EDC – Target e*Studio Development Partners – Orphan Drug Meeting
Warren Pearlson, Target Health’s Director of Business Development will attend DIA’s US Conference on Rare Diseases and Orphan Products on October 7-9, 2013 North Bethesda Marriott. Please let us know if you will be attending.
Target Health Inc. is also pleased to announce that TechnoSTAT Ltd. (Israel), is now using Target e*Studio® to create Target e*CRF® EDC studies/applications. TechnoSTAT will be initiating a multicenter center study with approximately 170 subjects, lasting 18 months and will generate the EDC forms, program the edit checks, provide central randomization and manage users. Target e*Studio features include:
- One log-in for all features
- Fully functional data capture and data management system
- Barcode-enabled subject ID module
- Target e*CTR (eClinical Trial Record; eSource)
- Drug/device supply management module
- Pharmacovigilance module
- Risk-based monitoring reports
- Integration with Target Encoder
- And much more
For more information about Target Health contact Warren Pearlson (212-681-2100 ext. 104). For additional information about software tools for paperless clinical trials, please also feel free to contact Dr. Jules T. Mitchel or Ms. Joyce Hays. The Target Health software tools are designed to partner with both CROs and Sponsors. Please visit the Target Health Website
Horizontal Gene Transfer
Horizontal gene transfer (HGT) refers to the transfer of genes between organisms in a manner other than traditional 1) ___. Also termed lateral gene transfer, it contrasts with vertical transfer, the transmission of genes from the parental generation to offspring via sexual or asexual reproduction. HGT has been shown to be an important factor in the evolution of many organisms. Horizontal gene transfer is the primary reason for bacterial antibiotic resistance, and plays an important role in the evolution of bacteria that can degrade novel compounds such as human-created pesticides and in the evolution, maintenance, and transmission of virulence. This horizontal gene transfer often involves temperate bacteriophages and plasmids. Genes that are responsible for antibiotic resistance in one species of bacteria can be transferred to another 2) ___ of bacteria through various mechanisms (e.g., via F-pilus), subsequently arming the antibiotic resistant genes’ recipient against antibiotics. This is the most critical reason that 3) ___ must not be consumed and administered to patients without appropriate prescription from a medical physician.
Most thinking in genetics has focused upon vertical transfer, but there is a growing awareness that horizontal gene transfer is a highly significant phenomenon and among single-celled organisms perhaps the dominant form of genetic transfer. Artificial horizontal gene 4) ___ is a form of genetic engineering. There are several mechanisms for horizontal gene transfer:
1. Transformation, the genetic alteration of a cell resulting from the introduction, uptake and expression of foreign genetic material (DNA or RNA). This process is relatively common in bacteria, but less so in eukaryotes. Transformation is often used in laboratories to insert novel genes into 5) ___ for experiments or for industrial or medical applications.
2. Transduction, the process in which bacterial DNA is moved from one bacterium to another by a virus (a bacteriophage, or phage).
3. Bacterial conjugation, a process in which a bacterial cell transfers genetic material to another cell by cell-to-cell contact.
4. Gene transfer agents, virus-like elements encoded by the host that are found in the alphaproteobacteria order Rhodobacterales.
Genetic 6) ___ is essentially horizontal gene transfer, albeit with synthetic expression cassettes. The Sleeping Beauty transposon system (SB) was developed as a synthetic gene transfer agent that was based on the known abilities of Tc1/mariner transposons to invade genomes of extremely diverse species. The SB system has been used to introduce genetic sequences into a wide variety of animal genomes.
The virus called Mimivirus infects amoebae. Another virus, called Sputnik, also infects amoebae, but it cannot reproduce unless mimivirus has already infected the same cell. “Sputnik’s genome reveals further insight into its biology. Although 13 of its genes show little similarity to any other known 7) ___ genes, three are closely related to mimivirus and mamavirus genes, perhaps cannibalized by the tiny virus as it packaged up particles sometime in its history. This suggests that the satellite virus could perform horizontal gene transfer between viruses, paralleling the way that bacteriophages ferry genes between bacteria.”
Horizontal gene transfer is common among bacteria, even among very distantly related ones. This process is thought to be a significant cause of increased drug resistance when one bacterial cell acquires resistance and quickly transfers the 8) ___ genes to many species. Horizontal gene transfer also plays a role in the spread of virulence factors, such as exotoxins and exoenzymes, amongst bacteria. Strategies to combat certain bacterial infections by targeting these specific virulence factors and mobile genetic elements have been proposed.
Sequence comparisons suggest recent horizontal transfer of many genes among diverse species including across the boundaries of phylogenetic domains. Thus determining the phylogenetic history of a species cannot be done conclusively by determining evolutionary trees for single genes.
1. Analysis of DNA sequences suggests that 9) ___ gene transfer has also occurred within eukaryotes from the chloroplast and mitochondrial genomes to the nuclear genome. As stated in the endosymbiotic theory, chloroplasts and mitochondria probably originated as bacterial endosymbionts of a progenitor to the eukaryotic cell.
