Target e*CTR® – eClinical Trial Record and Direct Data Entry

 

Target Health is pleased to announce that it will be initiating at least 3 direct data entry (DDE) clinical trials this quarter. This comes on top 12 studies initiated over the past 3 years under 7 INDs and 1 IDE. We expect 2 regulatory submissions in 2014 where DDE was used exclusively.

 

Together with risk-based monitoring, we are reducing on-site monitoring by at least 50% with an estimated savings of at least $10,000/site/year. Other savings include virtual elimination of protocol violations, increased capacity for the study sites to see more subjects since there is virtually no additional work once the subject leaves the clinic, fewer queries and the ability to implement changes early in the trial before there is too much “damage.” Let us know if you want to see a demo.

 

A paper will be published online in Applied Clinical Trials, within a few weeks, which summarizes our experience from an 18 center study. It is a very convincing story.

 

ON TARGET is the newsletter of Target Health Inc., a NYC-based contract research organization (CRO), 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 Chief Editor of On Target

Jules Mitchel, Editor

Vanessa Hays, Editorial Contributor

Bacteriophages

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Since ancient times, reports of river waters having the ability to cure infectious diseases have been documented, such as leprosy. In 1896, Ernest Hanbury Hankin reported that something in the waters of the Ganges and Yamuna rivers in India had marked antibacterial action against cholera and could pass through a very fine porcelain filter. In 1915, British bacteriologist Frederick Twort, superintendent of the Brown Institution of London, discovered a small agent that infected and killed 1) ___. He believed the agent must be one of the following:

 

1. a stage in the life cycle of the bacteria;

2. an enzyme produced by the bacteria themselves; or

3. a virus that grew on and destroyed the bacteria.

 

Twort’s work was interrupted by the onset of World War I and shortage of funding. Independently, French-Canadian microbiologist Felix d’Herelle, working at the Pasteur Institute in Paris, announced on 3 September 1917, that he had discovered “an invisible, antagonistic microbe of the dysentery bacillus”. For d’Herelle, there was no question as to the nature of his discovery: “In a flash I had understood: what caused my clear spots was in fact an invisible microbe – a virus parasitic on bacteria.”  D’Herelle called the virus a bacteriophage or bacteria-eater (from the Greek phagein meaning to eat). He also recorded a dramatic account of a man suffering from dysentery who was restored to good health by the 2) ___.

 

In 1923, the Eliava Institute was opened to research this new science and put it into practice and in 1969, Max Delbrück, Alfred Hershey and Salvador Luria were awarded the Nobel Prize in Physiology and Medicine for their discoveries of the replication of viruses and their genetic structure.

 

Bacteriophages may have a lytic cycle or a lysogenic cycle, and a few viruses are capable of carrying out both. With lytic phages such as the T4 phage, bacterial 3) ___ are broken open (lysed) and destroyed after immediate replication of the virion. As soon as the cell is destroyed, the phage progeny can find new hosts to infect. Lytic phages are more suitable for phage therapy. Some lytic phages undergo a phenomenon known as lysis inhibition, where completed phage progeny will not immediately lyse out of the cell if extracellular phage concentrations are high. This mechanism is not identical to that of temperate phage going dormant and is usually temporary. In contrast, the lysogenic cycle does not result in immediate lysing of the host cell. Those phages able to undergo lysogeny are known as temperate phages. Their viral genome will integrate with host DNA and replicate along with it fairly harmlessly, or may even become established as a plasmid. The virus remains dormant until host conditions deteriorate, perhaps due to depletion of nutrients; then, the endogenous phages (known as prophages) become active. At this point they initiate the reproductive cycle, resulting in lysis of the 4) ___ cell. As the lysogenic cycle allows the host cell to continue to survive and reproduce, the virus is reproduced in all of the cell’s offspring. An example of a bacteriophage known to follow the lysogenic cycle and the lytic cycle is the phage lambda of E. coli. Sometimes prophages may provide benefits to the host bacterium while they are dormant by adding new functions to the bacterial genome in a phenomenon called lysogenic conversion. An eminent example is the conversion of a harmless strain of Vibrio cholerae by a phage into a highly virulent one, which causes cholera.

