eSource Publication in Applied Clinical Trials

 

Applied Clinical Trials has published our article in the June/July print edition as part of 4 articles on Clinical Trial Optimization. The article, entitled “Three-Pronged Approach to Optimizing Trial Monitoring Study – Results Using a Quality-by-Design [QbD] Method, Risk-Based Monitoring [RBM], and Real-Time Direct Data Entry [DDE],“  reports the results of the clinical trial initiated in the U.S. and Canada, which included 18 sites and 180 treated subjects where all the sites performed DDE and all the clinical research associates (CRAs) performed RBM, with the bulk of monitoring activities occurring centrally from the home office (central monitoring). For this publication, Target e*CRF® was used for EDC, Target e*CTR® Viewer was used to access the eSource records, and Target Document was used as the eTMF.

 

We are currently planning a PMA submission this year and an NDA next year, where the sites will have performed DDE at the time of the office visit and the CRAs, as part of the QbD methodology, will have performed RBM and central monitoring. We are also starting our 17th and 18th studies using DDE. There are 10 IND and 1 IDE programs, with the largest study being up to 45 centers and up to 400 subjects.

 

We are fully web-based so our system can be run using any Internet browser and at any time. We also create a certified Independent contemporaneous copy (CICC) of the eSource record before the data hit our EDC database, which is consistent with both the FDA Guidance and EMA Reflection Paper on eSource Records. We are also planning full integration with the electronic medical record (EMR) within the year with a clinical trial planned for Q3 2014. This program is being funded by the Bird Foundation.

 

We welcome collaboration with other EDC systems as we believe our solutions to DDE and EMR integration will be the industry standard.

 

Nature in New York City

 

20140623-11

Canadian Geese in Central Park ©Target Health Inc.

 

ON TARGET is the newsletter of Target Health Inc., a NYC-based, full-service, contract research organization (eCRO), providing strategic planning, regulatory affairs, clinical research, data management, biostatistics, medical writing and software services, including the paperless clinical trial, to the pharmaceutical and device industries.

 

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, and if you like the weekly newsletter, ON TARGET, you’ll love the Blog.

 

Joyce Hays, Founder and Editor in Chief of On Target

Jules Mitchel, Editor

 

 

Keeping Clean

20140623-10

An English early 20th Century bathroom

 

Dirty water has killed more humans than all the wars of history combined, but in the last 150 years a series of new ideas and innovations have changed our world and the way we live; including John Leal MD, who added chlorine to the 1) ___ water supply of 200,000 people but transformed the way we live. In 1908 the consensus was that chlorine was lethal but he believed differently. Without authorization Leal added it to the water supply and made it safe to drink.

 

The germ theory of disease states that some diseases are caused by microorganisms. These small organisms, too small to see without magnification, invade humans, animals, and other living hosts. Their growth and reproduction within their hosts can cause a disease. “Germ“ may refer to a virus, bacterium, protist, fungus, or prion. Microorganisms that cause disease are called pathogens, and the diseases they cause are called infectious diseases. Even when a pathogen is the principal cause of a disease, environmental and hereditary factors often influence the severity of the disease, and whether a particular host individual becomes infected when exposed to the 2) ___.

 

The germ theory was proposed in the mid-16th century and gained widespread credence when substantiated by scientific discoveries of the 17th through the late 19th century. It supplanted earlier explanations for disease, such as Galen’s miasma theory. Since the germ theory of disease, cleanliness has come to mean an effort to remove germs and other hazardous materials. A reaction to an excessive desire for a germ-free environment began to occur around 1989, when David Strachan put forth the “hygiene hypothesis“ in the British Medical Journal. In essence, this hypothesis holds that dirt plays a useful role in developing the 3) ___ system; the fewer germs people are exposed to in childhood, the more likely they are to get sick as adults. The valuation of cleanliness, therefore, has a social and cultural dimension beyond the requirements of hygiene for practical purposes.

 

Cleanliness customs swing back and forth like a pendulum over the ages, from society to society and century to century. The thought of a daily shower would have filled the 17th century Frenchman with fear. To open your 4) ___ and leave your body vulnerable to all that disease, would be asking to get sick. Our bathing habits would have disgusted him, much like his habits disgust us: never washing his body with water or soap, for instance. Or changing his linen shirt to get clean.