2. Horizontal transfer of genes from bacteria to some fungi, especially the yeast Saccharomyces cerevisiae, has been well documented.
3. There is also recent evidence that the adzuki bean beetle has somehow acquired genetic material from its (non-beneficial) endosymbiont Wolbachia. New examples have recently been reported demonstrating that Wolbachia bacteria represent an important potential source of genetic material in arthropods and filarial nematodes.
4. There is also evidence for horizontal transfer of mitochondrial genes to parasites of the Rafflesiaceae plant family from their hosts (also plants), from chloroplasts of a not-yet-identified plant to the mitochondria of the bean Phaseolus, and from a heterokont alga to its predator, the sea slug Elysia chlorotica.
5. Striga hermonthica, a eudicot, has undergone a horizontal gene transfer from sorghum (Sorghum bicolor) to its nuclear genome. The gene is of unknown functionality.
6. Researchers at the University of Arizona have found that the genome of pea aphids (Acyrthosiphon pisum) contains multiple genes that were horizontally transferred from fungi. Plants, fungi, and microorganisms can synthesize carotenoids, but torulene made by pea aphids is the only carotenoid known to be synthesized by an organism in the animal kingdom.
7. It was recently suggested that the malaria causing pathogen Plasmodium vivax has horizontally acquired genetic material from humans that might help facilitate its long stay in the body.
8. A 2012 paper proposes a novel bacteriophage-mediated mechanism of horizontal gene transfer between prokaryotes and eukaryotes. The authors show the widespread presence of nuclear localization signals in bacteriophage terminal proteins (TP), which prime DNA replication and become covalently linked to the viral genome. Taking into account the known role of virus and bacteriophages in HGT in bacteria, the authors propose that TP-containing genomes could be a vehicle of inter-kingdom genetic information transference all throughout 10) ___.
9. The HhMAN1 is a gene in the genome of the coffee borer beetle (Hypothenemus hampei) that resembles bacterial genes, and is thought to be transferred from bacteria in the beetle’s gut.
ANSWERS: 1) reproduction; 2) species; 3) antibiotics; 4) transfer 5) bacteria; 6) engineering; 7) genes; 8) resistance; 9) horizontal; 10) evolution
Sydney Brenner MD (1927 to present)
The Nobel Prize in Physiology or Medicine in 2002 awarded to Sydney Brenner, H. Robert Horvitz, John E. Sulston “for their discoveries concerning genetic regulation of organ development and programmed cell death”.
Sydney Brenner’s 2002 Nobel Prize Acceptance Speech
An autobiography published a few years ago records many of the salient events in my life which led me to become a scientist and my Nobel Lecture covers the intellectual background and consequences of the research work for which the Prize has been awarded.
In this somewhat compressed version, I start with my birth on the 13th January 1927 in a small town, Germiston, in South Africa. My parents were Jewish immigrants from Eastern Europe; my father came to South Africa from Lithuania in 1910, my mother, from Latvia, in 1922. My father was a shoe repairer and our first home was in some rooms at the back of his shop. He never learnt to read or write but, in addition to English, Yiddish and Russian, he learnt to speak Afrikaans and Zulu. I learnt to read at an early age, and a customer of my father, Miss Walkinshaw, persuaded my father to allow me to go at the age of five without charge to her kindergarten. I completed the first three years of primary school in one year and was admitted to the local school the age of six directly into the fourth year, some two years younger than all my contemporaries. After 4 years in primary school, I went to Germiston High School where I matriculated in December 1941, just before turning 15.
During this time I discovered the Public Library in Germiston, one of the many libraries set up all over the world with funding from Andrew Carnegie’s endowment. It was here that I found a source of knowledge and the means to acquire it by reading, a habit of learning which I still follow to this day. I also became interested in chemistry and gradually accumulated enough test tubes and other glassware to do chemical experiments, using small quantities of chemicals purchased from a pharmacy supply house. I soon graduated to biochemistry and tried to discover what gave flowers their distinctive colors. I made the (to me) astounding discovery that the pigments I extracted changed their colors when I changed the pH of the solution.
I was fortunate in that the Town Council of Germiston gave me a bursary of 60 pounds per year that allowed me to go to the University of the Witwatersrand in Johannesburg to study medicine and, in 1942, at the age of fifteen, I began the course studying Physics, Chemistry, Botany and Zoology. I lived at home and I cycled every morning to the railway station to travel by train to Johannesburg followed by a walk to the University, carrying sandwiches for my lunch and returning in the evening the same way. My Uncle Harry had given me a microscope as a present which allowed me to continue my personal explorations of the living world. This was the beginning of my contacts with the real science. In my second year, after moving to the Medical School, I began the courses of Anatomy and Physiology. I had begun to see that I was interested in cells and their functions.