 

Attachment and Penetration

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In this electron micrograph of bacteriophages attached to a bacterial cell, the viruses are the size and shape of coliphage T1. To enter a host cell, bacteriophages attach to specific 5) ___ on the surface of bacteria, including lipopolysaccharides, teichoic acids, proteins, or even flagella. This specificity means a bacteriophage can infect only certain bacteria bearing receptors to which they can bind, which in turn determines the phage’s host range. Host growth conditions also influence the ability of the phage to attach and invade them. As phage virions do not move independently, they must rely on random encounters with the right receptors when in solution (blood, lymphatic circulation, irrigation, soil water, etc.).

 

A bacteriophage is a virus that infects bacteria. Bacteriophages, first discovered around 1915, have played a unique role in viral biology. They are perhaps the best understood 6) ___, yet at the same time, their structure can be extraordinarily complex. The use of bacteriophages played a prominent role in elucidating that DNA in viruses can reproduce through two mechanisms: the lytic cycle and the lysogenic cycle.

 

Viruses that kill their infected host cell are called 7) ___. The DNA in these types of viruses reproduce through the lytic cycle. When these viruses reproduce, they break open, or lyse, their host cells, resulting in the destruction of the host. The whole cycle can be complete in 20 – 30 minutes depending on a variety of factors such as temperature. Phage reproduction is much faster than typical bacterial reproduction, so entire colonies can be destroyed very quickly.

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Temperate Viruses and the Lysogenic Cycle

 

Temperate viruses are those that reproduce without killing their host cell. Typically they reproduce in two ways: through the lytic cycle and the lysogenic cycle. In the lysogenic 8) ___, the phage’s DNA recombines with the bacterial chromosome. Once it has inserted itself, it is known as a prophage. A host cell that carries a prophage has the potential to lyse, thus it is called a lysogenic cell. The image above illustrates both the lytic and lysogenic cycles of a bacteriophage.

 

ANSWERS: 1) bacteria; 2) bacteriophages; 3) cells; 4) host; 5) receptors; 6) viruses; 7) virulent; 8) cycle

Felix d’Herelle (April 25, 1873 – February 22, 1949)

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Felix d’Herelle

 

Editor’s note: The short bio information, compiled below, reads like a movie promo about a scientific genius (nominated many times for a Nobel Prize) jumping from one biological adventure to another, across many continents. One extraordinary aspect of all this, is that Felix d’Herelle, who finished high school but never attended college, was completely self-taught. His brilliance was acknowledged with an honorary doctorate, plus other awards for outstanding discoveries in areas of microbiology. He became a professor at Yale University. We’re giving this week’s History of Medicine biography more space than usual because the story is so colorful and unusual and because Felix d’Herelle has caught our attention and respect.

 

Felix d’Herelle (April 25, 1873 – February 22, 1949) was a French-Canadian microbiologist, the co-discoverer of bacteriophages (viruses that infect bacteria) and experimented with the possibility of phage therapy. D’Herelle has also been credited for his contributions to the larger concept of applied microbiology.

 

D’Herelle was born in Montreal, Quebec, the son of French emigrants. His father died when Felix was 6 years old. Following his father’s death, Felix, his mother and his younger brother Daniel, moved back to Paris. From 7 to 17 years of age, d’Herelle attended school in Paris, including the Lycee Condorcet and Lycee Louis-le-Grand high schools. In the fall of 1891, d’Herelle traveled to Bonn where he attended lectures at the University of Bonn for several months. Thus, d’Herelle only obtained a high school education and was self-taught in the sciences.

