of the Duke Dance Program has developed a healing ceremony based in sub-Saharan African traditions. The investigators plan is to have 25 subjects with a variety of clinical conditions participate in this ceremony. Subjects will then be asked to write a commentary about their experience and to participate in a focus group discussion. It is anticipated that the study will give us some idea of how promising this approach would be and what kinds of patients might benefit. Safety issues are minimal and include the possibility of injury (though the dancing is not strenuous) and psychological distress.

Traditional African Healing Ceremony in a U.S. Population

Duke University

Herpes Simplex

Epstein-Barr Virus Infections

Virus Diseases

Communicable Diseases

Herpesviridae Infections

DNA Virus Infections

Tumor Virus Infections

All Drugs and Chemicals

Anti-Infective Agents

Antibodies

Immunoglobulins

Valganciclovir

Antiviral Agents

valganciclovir

Jose G Montoya, MD

The purpose of this study determine whether the drug valganciclovir has a significant and real benefit on the central core of symptoms experienced by patients who have high titers to EBV and HHV-6 and are experiencing long-standing fatigue and cognitive impairment (CFS).

In addition, to characterize a quantifiable biological marker in these patients that will facilitate the identification of those likely to respond to valganciclovir and will make it possible to assess response to treatment.

Chronic fatigue syndrome (CFS) is a clinically defined condition characterized by severe disabling fatigue and a combination of symptoms that prominently features self-reported impairment of concentration and short-term memory, sleep disturbances, and musculoskeletal pain. Prevalence of CFS in the adult population is estimated to be 0.007% to 2.8%. No pathognomonic signs or diagnostic tests for this condition have been yet validated in scientific studies; in addition, no definitive treatments are clinically available. Suggested etiologies of CFS include, but are not limited to: viral or bacterial infections, endocrine-metabolic dysfunction, immunological imbalance, neurally-mediated hypotension and depressioN. EBV and HHV-6 are among the viruses frequently thought as associated with CFS.

We recently encountered a group of patients at Stanford who were chronically infected with human herpes virus 6 (HHV-6) and Epstein-Barr virus (EBV), were suffering from debilitating fatigue for at least one year and experienced a significant improvement in their fatigue and cognitive symptoms following the administration of valganciclovir. Their antibody titers to both viruses were high (median antibody titer for EBV viral capsid antigen was 1:2560 and for HHV-6 IgG was 1:1280) despite the fact that some of them were known to have been infected with EBV and HHV-6 for several years. We suspected that their symptoms could be the result of an immune dysregulation triggered by high levels of replication of both EBV and HHV-6 (alterations in the immune system such as an aberrant cytokine profiles have been proposed as the central abnormality in patients with CFS associated with other viruses such as parvovirus B19. At the same time, we were familiar using valganciclovir in the context of several clinical settings including its known indications for reactivation of viral infections in immunocompromised patients. We were comfortable using valganciclovir (900 mg bid for three weeks followed by 900 mg qd to complete 3 to 12 months of treatment) in patients with solid and bone marrow transplants, cancer or other immunosuppressive disorders who had developed CMV, EBV, or HHV-6 disease.

We hypothesized that a long course (i.e. 6 months) of valganciclovir could effectively decrease or stop ongoing viral replication of both EBV and HHV-6 and that this virological effect could be translated in a clinical and laboratory benefit (i.e. decrease or resolution of lymphadenopathy, reversion of the CD4/CD8 ratio abnormalities). We were surprised to see that a dramatic recovery on the level of physical activity was also observed in the Stanford patients (from a median of 10% of energy level for daily activities at baseline to 90% after valganciclovir use). Of note, the drug has also been tried in patients in whom an improvement on their level of physical activity has not been observed. The total number of patients treated today is 30, 26 had "elevated titers" and 4 had "low titers". Of the 26 patients with "elevated titers", 25 have had a dramatic recovery. Of the 4 patients with "low titers", none have responded.

We believe that our successful experience with valganciclovir in a subset of patients with CFS at Stanford calls for a prospective study to exclude a placebo effect. We propose to measure viral, immunologic, and genomic endpoints to assess whether there are objective and measurable changes in these parameters and whether they correlate with clinical improvement. Clinical improvement will be assessed by objective measurements of daily physical and psychological activities. This will help to elucidate the possible role of HHV-6, EBV (or a yet to be known virus) and/or an altered immune system as triggers for the symptoms experienced by patients suffering CFS and to establish whether the drug valganciclovir does reverse these abnormalities. This study may also shed light on a biomarker or profile of biomarkers associated with (or diagnostic of) CFS.