It was noted then that I would be too young to qualify for the practice of medicine at the conclusion of my six year medical course and I was allowed to deviate and spend one year in a Medical B.Sc. course in Anatomy and Physiology. This was heaven. The small group of about a dozen students inhabited a small room in the Anatomy Department where we each had a small laboratory bench. We learnt how to do research by working in small groups with more advanced researchers in the Department. I learnt physical chemistry with Joel Mandelstam (later Professor at Oxford University), microscopy with Alfred Oettle, and neurology with Harold Daitz who became a close friend and who died at a very early age in Oxford. Raymond Dart and Robert Broom taught me anthropology and paleontology, and the man who inspired all this activity was Joseph Gillman, a histologist who had created a centre of research in that isolated place. He invited me (I needed no persuasion) to continue with research and I stayed on for two more years doing an Honors degree and then an M.Sc., supporting myself by working part-time as a laboratory technician. I read many books and taught myself many subjects during this period, learnt how to build equipment and how to do experiments, and had many arguments and discussions with Joe Gillman. I also began to publish papers. My scientific bibliography begins in 1945 with a paper published with Joe Gillman and his brother, Teddy, but my first paper as sole author appeared in 1946. This paper dealt with a histochemical reaction, and it was the first of several which reflected my growing interest in a subject which I later called cell physiology. My M.Sc. thesis was in the field of cytogenetics, another self-taught subject, and this was the beginning of my research in genetics. This background was to serve me well in later years when I became a molecular biologist.
In 1946, W. Le Gros Clark visited South Africa and invited me to come to his Department of Anatomy in Oxford, but I was advised by everybody to finish my medical course, because it was believed then that a medical qualification would be essential for a research position later. I did go back to my medical studies but I continued working in the Department of Anatomy and moved to the Department of Physiology when Joe Gillman became Professor there. I was not a good medical student and had an erratic career, brilliant in some subjects, absolutely dismal in others. In my final year I failed Medicine, scraped through Surgery but got a First Class in the third subject, Obstetrics and Gynecology. I had to go back and repeat Medicine and Surgery and six months later, in July 1951, I finally received the degrees of MB BCh. I had already decided that I would do research and that I needed to go abroad. CH Waddington, who had earlier visited South Africa had advised me to go to Cambridge. I applied to the Department of Biochemistry and never even received a reply. I had decided that the subject I was interested in was molecular biology which, of course, did not exist at the time, and when I was awarded a scholarship by the Commission for the Royal Exhibition of 1851, H. Raikes, head of the University of Witwatersrand, who was originally an Oxford trained chemist, advised me to write to C.N. Hinshelwood, the Professor of Physical Chemistry at Oxford University, who had interests in the applications of physical chemistry to biology. That sounded closer to what I wanted to do. Hinshelwood had written a book called the “Chemical Kinetics of the Bacterial Cell” which I read and thought was in the direction I wanted to go. He accepted me and suggested I work on bacteriophage resistance in bacteria. I immediately began to read about bacterial viruses and in October 1952 I arrived in Oxford to do a Ph.D. in the Physical Chemistry Laboratory.
There was still food rationing in England and life was difficult all through my 2 year stay in Oxford. In addition, I and the others were outsiders three times over; we were scientists, we were research students and we were colonials. Many of my friends in Oxford shared these stigmata and the only compensation was the opportunity to join Halifax House and lunch there. This was where I met Jack Dunitz, a crystallographer, and through him Leslie Orgel, a theoretical chemist, both of whom have remained lifelong friends and colleagues. We had many discussions on DNA, for I had come to Oxford with two half ideas both of which were more than half wrong. One was a way of working out the structure of DNA using dyes and the other was how nucleic acids could participate in the synthesis of proteins. I can remember in November 1952 Jack telling me about two fellows in Cambridge who were going to solve the structure of DNA. When in April 1953, Jack told us that these two fellows in Cambridge, Francis Crick and Jim Watson, had indeed solved the structure of DNA, Jack, Leslie and I drove to Cambridge on a day between the 16 and 18th April to see the model.
This was the watershed in my scientific life. The moment I saw the model and heard about the complementing base pairs I realized that it was the key to understanding all the problems in biology we had found intractable – it was the birth of molecular biology. It was a revelation reinforced by conversing with Jim Watson at greater length during a walk we took together, when I realized that working with bacteriophage had put me on the right road to enter this exciting new field, even though what I was doing was trivial.
My wife and I were married in London in December 1952 and she was also engaged in doing a Ph.D. in Psychology in London. She was allowed to move to Oxford and, until June 1954, we lived in a flat in Woodstock Road working on our theses, had a child in addition to my stepson, Jonathan, dreaming all the time of food and the warm climate of our native South Africa.