 

At age 24, now father of a daughter, d’Herelle and his family moved back to Canada. He built a home laboratory and studied microbiology from books and his own experiments. Through the influence of a friend of his late father, he earned a commission from the Canadian government to study the fermentation and distillation of maple syrup to schnapps. His father’s friend shrewdly pointed out that Pasteur “made a good beginning by studying fermentations, so it might be interesting to you, too.”  He also worked as a medic for a geological expedition, even though he had no medical degree or real experience. Together with his brother, he invested almost all his money in a chocolate factory, which soon went bankrupt. During this period, d’Herelle published his first scientific paper, “De la formation du carbone par les vegetaux”in the May 1901 issue of Le Naturaliste Canadien. The paper is noteworthy for two reasons: it shows an exceptional level of scientific development for a self-taught scientist and reveals a broad level of interest, namely the global balance of carbon in nature. However, the claims of the paper were in error, as d’Herelle contended that the results of his experiments indicated that carbon was a compound, not an element. With his money almost gone and his second daughter born, he took a contract with the government of Guatemala as a bacteriologist at the General Hospital in Guatemala City. Some of his work included organizing defenses against the dread diseases of the time: malaria and yellow fever. He also studied a local fungal infection of coffee plants, and discovered that acidifying the soil could serve as an effective treatment As a side job, he was asked to find a way to make whiskey from bananas. Life in the rough and dangerous environment of the country was hard on his family, but d’Herelle, always adventurer at heart, rather enjoyed working close to “real life”, compared to the sterile environments of a “civilized” clinic. He later stated that his scientific path began on this occasion.

 

In 1907, he took an offer from the Mexican government to continue his studies on fermentation. He and his family moved to a sisal plantation near Merida, Yucatan. Disease struck at him and his family, but in 1909, he had successfully established a method to produce sisal schnapps. Machines for mass production of sisal schnapps were ordered in Paris, where he oversaw the machines’ construction. Meanwhile, in his spare time, he worked for free in a laboratory at the Pasteur Institute. He was soon offered the job of running the new Mexican plant, but declined, considering it “too boring”. He did, however, take the time to attempt stopping a locust plague at the plantation using their own diseases. He extracted bacteria pathogenic to locusts from their guts. This innovative approach to locust plagues anticipated modern biological pest control using Bacillus thuringiensis also known as Bt. D’Herelle and his family finally moved to Paris in early 1911, where he worked again as an unpaid assistant in a lab at the Pasteur Institute. He got attention in the scientific community the same year, when the results of his successful attempt to counter the Mexican locust plague with Coccobacillus were published. At the end of the year, restless d’Herelle was again on the road, this time in Argentina, where he was offered a chance to test these results on a much larger scale. Thus, in 1912 and 1913, he fought the Argentinian locust plagues with coccobacillus experiments. Even though Argentina claimed his success was inconsistent, he himself declared it a full success, and was subsequently invited to other countries to demonstrate the method.

 

During World War I, d’Herelle and assistants (his wife and daughters among them) produced over 12 million doses of medication for the allied military. At this point in history, medical treatments were primitive, compared to today’s standards. The smallpox vaccine, developed by Edward Jenner, was one of the few vaccines available. The primary antibiotic was the arsenic-based salvarsan against syphilis, with severe side effects. Common treatments were based mercury, strychnine, and cocaine. As a result, in 1900, the average life span was 45 years, and WWI did not change that to the better. In 1915, British bacteriologist Frederick W. Twort discovered a small agent that infects and kills bacteria, but did not pursue the issue further. Independently, the discovery of “an invisible, antagonistic microbe of the dysentery bacillus” by d’Herelle was announced on September 3, 1917. The isolation of phages by d’Herelle works like this:

 

1. Nutritional medium is infected with bacteria; the medium turns opaque.

2. The bacteria are infected with phages and die, producing new phages; the medium clears up.

3. The medium is filtered through porcelain filter, holding back bacteria and larger objects; only the smaller phages pass through.

 

In early 1919, d’Herelle isolated phages from chicken feces, successfully treating a plague of chicken typhus with them. After this successful experiment on chicken, he felt ready for the first trial on humans. The first patient was healed of dysentery using phage therapy in August 1919. Many more followed. At the time, none, not even d’Herelle, knew exactly what a phage was. D’Herelle claimed that it was a biological organism that reproduces, somehow feeding off bacteria. Others, the Nobelist Jules Bordet chief among them, theorized that phages were inanimate chemicals, enzymes specifically, that were already present in bacteria, and only trigger the release of similar proteins, killing the bacteria in the process. Due to this uncertainty, and d’Herelle using phages without much hesitation on humans, his work was under constant attack from many other scientists. It was not until the first phage was observed under an electron microscope by Helmut Ruska in 1939 that its true nature was established.

