“May 1747, I selected twelve patients in the scurvy…
Two were ordered each a quart of cyder a day.
Two others took twenty-five drops of elixir vitriol three times a day
Two others took two spoonfuls of vinegar three times a day
Two of the worst patients were put on a course of sea-water
Two others had each two oranges and one lemon given them every day
The two remaining patients, took an electary recommended by a hospital surgeon…
562 BC - 1537: Pre-James Lind Era - The Bible Book of Daniel - King Nebuchadnezzar Result: Vegetarians appeared better nourished than the meat-eaters |
1547: Ambroise Pare - Boiling oil in short supply for battle wounds Result: Digestive made of yolks of eggs, oil of roses and turpentine inflicted less pain |
1747: James Lind and Scurvy Trial – Controlled clinical trial Result: Oranges and lemons improved scurvy, but was expensive |
1800: Arrival of Placebo - 1863 United States physician Austin Flint planned the first clinical study comparing a dummy remedy to an active treatment. He treated 13 patients suffering from rheumatism Result: The favorable progress of the cases was such as to secure for the remedy, generally the entire confidence of the patients |
1943: The First Double Blind Controlled Trial - Patulin for Common Cold – the first double blind comparative trial with concurrent controls non-randomized Result: Common cold was not cured |
1946: First Randomized Curative Trial - The first randomized control trial of streptomycin in pulmonary tuberculosis was carried out in 1946 by MRC of the UK Result: Streptomycin and bed-rest (S case) was better than bed-rest alone (C case). Note: Streptomycin was in short supply otherwise this study would not have been performed |
The last breakthrough in medical studies is attributed to Great Britain and the Medical Research Council of 1946. The trial was the first randomized controlled trial of streptomycin in pulmonary tuberculosis. One of the factors that helped launch this new medical research approach was the shortage of streptomycin. The trial was accepted because it gave patients an even chance to get the drug when there was not enough to go around. Randomization was a new concept championed by Sir Leonard Erskine Hill. “I deliberately left out the words ‘randomization’ and ‘random sampling numbers’ at that time, because I was trying to persuade doctors to come into controlled trials in the very simplest form and I might have scared them off “ [10].
Open Source research implies that a number of different protocols are available to solve a clinical problem. Access is open to all registered physicians. The source will provide clinical science information, research protocols, consent forms, and be designated as data collection center for all of the data entered by the approved protocols. A governing committee will oversee the protocols submitted for scientific merit and safety. A biostatistician will oversee the results of each protocol. The treating physician will choose a protocol from this site and obtain local approval from their Investigational Review Board (IRB). This task will be fast tracked by the IRB’s knowledge that governing committee approved the protocol before being made available as an open source protocol. The governing committee will routinely send to all local IRB’s the protocols that have been approved specifically for the treatment of peripartum myocardial infarction. The local committee will act on these protocols as they deem fit and the protocols will be active for recruitment when a patient presents in the future. Each site will be locally managed. The physician or his designee will be responsible for collecting data and entering the data into the Open Source site. These data are depersonalized for the privacy of the patient, but is accessible to all physicians. Outcomes are immediately available and can serve as an aid in the physicians’ choice of which protocol to choose for their patient. The Web site and data are part of a quality initiative to determine the safest and most effective therapies. The quality initiative nature of the site should grant protective disclosure.
370 BC: Hippocratic Oath that specified a prime duty of a physician – to avoid harming the patient. |
1947: Nuremberg Code highlighted the essentiality of voluntariness of this consent. |
1948: Universal Declaration of Human Rights expressed concern about rights of human beings being subjected to involuntary maltreatment. |
1962: Kefauver-Harris amendments manufacturer provides proof of the effectiveness and safety of their drugs before approval. |
1964: Helsinki Declaration outlines general principles and specific guidelines on use of human subjects in medical research. |
1974: US National Research Act and 1979: Belmont Report were major efforts in shaping ethics of human experimentation a result of Henry Beecher's 1966 study of abuses and the discovery of human exploitation of Tuskegee study
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1996: International Conference on Harmonization, Good Clinical Practice, is the universal standard for ethical conduct of clinical trials. |
Governing Body Personnel will be selected by professional societies directly impacted by the clinical problems the open resource research is trying to answer. For example, for peripartum myocardial infarction – world-wide professional societies of cardiology, ob/gyn, heart failure, immunology, and others will be invited. Their responsibilities will be to review and approve protocols for scientific merit and safety concerns, data monitoring for safety concerns, and provide periodic summary of data. All publications will be reviewed by this committee. After peer review of the publications, the journal articles will then be posted on the site as online open access. Intellectual property will belong to the governing body and resources obtained from the intellectual property will be managed by this committee and distributed to worthy researchers. The governing body will be composed of selected respected researchers who will serve only as advisors. The voting body will be made up of two young investigators selected by each respected researchers. This youthful group will be the voting and regulatory arm. They should serve for three years and then be replaced.