We will be executing a randomized, double-blind, placebo-controlled clinical trial to evaluate the efficacy and safety of valganciclovir in patients experiencing chronic fatigue syndrome with elevated antibody titres against Human Herpesvirus-6 (HHV-6) and Epstein-Barr Virus (EBV)

Objectives

1. To determine whether the drug valganciclovir has a significant and real benefit on the central core of symptoms experienced by patients who have high titers to EBV and HHV-6 and are experiencing long-standing fatigue and cognitive impairment (CFS).
2. To characterize a quantifiable biological marker in these patients that will facilitate the identification of those likely to respond to valganciclovir and will make it possible to assess response to treatment.

Design of the study A double-blind, placebo-controlled, randomized clinical trial. All patients will be given the active drug (20 patients) or placebo (10 patients) for 6 months and followed for an additional 3 months. Patients on the placebo arm will take a valganciclovir look-alike tablet that does not contain the active drug for the initial six month period. Subsequently these patients will be offered a 6 month trial of valganciclovir if at the end of the study (when the last enrolled patient reaches 9 months from initiating therapy) it is clear that there is a benefit of valganciclovir therapy and patients have not spontaneously improved.

Kogelnik A, Rosso F, Hoegh-Petersen M and Montoya JG. Use of Valganciclovir in Patients Chronically Co-infected with Human Herpes Virus 6 (HHV-6) and Epstein-Barr Virus (EBV) who were Experiencing Long-standing Fatigue. J Clin Virol 2006 Volume 37, Supplement 1 S33-S38

Kerr JR, Cunniffe VS, Kelleher P, Bernstein RM and Bruce IN. Successful intravenous immunoglobulin therapy in 3 cases of parvovirus B19-associated chronic fatigue syndrome. Clin Infect Dis 2003;36:e100-6

Valganciclovir (Valcyte) for Chronic Fatigue Syndrome Patients Who Have Elevated Antibody Titers Against Human Herpes Virus 6 (HHV-6)and Epstein-Barr Virus (EBV)

A Randomized, Double-blind, Placebo-controlled Clinical Trial to Evaluate the Efficacy and Safety of Valganciclovir (Valcyte) in Patients Experiencing Chronic Fatigue Syndrome With Elevated Antibody Titers Against Human Herpesvirus-6 (HHV-6) and Epstein-Barr Virus (EBV)

Stanford University

Nutritional and Metabolic Diseases

Gland and Hormone Related Diseases

Heart and Blood Diseases

Diabetes Mellitus

Syncope

Syncope, Vasovagal

Acute Coronary Syndrome

Hypotension

Heart Failure

Atrial Fibrillation

Coronary Artery Disease

Myocardial Ischemia

Coronary Disease

Myocardial Infarction

Infarction

Hypertension

Heart Diseases

Ischemia

Heart Failure, Systolic

Cerebrovascular Disorders

Systolic Murmurs

Fibromyalgia

Myofascial Pain Syndromes

Autonomic Nervous System Diseases

Primary Dysautonomias

Ischemic Attack, Transient

Tachycardia

Heart Failure, Diastolic

Tachycardia, Sinus

Panic Disorder

Arrhythmias, Cardiac

Necrosis

Vascular Diseases

Rheumatic Diseases

Collagen Diseases

Cardiac Conduction System Disease

Unconsciousness

Consciousness Disorders

Neurobehavioral Manifestations

Neurologic Manifestations

Brain Ischemia

Brain Diseases

Central Nervous System Diseases

Orthostatic Intolerance

Mental Disorders

Psychotic Disorders

Tachycardia, Supraventricular

Acute Graft Versus Host Disease

Consecutive patients who consult a cardiologist - electrophysiologist since June 2006, regardless of the age or gender in the city of Medellin, Colombia. They could have consulted previously (considered as the enrollment date) if they had, at least, one measurement of their BP in supine position, and an immediate measurement of their BP in standing position that allows diagnosing their group of blood pressure. All patients have a record in paper and/or magnetic file and in OpenClinica.

No interventions.

Luis Eduardo Medina, MD.

Luis E Medina, MD

Jose F Florez, PhD

Jose M Cotes, PhD

The essential arterial hypotension and allostasis registry is a prospective, observational research that has the purpose of demonstrating that essential blood pressure (BP) disorders and the associated comorbidities are a result of the inappropriate allostatic response to daily life stress. This required a functioning brain orchestrating the evaluation of the threat and choosing the response, this is a mind-mediated phenomenon. If the response is excessive it contributes to high BP, if deficient to low BP, and the BP itself will identify the allostatic pattern, which in turn will play an important role in the development of the comorbidities.