 

In 1920, d’Herelle travelled to Indochina, pursuing studies of cholera and the plague, from where he returned at the end of the year. D’Herelle, officially still an unpaid assistant, found himself without a lab; d’Herelle later claimed this was a result of a quarrel with the assistant director of the Pasteur Institute, Albert Calmette. The biologist Edouard Pozerski had mercy on d’Herelle and lent him a stool (literally) in his laboratory. In 1921, he managed to publish a monograph, The Bacteriophage: Its Role in Immunity about his works as an official Institute publication, by tricking Calmette. During the following year, doctors and scientists across western Europe took a heightened interest in phage therapy, successfully testing it against a variety of diseases. Since bacteria become resistant against a single phage, d’Herelle suggested using “phage cocktails” containing different phage strains. Phage therapy soon became a boom, and a great hope in medicine. In 1924, January 25, d’Herelle received the honorary doctorate of the University of Leiden, as well as the Leeuwenhoek medal, which is only awarded once every ten years. The latter was especially important to him, as his idol Louis Pasteur received the same medal in 1895). The next year, he was nominated eight times for the Nobel prize, though he was never awarded one.

 

After holding a temporary position at the University of Leiden, d’Herelle got a position with the Conseil Sanitaire, Maritime et Quarantenaire d’Egypte in Alexandria. The Conseil was put in place to prevent plague and cholera spreading to Europe, with special emphasis on the sanitary concerns about Muslim pilgrim groups returning from Mecca and Medina. D’Herelle used phages he collected from plague-infected rats during his 1920 visit to Indochina on human plague patients, with claimed success. The British Empire initiated a vast campaign against plague based on his results. 1927, d’Herelle himself changed his focus to new targets: India and cholera. D’Herelle isolated phages from cholera victims in India. As usual, he did not choose a hospital run by European standards, but rather sought out a medical tent in a slum. According to his theory, one had to leave the sterile hospitals and study and defeat illness in its “natural” environment. His team then dropped phage solution in the wells of villages with cholera patients; the death toll went down from 60% to 8%. The whole India enterprise took less than seven months. D’Herelle refused a request the following year by the British government to work in India, as he had been offered a professorship at Yale University, which he accepted. Meanwhile, European and US pharmaceutical companies had taken up the production of their own phage medicine, and were promising impossible effects. To counteract this, d’Herelle agreed to co-found a French phage-producing company, piping the money back into phage research. All of the companies suffered from production problems, as results from commercial phage medicine were erratic. This was most likely due to the attempt to mass-produce something that was barely understood, leading to damaged phages in the product, or to insufficient amounts thereof. Another possibility is that wrong diagnoses lead to the use of the wrong type of phages, which are specific in the choice of their hosts. Furthermore, many studies on the healing effects of phages were badly conducted. All this led to important parts of the scientific community turning against d’Herelle, who, known for his temper, had made not a few enemies.

 

In or around 1934, d’Herelle went to Tbilisi. D’Herelle was welcomed to the Soviet Union as a hero, bringing the knowledge of salvation from diseases ravaging the eastern states all the way to Russia. He accepted Stalin’s invitation for two reasons: it was said he was enamored of communism, and he was happy to be working with his friend, Prof. George Eliava, founder of the Tbilisi Institute, in 1923. Eliava had become friendly with d’Herelle during a visit to the Pasteur Institute in Paris, where he had learned about phages in 1926. D’Herelle worked at the Tbilisi Institute off and on for about a year – and even dedicated one of his books, “The Bacteriophage and the Phenomenon of Recovery,” written and published in Tbilisi in 1935, to Comrade Stalin. He had planned to take up permanent residence in Tbililsi and had already started to build a cottage on the grounds of the Institute (it would later house KGB headquarters). But just then, his friend Eliava fell in love with the woman with whom the head of the secret police, Lavrenty Beria also happened to be in love, and Eliava’s fate was sealed. He was executed and denounced as an enemy of the people during one of Stalin’s purges. D’Herelle ran for his life and never returned to Tbilisi. His book was banned from distribution. Then, World War II began.

