DIA Annual Meeting Presentation on the Paperless Clinical Trial and its Impact on the Clinical Trial Enterprise

 

Target Health Inc. is pleased to announce that Dr. Jules T. Mitchel will be chairing a Content Hub presentation/conversation which will take place during DIA Annual Meeting in Chicago. Please join us at 4pm on Tuesday June 20, 2017 at the S400 Concourse. The topic is:

 

How eSource Solutions are Impacting Clinical Research Sites, Patients, Regulators and Drug and Device Companies

 

Co-presenting will be our colleagues and friends:

 

Jonathan Helfgott, MS, who is currently the Coordinator of the Regulatory Science Graduate Program at Johns Hopkins University, and previously the Associate Director for Risk Science at FDA CDER OSI and the main author of FDA’s eSource Guidance, and;

 

Mitchell D. Efros MD FACS, CEO of Verified Clinical Trials

 

The following is an outline of the presentation and we look forward to seeing you there:

 

In the not too distant future, we as an industry will execute, manage and monitor clinical trials the same way we execute, manage and monitor banking transactions online, quickly and without the need to maintain paper records. However, as we bring new and innovative technology solutions to the market, we must assess and address the concerns of all of the stakeholders within the clinical trial enterprise. We need to assure patients, clinical research sites, pharmaceutical and device companies, as well as regulators, that there will be improved efficiencies, improved data quality and integrity, improved patient safety, reduced fraud and an overall better experience during the clinical trial process. Topics to be addressed include clinical site acceptance, regulatory concerns, software validation, risk assessments, change management within companies, and a comprehensive assessments of the risks and rewards.

 

For more information about Target Health contact Warren Pearlson (212-681-2100 ext. 165). For additional information about software tools for paperless clinical trials, please also feel free to contact Dr. Jules T. Mitchel. The Target Health software tools are designed to partner with both CROs and Sponsors. Please visit the Target Health Website.

 

Joyce Hays, Founder and Editor in Chief of On Target

Jules Mitchel, Editor

 

QUIZ

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Fat Cells Step in to Help Liver During Fasting

This UT Southwestern study determined that the metabolite uridine helps the body regulate glucose. This graphic depicts how the body’s fat cell-liver-uridine axis works to maintain energy balance.

Credit: UT Southwestern

 

How do mammals keep two biologically crucial metabolites in balance during times when they are feeding, sleeping, and fasting? In a study published in Science, UT Southwestern Medical Center it was reported that that fat 1) ___ is directly involved in maintaining tight regulation of glucose (2) ___ sugar), as well as uridine, a metabolite the body uses in a range of fundamental processes such as building RNA molecules, properly making proteins, and storing glucose as energy reserves. Their study may have implications for several diseases, including diabetes, cancer, and neurological disorders.

 

Metabolites are substances produced by a metabolic process, such as glucose generated in the metabolism of complex sugars and starches, or amino acids used in the biosynthesis of 3) ___. According to Dr. Philipp Scherer, senior author of the study and Director of UT Southwestern’s Touchstone Center for Diabetes Research “Like glucose, every cell in the body needs uridine to stay alive. Glucose is needed for 4) ___, particularly in the brain’s neurons. Uridine is a basic building block for a lot of things inside the cell.“ The study found that while the liver serves as the primary producer of this metabolite only in the fed state, in the fasted state, the body’s 5) ___ cells take over the production of uridine. Basically, this method of uridine production can be viewed as a division of labor. Researchers found that during fasting, the 6) ___ is busy producing glucose — and so fat cells take over the role of producing uridine for the bloodstream. These findings were replicated in human, mouse, and rat studies. Although uridine has many roles, this study is the first to report that fat cells produce plasma uridine during fasting and that a fat cell-liver-uridine axis regulates the 7) ___ energy balance. Study lead author Dr. Yingfeng Deng, Assistant Professor of Internal Medicine, found that blood uridine levels go up during fasting and down when feeding. During feeding, the liver reduces uridine levels by secreting uridine into bile, which is transferred to the gallbladder and then sent to the 8) ___, where it helps in the absorption of nutrients. According to the authors, the 9) ___ in the blood works through the hypothalamus in the brain to affect another tightly regulated system — body temperature, and that it appears that only uridine made by fat cells reduces body temperature.

 

Among the study’s other key findings:

 

– Blood uridine levels are elevated during fasting and drop rapidly during feeding. Excess uridine is released through the bile.

– The liver is the predominant uridine biosynthesis organ, contributing to blood uridine levels in the fed state.