 

Habits of cleanliness go from ancient Roman afternoons at the public baths to today’s obsession with hand sanitizer and teeth-whitening strips. Contemporary cleanliness has more to do with appearances than hygiene. If you were a man in ancient Rome, you would take off all your clothes, put a little oil on your body, rub it with dust and go out into the playing field to work up a sweat. Then you would get somebody to scrape off your perspiration with an instrument that looks like a little tiny rake, called a strigil. You would get into a tepid bath, then a hot bath, then into a cold bath. They never used any soap, and it was all done in public. 5) ___ was a combination of animal fat and lye. The Egyptians, (wealthy Egyptians cleaned themselves with fresh limes) went to great lengths to make a soap that was mild enough to use on bodies, but many cultures, including the Romans and Greeks, didn’t. So they scraped themselves. Basically, it was a kind of drastic exfoliation. They probably got as clean as soap makes you. Most people, except very rich people, didn’t use soap until about the second half of the 19th century; that’s like two thousand years.

 

The Romans had amazing technology. The great imperial baths were fed by the 6) ___ to enormous tanks called castella. Romans heated the bathhouse with impressive underfloor heating and heating within the walls. Public baths went out of fashion, probably because the infrastructure to run them – the mechanisms that brought them water, that heated their water, that separated out the different heats of the various pools – required an enormously sophisticated and complicated infrastructure, which the Roman Empire had. But when the empire started to fall apart, people couldn’t maintain that, and the invading barbarians disabled the aqueducts. There was never an empire large enough to support that again.

 

For more than 1,000 years, cleanliness was not a priority. Attitudes about which cleans better, cold water or hot water, haven’t changed much. People who support cold-water bathing, think it’s virile and virtuous, and think those who bathe in warm or hot water are feminine and not masculine. Europe suffered a hiatus in cleanliness for centuries. When the great plagues came with the Black 7) ___, in the 14th century, the king of France asked the medical faculty at the Sorbonne in Paris, “What is causing this hideous plague that is killing one out of every three Europeans, and what can we do to prevent it?“ The 14th century doctors said that people who were at risk for getting the plague had opened their pores in warm or hot water, in the baths, and they were much more susceptible. In France and England and most European countries, for about five centuries, people really believed that it was dangerous to get into water. This strong belief broke down in the 19th century.

 

There was nothing that corresponded to that belief, in Asia or in India, where they had an unbroken tradition of cleanliness. They also had religions, like Islam and Hinduism, that took cleanliness very seriously. And, yet, in some societies, the holier you were – and this really applied to monks and hermits and saints – the less you would wash. And the more you smelled, the closer to God people thought you were. In the U.S., this meant your clothes were dirty, and you needed to wash them. But the 17th century looked at the ring around your cuffs and collar and thought linen was like a wick that drew out the dirt. They believed, not only was it safer to change your linen shirt, but that it actually cleaned you better. They thought the flax in the linen exerted a kind of magnetic attraction to the sweat and drew it out of your body. So, at that time, changing your 8) ___ was the cleanest thing to do.

 

During the 17th century, people put on perfume so they wouldn’t smell their neighbors. Madame de Montespan, one of Louis XIV’s mistresses, wore clouds of self-defensive perfume so that she wouldn’t smell the king’s halitosis. She didn’t like the way he smelled, and he hated the way she smelled, because perfume gave him headaches. By about the 1840s in America, architects who made pattern books – books that everybody could buy and then build according to the patterns in the book – added a little room that was called a “bathing-room or bath-room“ for the first time, since the ancient Romans, which meant that, eventually, there would be fixed plumbing in that room. But for a long time, well into the 1920s in rural places, you would just move a tin tub into the kitchen on Saturday night and fill it with warm water, and then everybody in the family, one by one, would get into the same water, starting with the father, considered to be the most important, and going down to the daughter-in-law, who was the least important.