An opportunity to visit the United States came about when Dr. M. Demerec, the director of the Carnegie Institution Laboratory at Cold Spring Harbor visited Sir Cyril Hinshelwood. It was Demerec who invited me to Cold Spring Harbor and who helped me to obtain a Carnegie Corporation Travelling Fellowship which enabled me at the end of the summer in Cold Spring Harbor to make a trip across the United States to visit other laboratories. I drove across America with Jim Watson to Cal Tech and I then had a period of research at the Virus Laboratory in Berkeley, working with Gunther Stent. I also had made a short visit to Washington, D.C.
My visit to America was important because through it I met many of the then important workers of the Phage School, Seymour Benzer, who became a lifelong colleague and friend, Max Delbruck, the founder of the phage school, Salvador Luria and many others who were destined to play important roles in the development of the new science of molecular biology. I had also met Francis Crick again in Woods Hole and Cold Spring Harbor and visited him in Cambridge in December 1954 on my way back to South Africa. At this meeting we discussed how I might join him in the future and I returned to South Africa at the end of 1954 as I was committed to do so by the terms of the Carnegie Corporation Fellowship.
I set up a laboratory in the Department of Physiology in the Medical School in South Africa and begin to try to find a bacteriophage system which we might use to solve the genetic code. I also continued to work on some theoretical aspects of the genetic code and during this period was able to prove the impossibility of all overlapping triplet codes which was circulated in an RNA Tie Club note and later communicated to the Proceedings of the National Academy of Sciences by George Gamow. Francis worked hard to get me an appointment at the Medical Research Council Unit in Cambridge and in December 1956 we left South Africa for a new career in England. I did all of my work on molecular genetics in the Cavendish Unit and its successor, the MRC Laboratory of Molecular Biology, where the work on C. elegans was initiated and developed. I spent 20 years sharing an office with Francis Crick and many new and exciting ideas (both right and wrong) were generated from our conversations. The centre point of our interests had begun to diverge and whereas we were both interested in the nervous system, I was far more interested in finding a simple experimental system which might tell me how brains were constructed, whereas Francis wanted to know about the complex activities of higher nervous systems. He left Cambridge in 1976 to join the Salk Institute where he pursued an entirely new career in neuroscience.
In 1977, I was appointed proleptic Director of the MRC Laboratory to succeed Max Perutz on his retirement in 1979. However, I immediately took over the financial management of the laboratory and spent several years in trying to get the finances on a proper basis. These were times of hyperinflation in Britain and not enough attention had been given to the rising costs of our research. I often referred to myself as the epileptic Director. During this period, I became interested in how the new techniques of cloning and sequencing DNA could influence the study of genetics and I was an early and active proponent of the Human Genome Sequencing Project. By 1985, I found that the administrative load of the Director was becoming tiresome and interfering with what I still wanted to do in research and so when I was asked whether I wanted to continue as Director after 1987 when my term of appointment ended, I jumped at the opportunity and left the laboratory in 1986 when my successor took office. The MRC gave me a small Unit and, with some added resources, I set up a Unit of Molecular Genetics based in the Department of Medicine where space was provided for me by Professor Keith Peters. It was in this Unit that the pufferfish project began. The Unit was closed by the MRC in 1992 when I was 65 but I continued the laboratory with other support for some years thereafter. In the meantime, it became imperative for health reasons that I spend the winter months in a warmer climate and Richard Lerner made this possible by giving me a part time appointment in The Scripps Research Institute in La Jolla, California. Here I found I could pursue new interests in chemistry and especially in the interface between chemistry and biology. I also became involved in a company in the San Francisco Bay Area called Lynx where together with another friend, Sam Eletr, we developed a new massively parallel method for sequencing DNA. In 1995, I founded The Molecular Sciences Institute with a gift from the Philip Morris Company where I hoped that we could create an environment where young people could pursue science in an atmosphere of harmonious purpose and high intellectual challenge. I retired from the Institute in 2000 and in 2001 was appointed a Distinguished Professor in the Salk Institute in La Jolla where I rejoined Francis Crick.
I owe a great debt to the many people who have helped me in my life. My parents would have preferred me to become a surgeon or a physician but were most understanding of the ambitions of their son. My wife and family have borne the burden of a preoccupied husband and father for fifty years. Living most of the time in a world created mostly in one’s head, does not make for an easy passage in the real world. Throughout my scientific life and in all my projects I have been joined by many scientists, young and old, whose work was absolutely essential for the success of our scientific endeavors. Many have gone on to do important scientific work but all remember those wonderful times when we and our science were young and our excitement in meeting new challenges knew no bounds. I believe that a scientist should be judged by the quality of the people he has helped to produce and not by prizes or other honors bestowed on him. Let my works speak for themselves.
I am still, at the age of 76, excited by scientific research and the prospect of what can be done in biology. Science is something one is tied to for life and one should never retire from anything until one has secured one’s next job. The endless quest for knowledge will continue as long as humans exist.
From Les Prix Nobel. The Nobel Prizes 2002, Editor Tore Frangsmyr, [Nobel Foundation], Stockholm, 2003 This autobiography/biography was written at the time of the award and later published in the book series Les Prix Nobel/Nobel Lectures. The information is sometimes updated with an addendum submitted by the Laureate.