– The fat cells dominate uridine biosynthesis and blood levels in the fasted state.

– The fasting-induced rise in uridine is linked to a drop in core body temperature driven by a reduction in the metabolic rate.

 

In dietary studies, tit was found that prolonged exposure to a high-fat diet blunted the effects of fasting on lowering body temperature, an effect also associated with obesity. Further testing indicated those findings were due to the reduced elevation in uridine in response to fasting.

 

Future research questions include studying the effects of feeding-induced reductions in uridine levels in organs that rely heavily on uridine from plasma, such as the 10) ___, and whether bariatric surgery affects blood uridine levels.

 

The authors concluded that the studies reveal a direct link between temperature regulation and metabolism, indicating that a uridine-centered model of energy balance may pave the way for future studies on uridine balance and how this process is dysregulated in the diabetic state.

 

Sources: UT Southwestern Medical Center; Yingfeng Deng, Zhao V. Wang, Ruth Gordillo, Yu An, Chen Zhang, Qiren Liang, Jun Yoshino, Kelly M. Cautivo, Jef De Brabander, Joel K. Elmquist, Jay D. Horton, Joseph A. Hill, Samuel Klein, Philipp E. Scherer. An adipo-biliary-uridine axis that regulates energy homeostasisScience, 2017; 355 (6330): eaaf5375 DOI: 10.1126/science.aaf5375; ScienceDaily.com

 

ANSWERS: 1) cells; 2) blood; 3) proteins; 4) energy; 5) fat; 6) liver; 7) body’s; 8) gut; 9) uridine; 10) heart

 

Short History of Fasting

The Buddha emaciated after undergoing severe ascetic practices, including fasting. Gandhara, 2nd to 3rd Century CE. British Museum. Credit: User:World Imaging – Own work, Public Domain; Wikipedia Commons

 

Once when the Buddha was touring in the region of Kasi together with a large sangha of monks he addressed them saying:

 

I, monks, do not eat a meal in the evening. Not eating a meal in the evening I, monks, am aware of good health and of being without illness and of buoyancy and strength and living in comfort. Come, do you too, monks, not eat a meal in the evening. Not eating a meal in the evening you too, monks, will be aware of good health and….. and living in comfort.

 

Used for thousands of years, fasting is one of the oldest therapies in medicine. Many of the great doctors of ancient times and many of the oldest healing systems have recommended it as an integral method of healing and prevention. Hippocrates, the father of Western medicine, believed fasting enabled the body to heal itself. Paracelsus, another great healer in the Western tradition, wrote 500 years ago that “fasting is the greatest remedy, the physician within.“ Ayurvedic medicine, has long advocated fasting as a major treatment. In ancient Greece, Pythagoras was among many who extolled its virtues. During the 14th century, fasting was practiced by St Catherine of Siena, while the Renaissance doctor Paracelsus called it the “physician within“. Indeed, fasting in one form or another is a distinguished tradition and throughout the centuries, devotees have claimed it brings physical and spiritual renewal.

 

In primitive cultures, a fast was often demanded before going to war, or as part of a coming-of-age ritual. It was used to assuage an angry deity and by native north Americans, as a rite to avoid catastrophes such as famine. Fasting has played a key role in all the world’s major religions (apart from Zoroastrianism which prohibits it), being associated with penitence and other forms of self-control. Judaism has several annual fast days including Yom Kippur, the Day of Atonements; in Islam, Muslims fast during the holy month of Ramadan, while Roman Catholics and Eastern orthodoxy observe a 40 day fast during Lent, the period when Christ fasted 40 days in the desert.

 

Women in particular seem to have had a proclivity for religious fasting, known as “anorexia mirabilis“ (miraculous lack of appetite); surviving for periods without nourishment was regarded as a sign of holiness and chastity. Julian of Norwich, an English anchoress and mystic who lived in the 14th century used it as a means of communicating with Christ. In other belief systems, the gods were thought to reveal their divine teaching in dreams and visions only after a fast by the temple priests. Fasting has also long been used as a gesture of political protest, the classic example being the Suffragettes and Mahatma Gandhi who undertook 17 fasts during the struggle for Indian independence: his longest fast lasted 21 days. Gandhi famously led Indians in challenging the British-imposed salt tax with the 250 mile Dandi Salt March in 1930, and later in calling for the British to Quit India in 1942. He was imprisoned for many years, upon many occasions, in both South Africa and India. Gandhi attempted to practice nonviolence and truth in all situations, and advocated that others do the same. He lived modestly in a self-sufficient residential community and wore the traditional Indian dhoti and shawl, woven with yarn hand-spun on a charkha. He ate simple vegetarian food, and also undertook long fasts as a means of both self-purification and social protest.