 

Phage therapy boomed, despite all problems, driven by the military on both sides in an effort to keep the troops safe, at least from infections. D’Herelle could not really enjoy this development; he was kept under house arrest by the German “Wehrmacht” in Vichy, France. He used the time to write his book “The Value of Experiment”, as well as his memoirs, the latter being 800 pages in length. After D-Day, the new antibiotic drug penicillin became public knowledge and found its way into the hospitals in the west. As it was more reliable and easier to use than phage therapy, it soon became the method of choice, despite side effects and problems with resistant bacteria. Phage therapy remained a common treatment in the states of the USSR, though, until its deconstruction.

 

Felix d’Herelle was stricken with pancreatic cancer and died a forgotten man in Paris in 1949. He was buried in Saint-Mards-en-Othe in the department of the Aube in France. In the 1960s Felix d’Hérelle’s name appeared on a list published by the Nobel Foundation of scientists who had been worthy of receiving the Nobel Prize but did not, for one reason or another. It is believed that d’Herelle was nominated for the prize eight times. However, France has not completely forgotten Felix d’Herelle. There is an avenue that bears his name in the 16th arrondissement in Paris. D’Herelle became widely known for his imaginative approaches to important problems in theoretical, as well as applied, microbiology. At the same time, he was widely reviled for his self-advertisement, his exaggerated claims of success and his sharp financial practices. He also had a talent for making enemies among powerful senior scientists. D’Herelle’s main legacy lies in the use of phage in the molecular revolution in biology. Max Delbruck and the “phage group” used bacteriophages to make the discoveries that led to the origins of molecular biology. Much of the initial work on the nature of genetic expression and its regulation was performed with bacteriophages by Francois Jacob, Andre Lwoff and Jacques Monod. In fact, immediately before his studies of the structure of DNA, James Watson had earned his Ph.D. by working on a bacteriophage-related project in Salvador Luria‘s laboratory. As one of the earliest applied microbiologists, d’Herelle’s microbe-centered worldview has been noted for its prescience, since microbes are playing increasingly important roles in bioremediation, microbial fuel cells, gene therapy, and other areas with relevance to human well-being.

 

The novel Arrowsmith written by Sinclair Lewis with scientific help from Paul de Kruif was based to a certain extent on the life of d’Herelle. The novel The French Cottage (Russ. Frantsuzskii kottedzh) by David Shrayer-Petrov deals at length with d’Herelle’s experiences in the Soviet Union.

Stem Cells as a Treatment for TB

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Mesenchymal stromal cells (MSCs) are immunomodulatory, and it has been hypothesized that adjunct autologous treatment with bone marrow-derived MSCs might improve clinical outcome by transforming chronic inflammation into productive immune responses. Therefore, novel treatment options are urgently needed for multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis, which are associated with immune dysfunction and poor treatment outcomes. As a result, a study published online in The Lancet Respiratory Medicine (9 January 2014), was performed to assess the safety of infusion of autologous MSCs as an adjunct treatment in patients with tuberculosis.

 

For the study, 30 patients with microbiologically confirmed MDR or XDR tuberculosis were treated with single-dose autologous bone marrow-derived MSCs (aimed for 1×106 cells/kg), within 4 weeks of the start of antituberculosis-drug treatment in a specialist centre in Minsk, Belarus. To be included in the study, patients had to present with pulmonary tuberculosis confirmed by sputum smear microscopy, culture, or both; or had to present with MDR or XDR tuberculosis confirmed by drug-susceptibility testing to first-line and second-line drugs. In addition to the inclusion criteria, patients were excluded if they were pregnant, coinfected with HIV, or infected with hepatitis B, C, or both. The primary endpoint was safety measured by MSC-infusion related events; any tuberculosis-related event within the 6 month observation period that related to a worsening of the underlying infectious disease, measured by conversion of Mycobacterium tuberculosis culture or microscopic examination; or any adverse event defined clinically or by changes in blood hematology and biochemistry variables, measured monthly for 6 months after MSC infusion per protocol.