 

Very gradually. One of the things that probably enabled indoor bathing to happen was the fashion for spas in naturally occurring springs all over Europe. The Romans always situated their baths near a mineral spring if they could, because their doctors believed there were health-giving properties in them. Even when people were afraid to get into 9) ___ on a regular basis, if you were sick, if you had arthritis or were infertile or had some medical condition, under your doctor’s care you would go to some place like Baden in Switzerland or Bath in England and take the treatments, which included getting into water. Perhaps, because only wealthy people could afford to go to these spas, bathing eventually became chic. About a third of London houses had in-house plumbing by the 1830s, which was far above what the people had in Paris. The water inspector for Paris said the Parisians would never want this, and it would render their houses damp forever.

 

By the mid-18th century, doctors had a little bit more understanding of physiology, and that your pores needed to be open so that they could let out sweat and other things. They thought you let out an awful lot more through your pores than people actually did. It gradually began to be thought of as healthy to clean your pores and let yourself perspire, but it took a long time. Perhaps the American obsession with cleanliness, is a continuation of something that started with the Civil War, when the Americans had surprising success with the Sanitation Commission, which was headed by Frederick Law Olmsted, the architect of Central Park. It achieved an enormous success in limiting deaths just by washing the patients, their linen, the walls of their rooms. It drastically cut into the deaths by disease and infection. Now, we know that just washing hands often, whether in a hospital or not, kills germs that matter.

 

Before the Civil War Americans had been just as dirty as Europeans, and they came out of the war thinking cleanliness is democratic because it doesn’t cost much money. It’s progressive. It’s forward-looking. It has wonderful results. They quickly thought this is yet another way in which life in the New World is so much better than life in the Old World. The invention of modern sophisticated advertising, which began in America at the end of the 19th century, achieved an enormous success, often by advertising things like toilet soap and deodorant.

 

And yet, Charles P. Gerba MD (Univ Arizona), sent his researchers into public washrooms and found that only about 15% of people there actually wash long enough and with soap, demonstrating that our current interest in cleanliness is really about appearance and not ever smelling like a human being. If we smell like mangoes or vanilla and our face looks clean and our teeth are paper white, that’s good enough. But really the one seriously disease-preventing practice of hand washing is not done enough. On the other hand, it’s increasingly believed by a large number of doctors and scientists, that we’re not giving part of our immune system enough of a challenge, with dirt and germs to deal with, overcome and get stronger (as a result). As a result we’re enabling a part of our immune system, the one that gets allergies and asthma, to take over.

 

It’s like a see-saw: The one that really can work on dirt and bacteria has nothing to do, and so it becomes unexercised (don’t use it, you lose it), and it stays on the ground. The other part is up in the air. Scientists couldn’t understand why we had these skyrocketing rates of asthma and allergies. Now the hypothesis is that we are oversanitized to the point of making our children sick. Bathing is now thought by many doctors to be a social convention. However, doctors make it clear that it’s very important to wash 10) ___. About a quarter of U.S. houses built in 2005 had three or more bathrooms. Has this room where you bathe become a status symbol?

 

In the 19th century, Harriet Beecher Stowe, who wrote “Uncle Tom’s Cabin,“ said she dreamed of a time when there would be one bathroom in an American house for every three or four bedrooms. People at the time thought this was utopian thinking, compared to what they were used to. Now a luxury apartment in Manhattan, has more bathrooms than bedrooms. We’ve never needed to wash less in the developed Western countries, and we’ve never had more pressure to wash more. If your job is in front of your computer, and if you have a house full of labor-saving devices, you’re not scrubbing floors very often, and if you have access to a car or public transit where you live, you’re not sweating the way people did 50 years ago. However, a daily bath is the minimum. More and more people now take two showers a day. Advertising has pushed psychological hot buttons, and convinced Americans that they will be more popular and successful if they buy the myriad cleansing and beautifying products on the market. Caveat Emptor! Or, beware of what you wish for.

 

ANSWERS: 1) New Jersey; 2) pathogen; 3) immune; 4) pores; 5) Soap; 6) aqueducts; 7) Death; 8) shirt; 9) water; 10) hands

 

John Laing Leal MD

20140623-7

John Laing Leal (1858-1914) was a physician and water treatment expert who, in 1908, was responsible for conceiving and implementing the first disinfection of a U.S. drinking water supply using chlorine. He was one of the principal expert witnesses at two trials which examined the quality of the water supply in Jersey City, New Jersey, and which evaluated the safety and utility of chlorine for production of “pure and wholesome“ drinking water. The second trial verdict approved the use of chlorine to disinfect drinking water which led to an explosion of its use in water supplies of the U.S. Leal contracted a chronic case of amoebic dysentery (most likely from contaminated drinking water) at Folly Island from which he suffered for the next 17 years before the disease caused his death in 1882.