 

The practice of fasting, has had its dark side, having been exploited by exhibitionists and fraudsters, and foisted on the gullible. Take “Doctor“ Linda Burfield Hazzard, from Minnesota, thought to have caused the death of over 40 patients whom she put on strict fasts, before being convicted of manslaughter in 1912. She died from her own fasting regime in 1938. Then there were the Victorian “fasting girls“ who claimed to be able to survive indefinitely without food; one of them, Sarah Jacobs, was allowed to starve to death at aged 12, as doctors tested her claims in hospital.

 

Therapeutic fasting – in which fasting is used to either treat or prevent ill health, with medical supervision – became popular in the 19th century as part of the “Natural Hygiene Movement“ in the US. Dr Herbert Shelton 1895-1985) was one revered pioneer, opening “Dr Shelton’s Health school“ in San Antonio, Texas, in 1928. He claimed to have helped 40,000 patients recover their health with a water fast. Shelton wrote “Fasting must be recognized as a fundamental and radical process that is older than any other mode of caring for the sick organism, for it is employed on the plane of instinct.“ Shelton was an advocate, of alternative medicine, an author, pacifist, vegetarian, supporter of rawism and fasting. Shelton was nominated by the American Vegetarian Party to run as its candidate for President of the United States in 1956. He saw himself as the champion of original natural hygiene ideas from the 1830s. His ideas have been described as quackery by critics.

 

In the UK, too, fasting became part of the “Nature Cure“, an approach which also stressed the importance of exercise, diet, sunshine, fresh air and “positive thinking“. “Fasting in Great Britain was at its most popular in the 1920s,“ according to Tom Greenfield, a naturopath who now runs a clinic in Canterbury, England. “The first Nature Cure clinic to offer fasting opened in Edinburgh and I still have one or two patients who fasted there many decades ago.“ Other clinics which offered therapeutic fasting included the legendary Tyringham Hall in Buckinghamshire, now closed, and Champneys in Tring, Hertforshire – in those days a naturopathic center, now a destination spa. “Fasting was used to treat heart disease, high blood pressure, obesity, digestive problems, allergies, headaches – pretty much everything,“ says Greenfield. “Fasts were individually tailored and could be anything from a day or two to three months, for obese patients. The clinics would take a full case history to see if people were suitable and they would be closely monitored.“ Eventually, he says, “scientific“ medicine became dominant as better drugs were developed. Fasting and the “Nature Cure“ fell out of favor in Britain.

 

By contrast, in Germany where fasting was pioneered by Dr Otto Buchinger, therapeutic fasting is still popular and offered at various centers. Many German hospitals now run fasting weeks, funded by health insurance programs, to help manage obesity. Fasting holidays, held at centers and spas throughout Europe, include Hungary, the Czech Republic and Austria, and are growing in popularity. “In Germany fasting is part of the naturheilkunde – natural health practice,“ says Greenfield. “It has remained popular because it became integrated into medical practice so patients could be referred for a fast by their doctors.“ More recently, interest in fasting has revived in the UK and in the United States, with millions trying intermittent fasting such as the 5:2 diet, or on modified fasts where only certain foods or juices are taken for a period of time. According to Greenfield, “If people can do a one day fast for a minimum of twice a year – maybe one in spring and one in the autumn and setting aside a day they can rest, when they just drink water – this will help mitigate the toxic effects of daily living.“

 

Fasting has been used in Europe as a medical treatment for years. Many spas and treatment centers, particularly those in Germany, Sweden, and Russia, use medically supervised fasting. Fasting has gained popularity in American alternative medicine over the past several decades, and many doctors feel it is beneficial. Fasting is a central therapy in detoxification , a healing method founded on the principle that the buildup of toxic substances in the body is responsible for many illnesses and conditions.