“American plan” and “European plan”
The “American plan” and “European Plan” were proposed by Sydney Brenner as competing models for the way brain cells determine their neural functions. According to the European plan (sometimes referred to as the British plan), the function of cells is determined by its genetic lineage. Therefore, a mother cell with a specific function (for instance, interpreting visual information) would create daughter cells with similar functions. According to the American plan, a brain cell’s function is determined by the function of its neighbors after cell migration. If a cell migrates to an area in the visual cortex, the cell will adopt the function of its neighboring.
Editor’s note: To read more about the life of Sydney Brenner and his thrilling contributions to science, start by clicking here: http://en.wikipedia.org/wiki/Sydney_Brenner
Adenovirus-Associated Virus Vector–Mediated Gene Transfer in Hemophilia B
Hemophilia B, an X-linked disorder, is ideally suited for gene therapy. As a result, a study published in the New England Journal of Medicine (2011;365: 2357–2365) investigated the use of a new gene therapy in patients with the disorder.
For the study, a single dose of a serotype-8–pseudotyped, self-complementary adenovirus-associated virus (AAV) vector expressing a codon-optimized human factor IX (FIX) transgene (scAAV2/8-LP1-hFIXco) was infused in a peripheral vein in 6 patients with severe hemophilia B (FIX activity, <1% of normal values). Study participants were enrolled sequentially in one of three cohorts (given a high, intermediate, or low dose of vector), with two participants in each group. Vector was administered without immunosuppressive therapy, and participants were followed for 6 to 16 months.
Results showed that AAV-mediated expression of FIX at 2 to 11% of normal levels was observed in all participants. Four of the six discontinued FIX prophylaxis and remained free of spontaneous hemorrhage; in the other two, the interval between prophylactic injections was increased. Of the two participants who received the high dose of vector, one had a transient, asymptomatic elevation of serum aminotransferase levels, which was associated with the detection of AAV8-capsid-specific T cells in the peripheral blood; the other had a slight increase in liver-enzyme levels, the cause of which was less clear. Each of these two participants received a short course of glucocorticoid therapy, which rapidly normalized aminotransferase levels and maintained FIX levels in the range of 3 to 11% of normal values.
According to the authors, peripheral-vein infusion of scAAV2/8-LP1-hFIXco resulted in FIX transgene expression at levels sufficient to improve the bleeding phenotype, with few side effects, and that although immune-mediated clearance of AAV-transduced hepatocytes remains a concern, this process may be controlled with a short course of glucocorticoids without loss of transgene expression.
90-Day Mortality After Total Hip Replacements For Osteoarthritis
Death within 90 days after total hip replacement is rare but might be avoidable dependent on patient and treatment factors. As a result, a study published in The Lancet (2013:382;1097-1104), a study was assessed whether a secular decrease in death caused by hip replacement has occurred in England and Wales and whether modifiable perioperative factors exist that could reduce deaths.
The study accumulated data about hip replacements done in England and Wales between April, 2003, and December, 2011, from the National Joint Registry for England and Wales. Patient identifiers were used to link these data to the national mortality database and the Hospital Episode Statistics database to obtain details of death, socio-demographics, and comorbidity. The authors assessed mortality within 90 days of operation by Kaplan-Meier analysis and evaluated the role of patient and treatment factors by Cox proportional hazards model.
Results showed that after 409,096 primary hip replacements were done to treat osteoarthritis, 1,743 patients died within 90 days of surgery during the 8 year followup, with a substantial decrease in mortality, from 0.56% in 2003 to 0.29% in 2011, even after adjustment for age, gender, and comorbidity. Several modifiable clinical factors were associated with decreased mortality according to an adjusted model: posterior surgical approach (hazard ratio [HR] 0.82; p=0.001), mechanical thromboprophylaxis (0.85; p=0.036), chemical thromboprophylaxis with heparin with or without aspirin (0.79; p=0.005), and spinal versus general anesthesia (0.85; p=0.019). Type of prosthesis was unrelated to mortality. Interestingly, being overweight was associated with lower mortality (0.76; p=0.006).
According to the authors, postoperative mortality after hip joint replacement has fallen substantially, and widespread adoption of four simple clinical management strategies (posterior surgical approach, mechanical and chemical prophylaxis, and spinal anesthesia) could, if causally related, reduce mortality further.
TARGET HEALTH excels in Regulatory Affairs. Each week we highlight new information in this challenging area.
Mobile Medical Applications
The widespread adoption and use of mobile technologies is opening new and innovative ways to improve health and health care delivery. According to FDA, apps can help people manage their own health and wellness, promote healthy living, and gain access to useful information when and where they need it. In addition, these tools are being adopted almost as quickly as they can be developed. According to industry estimates, 500 million smartphone users worldwide will be using a health care application by 2015, and by 2018, 50% of the more than 3.4 billion smartphone and tablet users will have downloaded mobile health applications. These users include health care professionals, consumers, and patients.