 

John L. Leal was born in Andes, New York, in 1858. In 1862, his father, John R. Leal who was a physician, joined the 144th New York Volunteer Infantry Regiment. Leal saw service in a number of areas during the Civil War including Folly Island during the Siege of Charleston, South Carolina. In 1867, Dr. John R. Leal moved his family from Andes to the rapidly growing industrial city of Paterson, New Jersey.

 

John L. Leal received his primary education at the Paterson Seminary. He attended Princeton College (now Princeton University) from 1876 to 1880. John L. Leal attended medical school at the Columbia College of Physicians and Surgeons from 1880 to 1884 where he received his medical degree. After obtaining his medical degree, Leal opened a medical practice in Paterson, New Jersey, and was appointed City Physician in 1886. Along with other physicians, he founded the outpatient clinic at Paterson General Hospital in 1887 and worked there until 1892. In 1888, he married Amy Arrowsmith and their only son, Graham, was born within the year. Leal’s career in Paterson city government continued with his appointment as Health Inspector in 1891 and Health Officer in 1892. As Health Officer, Leal was responsible for the identification of epidemics of communicable diseases and for the disinfection of the homes of the afflicted. He also oversaw the public water supply and was responsible for constructing the growing network of sewers to remove domestic and industrial wastes from the City. To prevent the spread of contagious diseases, he was responsible for building an Isolation Hospital in Paterson in 1897, which, at the time, was considered a model facility. He published several papers during his tenure as Health Officer including one that described the cause of a waterborne typhoid fever outbreak in Paterson.

 

In 1899, Leal left the city’s service and became the sanitary adviser to the East Jersey Water Company. His decision to focus on matters of public health and the safety of drinking water was driven in part by his personal experiences and from the influence of Garret Hobart, who became the 24th Vice President of the United States in 1896. Toward the end of his life, Leal was President of the Board of Health for the City of Paterson.

 

Leal belonged to a large number of professional associations. In 1884, he was elected a member of the Medical Society of New Jersey, and he was an active member of the Passaic County Medical Society. In 1900, he was Vice President of that organization. Despite his concentration on water treatment affairs after 1899, he was still involved in the Passaic County Medical Society, serving on the Legislative Committee in 1900 and in 1901 he was President. In 1905, he was active in the State Medical Society and he served as a permanent delegate from Passaic County.

 

In 1903, Leal was president of the New Jersey Sanitary Association. On the program for the Sanitary Association meeting on December 4-5, 1903, Leal was noted for giving the President’s Address on “Present Attitude of Sanitary Science“. Moses N. Baker was chair of the Garbage Disposal committee of the association and at a topic session entitled Sewage Disposal in New Jersey, the speakers included Rudolph Hering, Allen Hazen, George W. Fuller and the New Jersey water supply expert Charles A. Vermeule. These professionals interacted with one another throughout their careers.

 

He was a member of the American Medical Association and the American Public Health Association. At the APHA annual meeting in 1897, Leal read a paper entitled, “House Sanitation with Reference to Drainage, Plumbing, and Ventilation“. At the 1902 annual meeting of the APHA in New Orleans, Leal was elected second vice-president of the organization. In 1899, Jersey City entered into a contract with Patrick H. Flynn to build a water supply to replace the one that was significantly contaminated by sewage. A large dam was built on the Rockaway River which resulted in the formation of Boonton Reservoir that had a capacity of over 7 billion gallons of water. During construction, the project was taken over by the Jersey City Water Supply Company (JCWSC), which was a private water company that employed John L. Leal as its sanitary adviser. Included in Leal’s responsibilities was the removal of illegally constructed privies and other obvious sources of sewage contamination from the watershed above Boonton Reservoir. The dam, reservoir and 23-mile pipeline was completed and on May 4, 1904, water from the project was first delivered to Jersey City. As was common at this time, no treatment of any kind was provided to the water supply. City officials were not pleased with the project as delivered by the JCWSC and filed a lawsuit in the Chancery Court of New Jersey. Among the many complaints by Jersey City officials was the contention that the water served to the city was not “pure and wholesome“ as required by the contract.