To do so, consecutive patients of any age and gender that visit a cardiologist's office in Medellin, Colombia, are recruited. Individuals are classified according to their arterial BP and allostasis and follow them in time to see what kind of diseases develops the most (including BP) in the follow up according to the categorization of the characteristic chosen and after adjustment for confounder's variables. In addition, stress events with their date are registered.

HYPOTHESIS

The causes of the diseases are multifactorial.

Physical, biochemical, psychological, social, and cultural dimensions of development dynamically interact to shape the health development process.

A person´s health depends on their:

1. Biological and physiologic systems
2. External and internal environment (a) physical, b) internal behavioural and arousal state as registered by the brain.
3. Their interaction.

The allostatic mechanisms to the internal and external stressors (allostatic load) involves a network composed by:

1. Functional systems; mediated by:

   1. The Autonomic Nervous System
   2. The endocrine system
   3. The immune system
2. Structural changes: whenever the internal and/or external stressors are long lasting and/or strength enough, they may induce changes in:

   1. Epigenetic, endophenotypes, polyphenism.
   2. Plasticity
3. The interaction between a) and b).

The network response do not affect exclusively the BP, propitiating the development of comorbidities, which may prompt strategies for prevention, recognition and ultimately, treatment.

The allostatic model defines health as a state of responsiveness.

The concept of psycho-biotype: The allostasis is the result of both: biological (allostasis) and psychological (psychostasis) abilities. It is proposed that both components behave in similar direction and magnitude.

Immune disorders may be associated with the development of cancer. High BP population has a higher sympathetic and lower vagal tone, this has been associated with a decrease in the immune´s system function.

Resources and energy depletion: Terms like weathering have been used to describe how exposures to different allostatic loads gradually scrape away at the protective coating that keeps people healthy. It is postulated that High BP individuals have more resources and energy.

Essential Hypotension and Allostasis Registry

Essential Arterial Hypotension and Allostasis Registry

Clinical syncope characteristics (age of first syncope, number of syncope episodes, trauma, duration, clinical score, convulse, sphincter relaxation, etc.) Syncope cause Blood pressure group Adaptability group Prognosis

TTT protocol: describe the protocol, the time at positive response, nitroglycerine use, autonomic and hemodynamic variables.

TTT outcome for syncope: positive or negative TTT other outcomes: 1) Chronotropic incompetence, 2) arterial orthostatic hypotension, 3) carotid hypersensitivity, 4) POTS, 5) IST The relationship between TTT results and Clinical score for syncope in regard to: syncope behaviour and other orthostatic intolerance entities, symptoms and comorbidities.

The relationship between neurally mediated syncope response at the TTT and comorbidities.

EPS variables: AH, AV, CL, sino atrial conduction time (SACT), sinus node recovery time (SNRT), corrected sinus node recovery time (CSNRT), response to Isoproterenol, intrinsic heart rate Diagnosis: control, sick sinus syndrome, IST, chronotropic incompetence at the TTT HR at the ECG HR at the Holter monitoring HR at the TTT HRV at the Holter monitoring Syncope, cardiac or neurally mediated HR at the physical treadmill test Relationship with the blood pressure group Relationship with the adaptability group

Define how the blood pressure group and/or the adaptability group may add to the already known and include in this registry, in the diagnosis of cardiovascular complications as coronary artery disease, cerebrovascular disease, peripheral artery disease, nephropathy.

Blood pressure group: 1) Essential arterial hypotension, 2) normotension and 3) Essential arterial hypertension.

Adaptability group: Hyper adaptable, normal adaptability, hypo adaptable. Comorbidities: As describe in the protocol, as a summary: 1) cardiovascular, 2) metabolic, 3) Endocrine, 4) psychiatric disorders: depression and panic disorder, 5) orthostatic intolerance: neurally mediated syncope, vasovagal syncope, inappropriate sinus tachycardia, Postural orthostatic syndrome, carotid sinus hypersensitivity; 6) others: chronic fatigue syndrome, fibromyalgia, arthritis, autoimmune diseases, pulmonary thromboembolism, OSA (obstructive sleep apnea), Alzheimer disease, Parkinson disease, others dementias, epilepsia, nephropathies, COPD, and others.

Mortality

Blood pressure group: 1) Essential arterial hypotension, 2) normotension and 3) Essential arterial hypertension.