Data Partner is an integral part of open access to assure security, accurate data collection and analytic review. The partner will have to have a global network of servers and redundancy of data to assure the input of data and data banks are accurate and to standards. Data collected will be demographic, laboratory results, protocol used, protocol deviations, medical images. The physicians who entered their patients will complete the data set. The case material with full de-identified clinical information will be immediately available to physicians deciding on a protocol and for expert adjudication.
Biostatistician This individual will be employed by the governing body to assure accuracy of clinical data and provide statistical review as data accumulates. Initially, results will be compared to historical controls and as more data is accumulated the individual protocols will be compared. His job will be similar to James Lind finding the protocols that have the best success.
Tissue, genetic, proteomic specimens will be collected with the appropriate consent of the patients for analysis. The specimens will be released by the governing committee to laboratories across the world that have applied for specimens and have demonstrated expertise. All results will be open and shared with the entire community of researchers. Intellectual property will belong to the group and not the individual. Open forum between researchers around the world will be provided by the data manager. Transparency at all levels is necessary. The goal is to solve problems and not obtain research grants, fame, or fortune. Reward the group and not the individual.
Funding of the governing body will be sponsored by professional societies since the goal of disease management is the same goal as professional societies. The web site could be sponsored by major medical journals or government. The data partner would be the industry that manages the “Cloud”, approached as an altruistic motive. Other incentives to the data partner are this new innovative platform can be applied to other disciplines as well. Therapies provided will be at the expense of the local health care system. The advantage to them is a timely solution that can save future dollars in these rare, but expensive medical problems. The income from intellectual property could be used to fund future research independent of government funding eventually self-funding its research efforts. Contractual agreements with governments and industry will be allowed as long as these agreements meet the needs of disease management and are approved by the governing committee. Funds will be distributed by the same organization to researchers who do the work.
Physician Prospective - Rare diseases like peripartum myocardial infarction, peripartum cardiomyopathy, and myocarditis have no clinical treatment guidelines. They are difficult to study. When confronted with an unusual disease process, it is frustrating to watch patients suffer. Open source research provides to the physician treatment protocols based on biologic models. They can select the therapy that they feel best represents the biological model. Treating the patient and entering the data will soon give evidence that the treatment was successful. Physicians will be more likely to enroll patients when they have active control of the therapies. Protocol violations can also be studied that may lead to other knowledge that can affect the model of disease.
Researcher Prospective – The researcher can have access to difficult to obtain biological samples. Networking with other researchers can solve problems at a faster rate by not only reducing duplications, but by also allowing confirmation of results. The researcher will have to give up the individual glory that has been the incentive and the disincentive of these individuals as they apply their knowledge. The model of rewarding the individual will be replaced by rewards to the group. The researcher will have to shift ideas of success from individual to group. The openness of this model can simplify applications and replace lengthy grant writing. Chat rooms provided by the site open to registered researchers can be an intellectual boom.
We have reported two case reports, figure 1, using the protocol listed in table 3 that only intervened on the immune and thrombotic pathways. These cases occurred 7 years apart; both, had multi-vessel infarctions and had dramatic improvement in their outcome with no residual cardiac disease. There was evidence in both of these cases of thrombosis and dissection and spasm events. The biologic model behind these two rare events is proposed as fetal paternal antigens stimulating an abnormal immune response to maternal coronary endothelium.6 The protocol uses multiple interventions to reset the immune system. It appears to be safe since it is immune modifying and not immune suppressive. It can provide sera from the plasmapheresis which may be analyzed by research groups to identify the abnormal immune pathways and abnormal antibodies. Our proposed method to treat the underlying ivmmune process is appealing when the coronary anatomy cannot be re-vascularized. This method is listed in table 3.
The interventionist could choose to intervene in the discrete groups 2 through 7. In these groups the specific aim (1) would be to determine if intervention is beneficial or harmful and characterize the angiographic characteristics of each. Flow in the vessel, additional complications such as closure of a new vessel because of dissection would be one metric, death or need for bailout procedure is another metric along with current echo and follow up echo in 6 months. The hypothesis (1) is intervention and surgery is harmful in these groups.
In groups 8 through 11 the diffuse nature of the disease could be treated by multiple vessel angioplasties, surgery, standard medication, or treated by the immune modifying protocol. In these groups outcomes can be compared. The outcomes would be death, left ventricular function during hospitalization and at 6 months. In the cases that were treated with angioplasty similar angiographic scores will be evaluated. The specific aim (2) would be determine if immune modification is better than traditional angioplasty, surgery, or medications. The Hypothesis (2) peripartum myocardial infarction is an immune disease and immune modification can favorably alter the outcome.