The FDA issued the Mobile Medical Applications Guidance for Industry and Food and Drug Administration Staff on September 25, 2013, which explains the agency’s oversight of mobile applications (apps) as devices and their focus on the apps that present a greater risk to patients if they don’t work as intended and on apps that cause smartphones or other mobile platforms to impact the functionality or performance of traditional medical devices.
The FDA encourages the development of mobile medical apps that improve health care and provide consumers and health care professionals with valuable health information. The FDA also has a public health responsibility to oversee the safety and effectiveness of medical devices – including mobile medical apps.
What are Mobile Medical Apps?
Mobile apps are software programs that run on smartphones and other mobile communication devices. They can also be accessories that attach to a smartphone or other mobile communication devices, or a combination of accessories and software. Mobile medical apps are medical devices that are mobile apps, meet the definition of a medical device and are an accessory to a regulated medical device or transform a mobile platform into a regulated medical device. Consumers can use both mobile medical apps and mobile apps to manage their own health and wellness, such as to monitor their caloric intake for healthy weight maintenance. For example, the NIH’s LactMed app provides nursing mothers with information about the effects of medicines on breast milk and nursing infants.
Other apps aim to help health care professionals improve and facilitate patient care. The Radiation Emergency Medical Management (REMM) app gives health care providers guidance on diagnosing and treating radiation injuries. Some mobile medical apps can diagnose cancer or heart rhythm abnormalities, or function as the “central command” for a glucose meter used by an insulin-dependent diabetic patient.
How will the FDA Regulate Mobile Medical Apps?
The FDA will apply the same risk-based approach the agency uses to assure safety and effectiveness for other medical devices. The guidance document provides examples of how the FDA might regulate certain moderate-risk (Class II) and high-risk (Class III) mobile medical apps. The guidance also provides examples of mobile apps that are not medical devices, mobile apps that the FDA intends to exercise enforcement discretion and mobile medical apps that the FDA will regulate in Appendix A, Appendix B and Appendix C. FDA is encouraging app developers to contact the FDA – as early as possible – if they have any questions about their mobile app, its level of risk, and whether a premarket application is required.
Mobile Medical Apps that the FDA will Regulate
The FDA is taking a tailored, risk-based approach that focuses on the small subset of mobile apps that meet the regulatory definition of “device” and that:
1. are intended to be used as an accessory to a regulated medical device, or
2. transform a mobile platform into a regulated medical device.
Mobile apps span a wide range of health functions. While many mobile apps carry minimal risk, those that can pose a greater risk to patients will require FDA review.
Please visit the mobile medical apps example page for a list of examples of mobile medical apps that have been cleared or approved by the FDA. Visit the Examples of MMAs the FDA regulates webpage for a more detailed list of examples of mobile apps that would require FDA review. For a list of what is considered a mobile medical application, manufacturers and developers of mobile applications can search FDA’s database of existing classification by type of mobile medical application (for example diagnostic). Approved/cleared mobile medical applications will also be listed in FDA’s 510(k) and PMA databases and on the FDA’s Registration & Listing Database.
FDA’s mobile medical apps policy does not require mobile medical app developers to seek Agency re-evaluation for minor, iterative product changes.
Mobile Apps for Which the FDA Intends to Exercise Enforcement Discretion
For many mobile apps that meet the regulatory definition of a “device” but pose minimal risk to patients and consumers, the FDA will exercise enforcement discretions and will not expect manufacturers to submit premarket review applications or to register and list their apps with the FDA. This includes mobile medical apps that:
1. Help patients/users self-manage their disease or condition without providing specific treatment suggestions;
2. Provide patients with simple tools to organize and track their health information;
3. Provide easy access to information related to health conditions or treatments;
4. Help patients document, show or communicate potential medical conditions to health care providers;
5. Automate simple tasks for health care providers; or
6. Enable patients or providers to interact with Personal Health Records (PHR) or Electronic Health Record (EHR) systems.
For a more detailed list of examples of these types of mobile medical apps that do not require FDA review, please visit the webpage Examples of Mobile Apps for which the FDA will exercise enforcement discretion.
Does the FDA Regulate Mobile Devices and Mobile App Stores?
FDA’s mobile medical apps policy does not regulate the sale or general consumer use of smartphones or tablets. FDA’s mobile medical apps policy does not consider entities that exclusively distribute mobile apps, such as the owners and operators of the “iTunes App store” or the “Google Play store,” to be medical device manufacturers. FDA’s mobile medical apps policy does not consider mobile platform manufacturers to be medical device manufacturers just because their mobile platform could be used to run a mobile medical app regulated by FDA.
Does the Guidance Apply to Electronic Health Records?
FDA’s mobile medical app policy does not apply to mobile apps that function as an electronic health record (EHR) system or personal health record system.