 

The most common (grade 1 or 2) adverse events were high cholesterol levels (14 of 30 patients), nausea (11 of 30 patients), and lymphopenia or diarrhea (ten of 30 patients). There were no serious adverse events reported. We recorded two grade 3 events that were transitory – i.e., increased plasma potassium ion concentrations in one patient and a transitory grade 3 gamma-glutamyltransferase elevation in another patient.

 

According to the authors, MSCs as an adjunct therapy are safe and can now be explored further for the treatment of patients with MDR or XDR tuberculosis in combination with standard drug regimens. The authors added that adjunct treatment with MSCs needs to be evaluated in controlled phase 2 trials to assess effects on immune responses and clinical and microbiological outcomes.

Family Structure and High Blood Pressure in African-American Men

 

Hypertension underlies an array of life-threatening conditions, including heart disease, stroke, heart attack and kidney disease. Diet, sedentary lifestyle and obesity all contribute to risk of hypertension, but researchers also think genetics plays an important role. About one-third of U.S. adults suffer from hypertension. The burden is considerably greater in the African-American community, in which the condition affects 39% of men and 43% of women.

 

According to a study published in the journal Hypertension (12 December 2013), African-American men who grew up in two-parent homes were less likely to have high blood pressure as adults compared to those raised by a single parent. This is the first study of an African-American population to document an association between childhood family living arrangements and blood pressure.

 

The authors analyzed blood pressure rates and the incidence of hypertension, a persistent state of high blood pressure, in a group of 515 African-American men enrolled in the Howard University Family Study (HUFS). The NIH-funded study conducted in the 2000s produced a repository of health history information about a group of African-American families from the Washington, D.C., metropolitan area.

 

According to the study, African-American men who grew up in a household with both parents, had a significantly lower blood pressure as adults compared with African- American men who grew up in a household with a single parent, regardless of whether the parent was a mother or father. The authors saw the most positive health effects in men who lived with both parents for one to 12 years. This group of adults had a 46% lower chance of being diagnosed with hypertension compared to adults who for those years were raised by a single parent.

 

Among several possible explanations for their findings, the authors suggested that compared with children who reside with two parents, those who live with their mothers alone are about three times more likely to live in poverty. Other studies have linked blood pressure rates with socioeconomic aspects of childhood, including household income and parents’ education and occupation. The findings reported in the current study held up, however, when these factors were statistically accounted for.

 

The authors suggest that living with both parents early in life may represent a critical opportunity when children develop biologically protective mechanisms that last throughout life. In an attempt to shed light on the potential molecular mechanisms, the authors are conducting research to understand the role that incremental DNA fine tuning, or epigenetics, impacts the way various cells behave or are transformed throughout the lifespan of an individual. Clearly, more research is needed in different settings to confirm that family living arrangements negatively affect children’s health outcomes later in life. The authors hope their study will be replicated on a larger scale in populations of ethnically diverse men and women.

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

 

FDA Approves Farxiga to Treat Type 2 Diabetes

 

Congratulations to our friends at BMS and AZ.

 

Type 2 diabetes affects about 24 million people and accounts for more than 90% of diabetes cases diagnosed in the United States. Over time, high blood sugar levels can increase the risk for serious complications, including heart disease, blindness, and nerve and kidney damage.

 

The FDA has approved Farxiga (dapaglifozin) tablets to improve glycemic control, along with diet and exercise, in adults with type 2 diabetes. Farxiga is a sodium-glucose co-transporter 2 (SGLT2) inhibitor that blocks the reabsorption of glucose by the kidney, increases glucose excretion, and lowers blood glucose levels. The drug’s safety and effectiveness were evaluated in 16 clinical trials involving more than 9,400 patients with type 2 diabetes. The trials showed improvement in HbA1c (hemoglogin A1c or glycosylated hemoglobin, a measure of blood sugar control).