Adaptability group: Hyper adaptable, normal adaptability, hypo adaptable.

Psychiatric variables:

1. Big Five Questionary (BFQ) for personality.
2. Modify of the Coping Scale (Scale of modified coping strategies)
3. Zung questionary for depression and anxiety
4. MINI in those patients with moderate or severe depression and/or anxiety at the Zung questionary

High sodium intake in the diet is recognized as a risk factor for hypertension development.

Essential hypotension population is advised to increase the sodium (at least 10 grams a day) and water intake (at least 2 liters a day), or as much as possible, several have taken Fludrocortisone (is not a exclusion criteria). Normal blood pressure population are advised to have a normal or low sodium intake. Physical exercise is recommended in both groups.

This registry is a good opportunity to test how important sodium diet is to induce hypertension, or if by the contrary adaptability could prevail over high sodium intake in this registry.

Blood pressure groups: essential hypotension and normotension and those with new essential hypertension. Adaptability groups.

The results will be adjusted for age, gender and BMI.

Consistent bradycardia in the ECG at the office and normal HR in the holter monitoring or the contrary.

There are patients with complaints that may be attributed to bradycardia, low blood pressure, hypothyroidism, or other entities.

Some patients very often have bradycardia in the ECG taken in the office and normal HR in the 24 Holter monitoring, the opposite is also possible.

Patients with bradycardia (without medication or physiological condition as exersice affecting heart rate) in at least 2 ECG (less 60 bpm) and at least 2 Holter monitoring will be analyzed,

Other variables to consider are:

Age, gender, blood pressure group, adaptability group, maximum HR in the treadmill test, white coat or masked hypertension, Tilt-Table-test result or syncope cause, Electrophysiological study if available.

The acknowledge of this phenomenon could have clinical implications in the diagnosis of sick sinus syndrome and physiopathological ones.

Bradycardia is the classical presentation form for sinus node dysfunction, mainly when associated with symptoms. Chronotropic incompetence is also a manifestation. Absence of medications with effects on the heart rate (HR) must be ruled out.

Variables

1. HR at the ECG, Holter monitoring, stress text, and at the physical examination previous to pacemaker implantation,
2. Electrophysiological study (EPS): Basic cycle length, Sino-atrial conduction time, Sinus node recovery time, Corrected sinus node recovery time, Intrinsic HR when available 3. Pacemaker variables: HR at day and night or rest time Percentage of stimulation in A and V chambers 4. Syncope: Clinical characteriscs and clinical score Tilt table test results Trans Thoracic Echocardiogram in rest and or stress text Hypothesis: patients with ANSD will start to decrease the percentage atrial stimulation.

A non invasive, beat to beat BP monitoring, with the ability to measure BP, HR, Cardiac Output and Systemic Vascular Resistance (SVR) was started to use in the EHAR registry since May 2017. A description of this variables in the three BP groups will be collected in the data base (DB).

This will allow to characterize whether SVR and/or CO maintain BP. Until now BP levels are related with prognosis. In the prognosis model SVR and CO will be add them to know what matter the most: BP levels, SVR and/or CO? In the EHAR registry a collection of the variables recognized as a risk factor for several comorbidities are available to adjust in multivariable analysis.

Blood pressure group: 1) Essential arterial hypotension, 2) normotension and 3) Essential arterial hypertension.

Comorbidities: As describe in the protocol, as a summary: 1) cardiovascular, 2) metabolic, 3) Endocrine, 4) psychiatric disorders: depression and panic disorder, 5) orthostatic intolerance: neurally mediated syncope, vasovagal syncope, inappropriate sinus tachycardia, Postural orthostatic syndrome, carotid sinus hypersensitivity; 6) others: chronic fatigue syndrome, fibromyalgia, arthritis, autoimmune diseases, pulmonary thromboembolism, OSA (obstructive sleep apnea), Alzheimer disease, Parkinson disease, others dementias, epilepsia, nephropathies, and others.

Cardiovascular mortality Total mortality

Adaptability group: Hyper adaptable, normal adaptability, hypo adaptable. Comorbidities: As describe in the protocol, as a summary: 1) cardiovascular, 2) metabolic, 3) Endocrine, 4) psychiatric disorders: depression and panic disorder, 5) orthostatic intolerance: neurally mediated syncope, vasovagal syncope, inappropriate sinus tachycardia, Postural orthostatic syndrome, carotid sinus hypersensitivity; 6) others: chronic fatigue syndrome, fibromyalgia, arthritis, autoimmune diseases, pulmonary thromboembolism, OSA (obstructive sleep apnea), Alzheimer disease, Parkinson disease, others dementias, epilepsia, nephropathies, and others.