The weather is still very hot in Manhattan. If you would rather not use your oven or stove, and get your kitchen sweltering, try one of my top favorite things to eat.
Actually, I love this dish enough to serve all year long. It’s quick and easy to prepare as an appetizer or as an entrée served as a cold plate: surround the salmon tartare with sliced cucumbers, sliced avocados and maybe some olives. AND there is no more delectable way to get your Omega-3 daily dose, than consumption of salmon tartare or heated but rare, salmon fillet.
First, buy the best sushi-grade salmon you can find, for the most mouthwatering salmon tartare and be sure to have the fishmonger, remove the skin. If you like the rich omega3-fatty skin, keep the removed skin, cut it at home into bite size pieces, and quickly broil it but don’t burn it. Now you have one more thing to serve, alongside the salmon tartare.
For garnish, sprinkle some chopped cilantro and/or toasted sesame seeds on top and you have a healthy wonderful delicious, lo-cal meal. Serve with cold beer or chilled white wine, and some fresh fruit for dessert and you’re all set.
Salmon tartare can be extremely varied. Take a look at some of the pictures below, which show just how much you can use your own creativity, and come up with infinite ways to serve this scrumptious dish.
Directly, below, is an easy (and quick) recipe for salmon tartare. Use this recipe as the base, to which you add some of your favorite ingredients. I am fine just with my favorite base recipe.
Ingredients (for 4 people as an appetizer or for 2-3 as an entree)
1 or 1.5 pounds of fresh salmon fillet (sushi grade, without skin)
1 teaspoon, fruity, high-quality olive oil
1 teaspoon best Asian sesame oil
1 or 2 teaspoons Korean seaweed (I get it from Amazon.com)
2 finely diced shallots
1 teaspoon mirin (like sake) (optional)
1 organic lime, juiced (or lemon)
Pinch coarse sea salt (or to your taste)
Pinch freshly ground black pepper (grind to your taste)
For easy slicing, put the salmon in your freezer for about 20 minutes before cutting. Then depending on how thick your fillet is, slice it through the middle, horizontally,comma carefully once, (twice for a very thick piece). Then carefully slice into long strips. Finally, take the long strips and slice again, until you get small cubes of the fresh salmon. Don’t chop. You don’t want to mash the salmon. You want to get distinct small cubes of the fish.
Put the cubes into a large bowl. Now add all of the other ingredients and stir carefully so as not to mash the fish or anything else. For example, if you decided to add small cubes of avocado, you wouldn’t want to mash that or the fish.
Now, serve on or with thin, toasted slices of baguette, bagel chips, rice crackers, water crackers, as an appetizer or a main dish.
Further variations: 1 or 2 teaspoons fresh ginger, green onions instead of shallots, 1 or 2 teaspoons chopped fresh herbs like cilantro, chives, dill, lemon grass. I like cilantro or parsley or no herbs. Top with flying fish roe or other caviar. Another good topping is radish sprouts or other sprouts (just a few, not a lot)
Another variation is to chop your cucumbers on paper towel (to catch excess liquid) and add them to the salmon mixture. You can do the same with avocados: chop into very small cubes and add to the salmon mixture. Some people also chop up hearts of palm, which I don’t like, but you decide.
Here’s a super quick way to serve appetizers using salmon tartare. After mixing the salmon with the other ingredients, simple serve on top of cucumber slices. Mirin, a low-alcohol rice wine, is one of the ingredients you can add or not.
In this variation, Salmon Tartare is turned into a gourmet appetizer, with black caviar (you choose according to your budget) on top, garnished with a quickly fried quail egg.
Another variation of salmon tartare is to top the salmon with avocado puree and rice crackers. The avocado puree is simply 1 or 2 avocados cut and put into a blender or food processer, with about 1/4 can of coconut milk. Blend slowly so it doesn’t get too runny.
For a faster version, you can simply cut the avocado into cubes instead of making the purée, stir all the ingredients together and serve with your favorite crackers or bagel chips
Here is salmon tartare served on a piece of broiled salmon skin (instead of a cracker or cucumber round) and topped with salmon roe (caviar) and a sprig of dill. If you plan to broil the salmon skin, be sure to tell the fishmonger to remove all of the scales off the skin. Be sure to make more than you think you need: They will get eaten fast.
Besides the above presentation, another variation is: add 1 or 2 teaspoons of low-sodium soy sauce to the tartare mix. Dice the cucumber and avocado and add to the salmon tartare, and serve in martini glasses with a small amount of your favorite topping
If you’re nervous about eating raw fish, freeze your salmon at -4°F or colder for a couple days and you are good to go; your home freezer is set at 0°F, so set it a little lower or leave the salmon in for more than 3 days.
The FDA has provided several guidelines for retailers who sell fish intended to be eaten raw. These guidelines include freezing the fish to -31°F for 15 hours or -4°F for 7 days.
Rare is the sushi restaurant that tells customers upfront that they may be eating fish that has been in deep freeze for up to two years. The majority of fresh fish is flash frozen right on the fishing boat. Many restaurants do their own flash freezing.