 

The first trial was held before Frederick W. Stevens, Vice Chancellor of the Chancery Court of New Jersey. The first day of trial was February 20, 1906, and the trial was not completed until dozens of witnesses had been heard over 40 days of trial comprising hundreds of exhibits and thousands of pages of testimony. On May 1, 1908, Vice Chancellor Stevens issued a 100-page opinion that supported many of the contract claims made by the JCWSC but, most importantly, found (for the plaintiffs) that two to three times per year, water that could not be considered “pure and wholesome“ was delivered to Jersey City from the Boonton Reservoir water supply. In his final decree dated June 4, 1908, Stevens ordered the JCWSC to pay for the construction of sewers to remove contaminants from the Rockaway River watershed or create “other plans or devices“ which could be used instead to produce water of the required purity. The JCWSC was given three months to come up with “other plans or devices“ and to present them to a special master, Justice William J. Magie.

 

As a physician who was trained in bacteriology, Leal knew that chlorine killed bacteria. As Health Officer for Paterson, Leal used solutions of chloride of lime (calcium hypochlorite) to “disinfect“ homes where scarlet fever, diphtheria and other communicable diseases were found. He was also aware of previous efforts to use chlorine in drinking water supplies. In 1897, high concentrations of chlorine derived from chloride of lime were used to disinfect the reservoir and pipelines of Maidstone, England, after an outbreak of typhoid fever. In 1905, Dr. Alexander Cruickshank Houston devised a crude sodium hypochlorite feed system to kill typhoid bacteria in the water supply of Lincoln, England, that was being treated with an inadequate filtration system. During Leal’s testimony in the second trial, he made extensive references to the Lincoln example. He also stated in the trial that he had conducted laboratory disinfection experiments using chlorine as early as 1898.

 

On June 19, 1908, Leal hired George W. Fuller to construct a chlorination plant at Boonton Reservoir to disinfect the water for Jersey City as a representation of “other plans or devices“. At the time, Fuller was, perhaps, the most respected sanitary engineer in the U.S. In 99 days, Fuller designed the chlorination plant and supervised its construction. Dilute solutions of chloride of lime were accurately fed by gravity to the water being treated. Fuller based his design on the successful aluminum sulfate feed system that he had built at the Little Falls Water Treatment Plant in 1902. The chlorination plant at Boonton Reservoir treating an average of 40 million gallons per day went on-line on September 26, 1908. Since then, water from this source has been continuously chlorinated, making it the water supply with the longest history of disinfection.

 

The second trial began on September 29, 1908, before Justice Magie. The purpose of this trial was to determine if the chloride of lime system that had been installed by JCWSC was effective in controlling harmful bacterial levels and capable of providing water that was “pure and wholesome“. Over 38 days, dozens of witnesses were heard and hundreds of exhibits were submitted. More than three thousand pages recorded the testimony of expert witnesses for both sides including William T. Sedgwick, George C. Whipple, Earle B. Phelps, Charles-Edward A. Winslow and a number of other experts for the plaintiffs and John L. Leal, George W. Fuller and Rudolph Hering (among others) for the defendants. Justice Magie issued his ruling on May 9, 1910, which was a victory for the defendants. Chlorine was an acceptable treatment for the removal of pathogens from drinking water and for making the water “pure and wholesome“ for human consumption. “I do therefore find and report that this device is capable of rendering the water delivered to Jersey City, pure and wholesome, for the purposes for which it is intended, and is effective in removing from the water those dangerous germs which were deemed by the decree to possibly exist therein at certain times.“ The ruling by Justice Magie was supported on appeal by the New Jersey Court of Errors and Appeals and the New Jersey Supreme Court.