The open source model displaying outcomes of each treatment for physician review will iterate to the most successful therapies. The final answer may be immune therapy for all cases or will describe cases that are best suited for catheter intervention. The open source model will determine if the immune hypothesis is correct and how effective is immune modification. Open source means that new protocols could be introduced based on new information. The protocols can be adjusted and eventually the
Plasmapheresis Plasmapheresis should be initiated as soon as possible and repeated early in the admission. The intended therapy is to rapidly address a humeral immune mediated process and to favorably alter rheological and thrombotic properties of blood. In addition, Intravenous Immune Globulin (IVIG) should be given after the first plasmapheresis is completed and repeated after exchanges or during a holiday from plasma exchange. In both cases, plasma exchange sequence was guided by response to therapy. Concern for bleeding risk was judged by fibrinogen value or by clinical impression of postpartum blood loss. Either albumin or fresh frozen plasma may be used for volume replacement. Daily clotting factors and fibrinogen levels should be obtained to help make this decision. |
IVIG 60 GM IV after completion of plasma exchange times 4. Pretreatment with Acetaminophen 500mg and Benadryl 50mg may be given. Infusion rate 0.5 ml/kg/hr for 30 minutes increased to 1ml/kg/hr for 30 minutes, then 2ml/kg/hr. Do not give prior to a plasma exchange. |
Steroids IV Solumedrol 1gm every day times 3 Then begin oral prednisone 50mg daily with every other day taper of 10 mg until 10 mg per day is achieved. This represents a burst for approximately two weeks. Continue 10 mg per day for three weeks, then reduce to 5 mg for one week, then 5 mg every other day for a week, then 2.5 mg every other day for an additional week, then stop. Increase dose for flares in disease activity |
Anti-Platelets Aspirin 324 mg initially, on discharge reduced to 81 mg for life Clopidogrel 300 mg load on presentation, 75mg daily for 6 months, discontinued after favorable performance on treadmill |
Anti-Thrombin anticoagulation Heparin bolus and infusion per protocol (plasmapheresis line placed with imaging while on heparin by experienced personnel) Warfarin therapeutic INR before heparin is discontinued and continued for 3 months |
Anti-Ischemic IV nitroglycerine transitioned to oral nitrates Calcium channel blockers if ischemia on nitrates |
Post Myocardial infarction (anti-inflammatory) ACEI for 6 months, consider discontinuing if left ventricular function is normal and blood pressure is normal Statin on admission at least 6 months consider discontinuing if Hs-CRP low Spironolactone if ejection fraction is reduced. |
Heart Failure (anti-inflammatory) ACEI for 6 months, consider discontinuing if left ventricular function is normal and blood pressure is normal Statin on admission at least 6 months, consider discontinuing if Hs-CRP is low Spironolactone Other congestive heart failure therapies as needed including balloon pump, loop diurectics, Nesseritide, RVAD, LVAD, and Defibrillators including bi-ventricular devices |
Lactation Lactation by breast pump is potentially beneficial; however, breast feeding of the infant should be avoided if maternal medications have an adverse effect on the infant. |
Birth Control Avoid birth control pills first 6 months, abstinence, barrier method and preferred method is vasectomy of partner. Advise against future pregnancies. |
2. The Doctor may select the protocol for his patient
3. The results are made available in real time to help select the protocol for the next case serving as continuous safety monitoring. Summaries presented by biostatistician.
4. Local IRB’s are sent protocols by the governing body for their approval instead of investigator-initiated protocol. The protocols are approved prior to a rare case presenting. The protocol, consent forms are immediately available without delay being available online.
5. This method fosters group participation and rewards moving away from the individual centered research promoting disclosure and cooperation.
6. Funding is minimal with the cooperation of professional societies, treatment costs being absorbed by local health systems.
7. The web site becomes the definitive source of information of medical literature on those rare diseases; chat room on the site will allow collaboration of researcher working on a common problem.
8. This model can be applied to other rare diseases
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- Roth A, Elkayam U. Acute Myocardial Infarction Associated With Pregnancy. Journal of the American College of Cardiology. 2008;52(3):171-180. doi: 10.1016/j.jacc.2008.03.049.
- http://www.cdph.ca.gov/data/statistics/Pages/CaliforniaPregnancy-AssociatedMortalityReview.aspx
- Elkayam U. Clinical characteristics of peripartum cardiomyopathy in the United States: diagnosis, prognosis, and managment. J Am Coll Cardiol. 2011;58(7):659-670. doi: 10.1016/j.jacc.2011.03.047.
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- Hill AB. Suspended judgment: Memories of the British Streptomycin Trial in Tuberculosis. The first randomized clinical trial. Controlled Clinical Trials. 1990:11(2);77-79.
- http://materiais.dbio.uevora.pt/MA/Modulo2/Artigos/SoCRA-Perlman.pdf
- Nolan JP, Morley PT, Vanden Hoek TL, et al. Therapeutic Hypothermia After Cardiac Arrest. An Advisory Statement by the Advanced Life Support Task Force of the International Liaison Committee on Resuscitation Circulation. 2003;108:118-21.
- Open-source movement. Available from: https://en.wikipedia.org/wiki/Open-source_movement
- Ladner HE, Danielson B, Gilbert WM. Acute myocardial infarction in pregnancy and the puerperium: a population-based study. Obstetrics and Gynecology. 2005;105(3):480-484.