 

Baby Teeth Link Autism and Heavy Metals

 

Prior studies relating toxic metals and essential nutrients to autism have faced key limitations, such as estimating exposure based on blood levels after autism diagnosis rather than before, or not being able to control for differences that could be due to genetic factors. Now, according to an article published online in the journal Nature Communications (1 June 2017), baby teeth from children with autism have been shown to contain more toxic lead and less of the essential nutrients zinc and manganese, compared to teeth from children without autism. The study evaluated twins in order to control genetic influences and focus on possible environmental contributors to the disease. The findings suggest that differences in early-life exposure to metals, or more importantly how a child’s body processes them, may affect the risk of autism. The differences in metal uptake between children with and without autism were especially notable during the months just before and after the children were born. The authors determined this by using lasers to map the growth rings in baby teeth generated during different developmental periods. Higher levels of lead were observed in children with autism throughout development, with the greatest disparity observed during the period following birth. The authors also observed lower uptake of manganese in children with autism, both before and after birth. The pattern was more complex for zinc. Children with autism had lower zinc levels earlier in the womb, but these levels then increased after birth, compared to children without autism. The authors noted that replication in larger studies is needed to confirm the connection between metal uptake and autism.

 

For the study, patterns of metal uptake were compared using teeth from 32 pairs of twins and 12 individual twins. The study then compared patterns in twins where only one had autism, as well as in twins where both or neither had autism. Results showed that smaller differences in the patterns of metal uptake occurred when both twins had autism, but that larger differences occurred in twins where only one sibling had autism. The findings build on prior research showing that exposure to toxic metals, such as lead, and deficiencies of essential nutrients, like manganese, may harm brain development while in the womb or during early childhood. Although manganese is an essential nutrient, it can also be toxic at high doses. Exposure to both lead and high levels of manganese has been associated with autism traits and severity.

 

Genetic Cause of Cushing Syndrome Identified

 

The excess cortisol found in Cushing syndrome can result from certain steroid medications or from tumors of the pituitary or adrenal glands. Symptoms of the disease include obesity, muscle weakness, fatigue, high blood pressure, high blood sugar, depression and anxiety. A new finding in a study appearing online in Endocrine-Related Cancer. (1 June 2017), suggests that mutations in the gene CABLES1 may lead to Cushing syndrome.

 

For the study, the authors scanned tumor and cell tissue from 146 children with pituitary tumors evaluated for Cushing syndrome at the NIH Clinical Center, as well as the genes of tumors from some of the children. Investigators in France scanned the genes of an additional 35 adult patients with Cushing syndrome and pituitary tumors. Results showed that 4 of the patients who presented with mutant forms of CABLES1, did not respond to cortisol. This is significant because, when functioning normally, the CABLES1 protein, expressed by the CABLES1 gene, slows the division and growth of pituitary cells that produce the hormone adrenocorticotropin (ACTH). In turn, ACTH stimulates the adrenal gland to produce cortisol, which then acts on the pituitary gland to halt the growth of ACTH-producing cells, effectively suppressing any tumor development. Because cortisol does not affect the four mutant forms of CABLES1, these genes leave production of ACTH-releasing cells unchecked.

 

According to the authors, the mutations impair the tumor suppressor function in the pituitary gland and that this discovery could lead to the development of treatment strategies that simulate the function of the CABLES1 protein, resulting in the prevention of recurrence of pituitary tumors in people with Cushing syndrome. The authors also noted that the CABLES1 mutants were found in a small proportion of patients and that other genes have been implicated in pituitary tumor formation. Additional studies are needed to fully understand how CABLES1 suppresses tumor formation in the pituitary gland.

 

First Drug Approved to Specifically Treat Giant Cell Arteritis

 

Giant cell arteritis is a form of vasculitis, a group of disorders that results in inflammation of blood vessels. This inflammation causes the arteries to narrow or become irregular, impeding adequate blood flow. In giant cell arteritis, the vessels most involved are those of the head, especially the temporal arteries (located on each side of the head). For this reason, the disorder is sometimes called temporal arteritis. However, other blood vessels, including large ones like the aorta, can become inflamed in giant cell arteritis. Standard treatment involves high doses of corticosteroids that are tapered over time.

 

The FDA has expanded the approved use of subcutaneous Actemra (tocilizumab) to treat adults with giant cell arteritis. This new indication provides the first FDA-approved therapy, specific to this type of vasculitis. The efficacy and safety of subcutaneous (injected under the skin) Actemra for giant cell arteritis were established in a double-blind, placebo-controlled study with 251 patients with giant cell arteritis. The primary efficacy endpoint was the proportion of patients achieving sustained remission from Week 12 through Week 52. Sustained remission was defined as the absence of symptoms of giant cell arteritis, normalization of inflammatory laboratory tests, and tapering the use of prednisone (a steroid drug). Results showed a greater proportion of patients receiving subcutaneous Actemra with standardized prednisone regimens achieved sustained remission from Week 12 through Week 52, as compared to patients receiving placebo with standardized prednisone regimens. The cumulative prednisone dose was also lower in treated patients with Actemra relative to placebo.