 

 

20140623-8

Death rates for typhoid fever in the U.S. 1906-1960

 

Leal’s application of chlorine disinfection technology and his defense of the chemical’s use, contributed significantly to the eradication of typhoid fever and other waterborne diseases in the U.S. On September 26, 1908, only the Jersey City water supply was disinfected using chlorine. A survey of water utilities showed that by 1914, over 21 million people were being served chlorinated water in the U.S. By 1918, more than 1,000 North American cities were using chlorine to disinfect their water supplies, which served approximately 33 million people. Statistics on the typhoid fever death rate in the U.S. showed a dramatic decrease in deaths due to this dreaded disease after the wide introduction of chlorine for disinfection. Filtration of water supplies contributed to the decrease in the typhoid fever death rate but chlorination is generally acknowledged as having a major impact on increased life expectancy in the U.S.

 

Unfortunately, Leal is seldom given credit for his pioneering work in the disinfection of drinking water. George A. Johnson was a plant operator and laboratory technician who worked on the chlorination plant at Boonton Reservoir. His later writings gave no credit to Leal and, by inference, Johnson took the credit for the decision to use chlorine on the Jersey City water supply. The record shows that Leal came up with the idea to disinfect the water supply of Jersey City and he should be given the credit for this major advance in public health.

 

 

20140623-9

Grave Monument to Dr. John L. Leal

 

On May 5, 2013, a number of people gathered at the gravesite of Leal in Paterson, New Jersey and dedicated a monument to him as a “Hero of Public Health.“ Present at the dedication were members of the New Jersey Section of the American Water Works Association and two great grandsons of Leal. In August 2013, the American Water Works Association established a major annual award in honor of Leal. Entitled the Dr. John L. Leal Award, the purpose of the award is to recognize any individual, group, or organization that has made a notable and outstanding public health contribution to the water profession. The first award will be given at the AWWA annual conference in June 2014.

 

ONCOLOGY

Filed Under News | Leave a Comment

Dietary Protein Sources in Early Adulthood and Breast Cancer Incidence

 

According to an article published online in the British Medical Journal (10 June 2014), a study was performed to investigate the association between dietary protein sources in early adulthood and risk of breast cancer. The investigation was a prospective cohort study performed in the United States. Study participants included 88,803 premenopausal women from the Nurses’ Health Study II who completed a questionnaire on diet in 1991. The main outcome measure was incident cases of invasive breast carcinoma, identified through a self-report and confirmed by a pathology report.

 

A total of 2,830 cases of breast cancer were documented during the 20 years of follow-up. Results showed that a higher intake of total red meat was associated with an increased risk of breast cancer overall (relative risk 1.22; Ptrend=0.01, for highest fifth vs. lowest fifth of intake). However, overall, higher intakes of poultry, fish, eggs, legumes, and nuts were not related to breast cancer. When the association was evaluated by menopausal status, higher intake of poultry was associated with a lower risk of breast cancer in postmenopausal women (0.73; Ptrend=0.02, for highest fifth vs. lowest fifth of intake) but not in premenopausal women for highest fifth vs. lowest fifth of intake). In estimating the effects of exchanging different protein sources, substituting one serving/day of legumes for one serving/day of red meat was associated with a 15% lower risk of breast cancer among all women and a 19% lower risk among premenopausal women. Also, substituting one serving/day of poultry for one serving/day of red meat was associated with a 17% lower risk of breast cancer overall and a 24% lower risk of postmenopausal breast cancer. Furthermore, substituting one serving/day of combined legumes, nuts, poultry, and fish for one serving/day of red meat was associated with a 14% lower risk of breast cancer overall and premenopausal breast cancer.

 

The authors concluded that higher red meat intake in early adulthood may be a risk factor for breast cancer, and replacing red meat with a combination of legumes, poultry, nuts and fish may reduce the risk of breast cancer.

Loss-of-Function Mutations in APOC3, Triglycerides, and Coronary Disease

 

Plasma triglyceride levels are heritable and are correlated with the risk of coronary heart disease. Sequencing of the protein-coding regions of the human genome (the exome) has the potential to identify rare mutations that have a large effect on phenotype. As a result, a study published online in the New England Journal of Medicine (18 June 2014), sequenced the protein-coding regions of 18,666 genes in each of 3734 participants of European or African ancestry in the Exome Sequencing Project. Tests were conducted to determine whether rare mutations in coding sequence, individually or in aggregate within a gene, were associated with plasma triglyceride levels. For mutations associated with triglyceride levels, the study subsequently evaluated their association with the risk of coronary heart disease in 110,970 persons.