 

Farxiga has been studied as a stand-alone therapy and in combination with other type 2 diabetes therapies including metformin, pioglitazone, glimepiride, sitagliptin, and insulin. Farxiga should not be used to treat people with type 1 diabetes; those who have increased ketones in their blood or urine (diabetic ketoacidosis); or those with moderate or severe renal impairment, end stage renal disease, or patients on dialysis.

 

An increased number of bladder cancers were diagnosed among Farxiga users in clinical trials so Farxiga is not recommended for patients with active bladder cancer. Patients with a history of bladder cancer should talk to their physician before using Farxiga. Farxiga can cause dehydration, leading to a drop in blood pressure (hypotension) that can result in dizziness and/or fainting and a decline in renal function. The elderly, patients with impaired renal function, and patients on diuretics to treat other conditions appeared to be more susceptible to this risk.

 

The FDA is requiring six post-marketing studies for Farxiga:

 

1. cardiovascular outcomes trial (CVOT) to evaluate the cardiovascular risk of Farxiga in patients with high baseline risk of cardiovascular disease;

2. double-blind, randomized, controlled assessment of bladder cancer risk in patients enrolled in the CVOT;

3. animal study evaluating the role of Farxiga-induced urinary flow/rate and composition changes on bladder tumor promotion in rodents;

4. two clinical trials to assess the pharmacokinetics, efficacy, and safety in pediatric patients; and

5. enhanced pharmacovigilance program to monitor reports of liver abnormalities and pregnancy outcomes.

 

In clinical trials the most common side effects observed in patients treated with Farxiga were genital mycotic (fungal) infections and urinary tract infections.

 

Farxiga is marketed by Bristol-Meyers Squibb Company, Princeton, N.J. and AstraZeneca Pharmaceuticals L.P., Wilmington, Del.

Kale and Pecorino Salad with Walnuts & Sherry-Soaked Raisins

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© Joyce Hays 2014

 

Ingredients

1 cup walnut halves and/or pieces
1/2 cup golden raisins
2 Tablespoons white wine vinegar or champagne vinegar
1 Tablespoon crème sherry
1 Tablespoon water
1/2 cup Panko crumbs
2 cloves garlic, pressed
Coarse or kosher salt (optional)
4 Tablespoons olive oil
1 bunch Tuscan kale washed and patted dry
2 oz. or 1/2 cup pecorino cheese, grated or ground in a food processor
Juice of 1/2 lemon
Pinch black pepper

 

Prepare walnuts:

Heat oven to 350 degrees. Toast walnuts on a baking sheet for 10 minutes, tossing once. Let cool and coarsely chop.

 

Prepare raisins:

In a small saucepan over low heat, simmer champagne vinegar, water, crème sherry and raisins for 5 minutes, until plump and soft. Set aside in liquid. (Keep in the liquid)

 

Prepare crumbs:

Toast panko, garlic and 2 teaspoons of the olive oil in a skillet together with a pinch of salt until golden. Set aside.

 

Prepare kale:

1. Trim heavy stems off kale and remove ribs. Stack sections of leaves and roll them into a tube, then cut them into very thin ribbons crosswise.

 

2. Put kale in a large salad bowl. Add the pecorino, walnuts and raisins (leaving any leftover vinegar mixture in dish), remaining 2 Tablespoons olive oil and lemon juice and toss until all the kale ribbons are coated. Taste and adjust seasonings with salt, pepper and some of the reserved vinegar mixture from the raisins, if needed. Let sit for 10 minutes before serving, if you can. This enables all of the lovely flavors to merge.