Cardiovascular mortality Total mortality

Blood pressure group: 1) Essential arterial hypotension, 2) normotension and 3) Essential arterial hypertension.

Adaptability group: Hyper adaptable, normal adaptability, hypo adaptable. Comorbidities: As describe in the protocol, as a summary: 1) cardiovascular, 2) metabolic, 3) Endocrine, 4) psychiatric disorders: depression and panic disorder, 5) orthostatic intolerance: neurally mediated syncope, vasovagal syncope, inappropriate sinus tachycardia, Postural orthostatic syndrome, carotid sinus hypersensitivity; 6) others: chronic fatigue syndrome, fibromyalgia, arthritis, autoimmune diseases, pulmonary thromboembolism, OSA (obstructive sleep apnea), Alzheimer disease, Parkinson disease, others dementias, epilepsia, nephropathies, and others.

Cardiovascular mortality Total mortality

Blood pressure group: 1) Essential arterial hypotension, 2) normotension and 3) Essential arterial hypertension.

Habits: smoke and drink

Anthropometric variables: Body mass index, waist, hip

Metabolic variables: Fasting glucose, 2 hs postprandial plasma glucose, insulin plasma levels, homoeostasis model assessment (HOMA), total cholesterol, LDL, HDL, triglycerides.

Endocrine variables: plasma cortisol, free cortisol in 24 hs. urine, epinephrine, norepinephrine, metanephrines, vanilmandelic acid, ACTH, aldosterone, renin, thyrotropine, free thyroxine, triiodothyronine, testosterone

Electrocardiogram: HR; PR interval, QRS complex, cQT interval

Holter variables: HR, standard deviation of NN intervals (SDNN) and sympathovagal balance, at day, night and 24 hs.

ABPM: Systolic, diastolic, and heart rate, at day, night and 24 hs., BP matinal surge.

Blood pressure group: 1) Essential arterial hypotension, 2) normotension and 3) Essential arterial hypertension.

Adaptability group: Hyper adaptable, normal adaptability, hypo adaptable.

Habits: smoke and drink

Anthropometric variables: Body mass index, waist, hip

Metabolic variables: Fasting glucose, 2 hs postprandial plasma glucose, insulin plasma levels, HOMA, total cholesterol, LDL, HDL, triglycerides.

Endocrine variables: plasma cortisol, free cortisol in 24 hs. urine, epinephrine, norepinephrine, metanephrines, vanilmandelic acid, ACTH, aldosterone, renin, thyrotropine, free thyroxine, triiodothyronine, testosterone

Electrocardiogram: PR interval, QRS complex, Heart rate, cQT interval

Holter variables: HR, SDNN and sympathovagal balance, at day, night and 24 hs.

ABPM: Systolic, diastolic, and heart rate, at day, night and 24 hs., BP matinal surge.

Blood pressure group: 1) Essential arterial hypotension, 2) normotension and 3) Essential arterial hypertension.

Adaptability group: 1) Hyper adaptable, 2) normal adaptability and 3) hypo adaptable.

Habits: smoke and drink, exercise

Anthropometric variables: Body mass index, waist, hip

Metabolic and other variables: Fasting glucose, 2 hs postprandial plasma glucose, insulin plasma levels, HOMA, total cholesterol, LDL, HDL, triglycerides; thyrotropine,

Holter variables: HR, standard deviation of NN intervals (SDNN) and sympathovagal balance, at day, night and 24 hs.

ABPM: Systolic, diastolic, and heart rate, at day, night and 24 hs., BP matinal surge.

Adaptability group: Hyper adaptable, normal adaptability, hypo adaptable.

Habits: smoke and drink Anthropometric variables: Body mass index, waist, hip

Metabolic variables: Fasting glucose, 2 hs postprandial plasma glucose, insulin plasma levels, HOMA, total cholesterol, LDL, HDL, triglycerides.

Endocrine variables: plasma cortisol, free cortisol in 24 hs. urine, epinephrine, norepinephrine, metanephrines, vanilmandelic acid, ACTH, aldosterone, renin, thyrotropine, free thyroxine, triiodothyronine, testosterone

Electrocardiogram: PR interval, QRS complex, Heart rate, cQT interval

Holter variables: HR, SDNN and sympathovagal balance, at day, night and 24 hs.

ABPM: Systolic, diastolic, and heart rate, at day, night and 24 hs., BP matinal surge.

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