 

Results demonstrated an aggregate of rare mutations in the gene encoding apolipoprotein C3 (APOC3) associated with lower plasma triglyceride levels. Among the four mutations that drove this result, three were loss-of-function mutations: a nonsense mutation (R19X) and two splice-site mutations (IVS2+1G- to-A and IVS3+1G-to-T). The fourth was a missense mutation (A43T). Approximately 1 in 150 persons in the study was a heterozygous carrier of at least one of these four mutations. Triglyceride levels in the carriers were 39% lower than levels in noncarriers (P<1×10-20), and circulating levels of APOC3 in carriers were 46% lower than levels in noncarriers (P=8 x10-10). The risk of coronary heart disease among 498 carriers of any rare APOC3 mutation was 40% lower than the risk among 110,472 noncarriers (odds ratio, 0.60; P=4 x10-6).

 

The authors concluded that rare mutations that disrupt APOC3 function were associated with lower levels of plasma triglycerides and APOC3, and that carriers of these mutations were found to have a reduced risk of coronary heart disease.

 

TARGET HEALTH excels in Regulatory Affairs. Each week we highlight new information in this challenging area.

 

FDA Approves Sivextro to Treat Skin Infections

 

The FDA has approved Sivextro (tedizolid phosphate), a new antibacterial drug, to treat adults with skin infections. Sivextro is approved to treat patients with acute bacterial skin and skin structure infections (ABSSSI) caused by certain susceptible bacteria, including Staphylococcus aureus (including methicillin-resistant strains (MRSA) and methicillin-susceptible strains), various Streptococcus species, and Enterococcus faecalis. Sivextro is available for intravenous and oral use. Sivextro is the second new antibacterial drug approved by the FDA in the past month to treat ABSSSI. On May 23, the agency approved Dalvance (dalbavancin), also to treat patients with ABSSSI caused by Staphylococcus aureus and various Streptococcus species.

 

The application for Sivextro, intended to treat serious or life-threatening infections, was designated as a qualified infectious disease product (QIDP) and received an expedited review. Sivextro’s QIDP designation also qualifies it for an additional five years of marketing exclusivity to be added to certain exclusivity periods already provided by the Food, Drug and Cosmetic Act.

 

Sivextro’s safety and efficacy were evaluated in two clinical trials with 1,315 adults with ABSSSI. Participants were randomly assigned to receive Sivextro or linezolid, another antibacterial drug approved to treat ABSSSI. Results showed Sivextro was as effective as linezolid for the treatment of ABSSSI. The most common side effects identified in the clinical trials were nausea, headache, diarrhea, vomiting and dizziness. The safety and efficacy of Sivextro have not been evaluated in patients with decreased levels of white blood cells (neutropenia), so alternative therapies should be considered.

 

Sivextro is marketed by Cubist Pharmaceuticals, based in Lexington, Massachusetts

 

Open-faced Homage to Burgers

20140623-1

Veggie Burger with all the toppings  ©Joyce Hays, Target Health Inc.

 

20140623-2

Veggie Burger with all the toppings except grated soy mozzarella ©Joyce Hays, Target Health Inc.

 

Ingredients

  • 1 cup quinoa
  • 2 cups water
  • 1 zucchini
  • 1/2 cup olive oil, divided
  • 1 large shallot, minced (used to make the burger)
  • 1/2 teaspoon crushed red pepper flakes
  • 4 large Portobello mushrooms caps, used as burger buns
  • 2 large Portobello mushroom caps, (stems removed) finely chopped in a food processor)
  • Kosher salt and freshly ground pepper, to taste
  • 1 1/2 cups Panko
  • 1/2 cup mashed cooked yam, more if needed. Bake 3 yams.
  • Avocado topping
  • 6 Tablespoons tomato, chopped, for garnish
  • Daikon sprouts, for garnish (optional)
  • Thinly sliced fried shallot “sticks,“ for garnish
  • Chunk of soy mozzarella, freshly grated for garnish

 

Directions

1. In a pan, saute the sliced shallot sticks, to be used for garnish, and set aside. Sticks should be the size of a toothpick, cut in half.