Most would be even more surprised to learn that if the sushi has not been frozen, it is illegal to serve it in the United States.
Food and Drug Administration regulations stipulate that fish to be eaten raw — whether as sushi, sashimi, seviche, or tartare — must be frozen first, to kill parasites. ”I would desperately hope that all the sushi we eat is frozen,” said George Hoskin, a director of the agency’s Office of Seafood. Tuna, a deep-sea fish with exceptionally clean flesh, is the only exception to the rule.
But tuna is often frozen, too, not necessarily to make it safe, but because global consumption of sushi continues to rise. Frozen fish usually costs about half as much wholesale as fresh. And some cuts, like the prized fatty toro, are not always available fresh.
Naomichi Yasuda, the owner of Sushi Yasuda, the acclaimed sushi restaurant in New York City, said he imported fresh tuna but froze it himself, selling it for $10 apiece.
Dry ice is used to prepare the “freshest” sushi by flash freezing freshly caught fish with dry ice, because the Food and Drug Administration requires that fish must be frozen first before eaten raw. Although, tuna is the exception, seafood experts believe that flash freezing tuna better preserves the flavor. Leading sushi chefs prefer fish frozen and kept at -70° F, rather than the industry standard of -10°F.
It takes about a day and a half to completely freeze a 500-pound tuna using dry ice and liquid nitrogen. The frozen fish can then be kept for as long as two years. The fish are cut into pieces and thawed in warm water just before serving.
What to Think? The Affordable Care Act and the Rule of Law
Mark L. Horn, MD, MPH, Chief Medical Officer, Target Health Inc.
Questions of how to frame the ongoing (as this is written) battle over the Affordable Care Act (the Act) loom large, and with menace, in our politics. There is an array of issues at play; among these are the specifics of the Act itself, about which at this point there seems little left to say, and another, increasingly troubling matter as how our political process seems increasingly incapable of grappling with the controversies and objections implicit in the Act.
To help structure discussion in a situation like this it is helpful to identify some basic facts around which all might coalesce (although there is no guarantee) simply because they can be documented and proved and construct a dialogue upon these. Let us try.
It is incontestable that the ACA was passed by Congress and reviewed by the Supreme Court. It is also provably true that the Act passed without support from the minority party. Nevertheless, it remains true that while the process of enactment may have been ugly, the essential legality of the legislation has been confirmed. Finally, since its initial passage the voters have had a chance to express their opinion on the ACA in a general election where the law was a major focus of debate and contention.
So, separately from our views on the ACA, we should collectively ask ourselves this question: What is the proper way for a frustrated minority to express its opposition to a law? Is it either appropriate or consistent with the proper and necessary functioning of government and our general welfare to threaten the financial security of (without exaggeration) potentially the entire world in order to overturn a law which has been passed by the Congress and affirmed by the Judiciary?
The question posed above is entirely separate from the mechanics of fixing the ACA, specifically identifying and addressing those elements that might benefit from revision. Perhaps, among the key problems evolving from passage without minority support, or the minorities’ unwavering disdain for the President, is that the amendment process, through debate and negotiation has become impossible. Therefore, we confront a complex piece of legislation with multiple moving parts that we cannot fix through our time tested procedures. The unyielding minority opposition at minimum complicates implementation of the Act; it remains to be seen if the damage is irrevocable.
Either way, e.g., should the damage prove irremediable or should the ACA ultimately prove functional and find public acceptance, perhaps even enthusiasm and affection (the Medicare model), we will have learned (at some cost) an important lesson. We will know that we simply cannot impose major social legislation without bipartisan support, or the opposite, that when consensus is impossible there are some problems that are sufficiently compelling that, when the political possibility to address them exists, however transiently, it should be seized, and damn the consequences.
In short, among the significant legacies of the ACA may be a permanent coarsening of our politics impacting the way we address the most controversial and sensitive issues. This would be a sad legacy indeed and one which responsible leaders would (and should) seek to avoid.
Editors’ note: Republicans and Democrats alike all seem to agree that when a law is passed, it must be followed. Part of our great democracy stands on the rule of law and not the rule of minority imbeciles who have not even read the ACA, let alone understand its contents, and who then (with abandon) flaunt the law, and hold the American people hostage, by shutting down the government, because they don’t like the new law. This minority is literally having a public tantrum . . . throwing things around . . . trying to break our democratic way of governing. Those Republicans and Democrats who have thought things out, feel that the ACA has passed the scrutiny of bipartisanship, because the ACA has been mandated by another pillar of our democracy, The Supreme Court, which at this time is a very conservative court. A law could not be on more solid ground then when passed by both Houses of Congress and upheld by our Supreme Court.
Lunatics should not run the asylum. On Monday, speaker, John Boehner should ask for a bipartisan vote in the House to open the U.S. government, immediately, if he cares about the American people and our rule of law.