 

3. Add the Panko crumbs, just before you serve the salad, and toss it one more time.

 

On his visit, over a year ago, our son, Alex, raised our consciousness of kale and its health virtues.  In December, when he came for 10 days, there were many new recipes waiting for him to try.  One was a kale salad, posted in this newsletter, about a year ago. On this recent trip, he wolfed down an entire large bowl of kale salad in one sitting. His appetite is so good when it comes to certain healthy foods, that it’s a pleasure to create recipes for him. We also served him an absolutely delicious recipe also posted on the newsletter, of warm kale patties made with quinoa topped with an avocado topping. He and my husband, gobbled these up

 

The salad posted today, was made, with Alex’s next visit in mind, as well as for the pleasure of my husband and me, eating at home, informally, at our kitchen table.  For some reason, when we had this kale pecorino salad, we each had 1/2 a bowl and felt satisfied enough, that we finished, with our usual fresh blueberry dessert and each lost weight by the following morning.

 

If we had wanted more, we would have had fresh halibut dipped in panko, and quickly cooked in a small amount of olive oil, and served with a creamy spinach topping.  Our default white wine is the easy-to-pair, Italian Orvieto; plus, soft fresh Italian bread that my husband loves to soak in good olive oil.

 

Happy New Year to Everyone!  Have a feeling, this will be an excellent year!  Life is good!

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A glass of white Orvieto wine near the Duomo di Orvieto

 

Cheers!

 

White Orvieto is composed primarily of Grechetto and Trebbiano and a blend of Malvasia, Drupeggio, Verdelloand Canaiolo biancograpes.  Grechetto is valued for the fruitiness and weight that it brings to the wine; some of the most highly rated examples of Orvieto have a high concentration of Grechetto.

Patient & Public Empowerment – We Need to Do a Better Job

 

Mark L. Horn, MD, MPH, Chief Medical Officer, Target Health Inc.

 

Up to 2014, the healthcare system has not been working for all Americans. The Affordable Care Act (ACT) attempts to rectify this problem, while at the same time create policies to reduce overall cost to both society and the patient. In this context, we need to rethink how both broad policy initiatives and individual clinical decisions, are presented and discussed with the public. Healthcare, irrespective of policy, is still intimate and personal.

 

During the past few weeks, one of the unreported stories has been the disconnect between the general public and the world of public policy. As some individual policies have been canceled and the reality of increased premiums (at least in some cases) has appeared, the broader public has become concerned by these unanticipated (to many) consequences of the law. In addition, some experts appear genuinely perplexed that these outcomes, which to them were obvious and predictable, have undermined some support of ACT in the general public and has led to widespread media criticism.

 

Clearly, increasing the number of covered individuals, offering broader benefits, and embracing a sicker population was based on noble and honorable intentions. However, an important lesson for policymakers and political leaders is that not communicating clearly to the public concerning complex policy issues can be perilous. Full, comprehensive–and comprehensible–disclosure, as would be required in any proper informed consent, would have been the safest and most prudent course in explaining the ACT. Had this tack been taken, much anguish could have been avoided.

 

Here is another example of good intentions, with a potential disconnect between the experts and the public they seek to serve. Authors from the well-known Dartmouth Institute for Health Policy and Clinical Practice1 have published an analysis of the risks and benefits of screening mammography. These authors created a presentation of the risks and benefits of screening in a manner designed to help women determine the value of screening (for themselves) based upon the outcomes of cancer deaths avoided, false alarms requiring additional workup (biopsy), and over-diagnosis leading to potentially dangerous and unnecessary treatments (surgery/radiation/chemotherapy). While ostensibly intended (I think) to provide a template for women to use in decision making, I was struck by both the complexity of the analysis and the reality of, for a potential patient, how difficult it might be to weigh the small likelihood of life saved by early screening against a much more likely false positive result leading to ‘unnecessary’ biopsy and even treatment. While the numbers are objective, I found the approach potentially inconsistent with how patients may think, react and act. In sum, as with the presentation of complex elements of the ACT, the authors’ analysis is interesting as a model for policymakers and professionals but may be less helpful for many patients.

 

However, any current or potential disconnects can all be easily remedied if the same approach is taken as was done to fix the website, www.healthcare.gov, when true experts were brought in to fix a fixable problem.

 

1 Welch, H.G., Passow H.J. JAMA Intern Med. doi:10.1001/jamainternmed.2013.13635; Published online December 30, 2013.