 

20140623-3

Cooking the Portobello caps.  ©Joyce Hays, Target Health Inc.

 

2. In the same pan, add 1 teaspoon olive oil, 1 garlic clove, sliced, a few Tablespoons of chicken stock and cook both sides of the 4 caps of large Portobello mushrooms. Then set aside. These will serve as half a bun for the burgers.

 

3. Cook the quinoa. Rinse the grains well. Bring the water to a boil and add the quinoa, cooking until it is translucent and tender, and the germ has spiraled out from the grain, 12 to 15 minutes, careful not to overcook. Drain, measure 2 cups and set aside. This makes about 2 1/2 cups cooked quinoa, more than is needed for the rest of the recipe; the remainder can be eaten by itself or added to soups or salads.

 

4. While the quinoa is cooking, coarsely grate the zucchini. Spread the grated zucchini out on a kitchen towel, then roll up the towel and wring it to squeeze out as much moisture as possible. Set aside.

 

5. In a large saute pan, heat the olive oil over low heat and add the minced shallot and red pepper flakes. Cook until the shallots are soft, about 3 minutes.

 

6. To the pan, add the mushroom puree and zucchini, and cook for 3 more minutes to soften, stirring often.

 

7. Place the mixture in a large bowl and add the quinoa, then add salt and pepper to taste. Set aside to cool.

 

8. Now, add the Panko and mashed yam to the large bowl.

 

9. With your hands, knead the mixture to fully incorporate and form the burger base. If the burger is too soft to hold together, add more mashed yam to bind. Make 6 patties by pressing the mixture firmly with your hands.

 

10. Heat a thin layer of olive oil in a large skillet or grill pan over medium heat. Cook the patties until golden-brown on both sides, 3 to 4 minutes per side.

 

20140623-4

Cooked patties on cooked Portobello “bun“ ©Joyce Hays, Target Heath Inc.

 

11. Place a cooked patty on one of the large cooked Portobello caps.

20140623-5

First spread the avocado topping on the cooked burger; then I added shallots. ©Joyce Hays, Target Health Inc.

 

12. Spread a tablespoon of avocado topping on each burger. Top each with a tablespoon of chopped tomato and small handful of daikon sprouts. Also, sprinkle the fried shallot sticks on top of the burgers.. Serve the burgers open-faced, so to speak.

 

Okay, so it was our anniversary weekend and I wanted to contribute a recipe just for him. This was taking a real gamble, since often he’s on the hunt and comes home a rough and tumble paleo-man. But I wanted to relax with some chilled wine and our 34 years of great memories. I decided to experiment further in order to get a veggie burger to be proud of. You wouldn’t be reading this, if I had failed.

 

He loved it!

 

I think part of the reason, this turned out to be such a good recipe, is that everything about this burger (visually) was based on a hamburger/cheeseburger, that we all have enjoyed. You could call my approach, a pastiche, a homage, to the beef burgers we all grew up with. This recipe is such a delicious alternative, that it holds its own as a succulent veggie burger with fabulous toppings. I urge you to try it.

 

We started our meal with an icy Orvieto and an Ugli tomato salad with endive, thinly sliced mini cucumbers, green olives, and avocados in lemon/oil dressing. (Ugli ripe tomato is a real old fashion beefsteak tomato, without a center core) Then, came the Veggie Burgers with all the colorful toppings.

 

His first bite was a “wow“ which went straight to my heart.

 

We both enjoyed adding the various toppings, which adds to the fun. If you decide to try this recipe, make it an adventure. In advance be sure everyone knows not to expect meat and to have a good time with an adventure of new flavors at the dinner table.

 

If there are theater lovers out there, Saturday, we went to a new play at Lincoln Center (Mitzi Newhouse Theater), “The City of Conversation.“ We recommend it highly. Wonderful acting, gorgeous set, and a plot that will stimulate much discussion. Another wonderful experience for us.

 

When we went out for dinner afterwards, there was a huge vase of perfect red roses, on our table, waiting for me. Need I say more?

20140623-6

A day of wine and roses.  ©Joyce Hays, Target Health Inc.

 

From Our Table to Yours, Bon Appetit !