 

The overall safety profile observed in the Actemra treatment groups was generally consistent with the known safety profile of Actemra. Actemra carries a Boxed Warning for serious infections. Patients treated with Actemra who develop a serious infection should stop that treatment until the infection is controlled. Live vaccines should be avoided during treatment with Actemra. Actemra should be used with caution in patients at increased risk of gastrointestinal perforation. Hypersensitivity reactions, including anaphylaxis and death, have occurred. Laboratory monitoring is recommended due to potential consequences of treatment-related changes in neutrophils (type of white blood cell), platelets, lipids and liver function tests.

 

Subcutaneous Actemra was previously approved for the treatment of moderate to severely active rheumatoid arthritis. Intravenous Actemra was also previously approved for the treatment of moderate to severely active rheumatoid arthritis, systemic juvenile idiopathic arthritis and polyarticular juvenile idiopathic arthritis. Intravenous administration is not approved for giant cell arteritis.

 

The FDA granted this application a Breakthrough Therapy designation and a Priority Review. Actemra is sold by Hoffman La Roche, Inc.

 

Red Potatoes: Baked, Smashed & Topped with Garlic-y Asparagus Sauce & Rosemary Pistachio Garnish

All you need for this recipe is basically, locally-grown tender Spring asparagus and a food processor. What would we do without food processors? This dish is quick, easy and very tasty. ©Joyce Hays, Target Health Inc.

 

If you’re eating indoors or out, these tasty little morsels can be an easy finger food/ ©Joyce Hays, Target Health Inc.

 

Ingredients

3 cups fresh pieces of asparagus (fat ones), clean and cut, save tips

1 and 1/2 cups pine nuts (toast them first)

6 cloves fresh garlic, peeled first of course

1/3 cup freshly grated Parmesan

1 cup extra virgin olive oil

Pinch salt

Pinch black pepper

Pinch chili flakes

1 teaspoon curry powder

1 or 2 pounds mini red potatoes or medium red potatoes

Garnish: 1 cup full of toasted, then chopped pistachios & almonds, mixed with ? teaspoon dried rosemary (I bought this ready-made at Nuts.com)

 

Directions for Sauce

  1. In a food processor, blend together asparagus, nuts, garlic, and cheese. Pour in oil slowly while still mixing. Stir in salt, pepper, chili flakes, curry.  Put tips aside for decoration, later.

 

Set aside the tips for use later, as a garnish or decoration. ©Joyce Hays, Target Health Inc.

 

Pulse until you get a smooth green, slightly thick topping. ©Joyce Hays, Target Health Inc.

 

Your asparagus sauce/topping, should look like this. ©Joyce Hays, Target Health Inc.

 

Directions for Red Potatoes

1. Wash and oil the red potato skins, then put them on a baking sheet and bake, uncovered in oven at 375 degrees for 60 minutes.  Pinch a little to see if done.  If not put back in oven for another 10 or more minutes.  You could also use medium size red potatoes but bake longer, like 80 minutes.  And, who says you can’t use large red potatoes?  I’m using smaller sizes, simply because I think they look prettier in the serving dish and on the individual plate.

2. While potatoes are baking, heat up the asparagus sauce.  If you think it’s too thin, slowly add a teaspoon of chickpea flour, stirring while you add.

3. When potatoes are done, put a piece of parchment over the potato and push down with your hand, or the back of a coffee mug, or the back of a large wooden spoon.  You want the potato to break open.

 

After smashing the red potatoes, they look like this. ©Joyce Hays, Target Health Inc.

 

4. On a flat serving dish, arrange the smashed potatoes. Using a teaspoon, put asparagus sauce on top of each potato.  Next sprinkle some of the rosemary pistachio/almond mixture as a garnish over the asparagus sauce. You could also be creative and use the cooked asparagus tips in a decorative way on the serving dish.

 

Here we had two red mini potatoes per individual plate, with asparagus sauce and the pistachio garnish – with filet mignon and mushroom/marsala sauce.  ©Joyce Hays, Target Health Inc.

 

This is the medium size red potato at another meal, with asparagus tip as garnish.  ©Joyce Hays, Target Health Inc.

 

Medium size red potatoes, with asparagus tip plus chopped pistachios & almonds for garnish.  ©Joyce Hays, Target Health Inc.

 

Here is the delicious pistachio nut garnish used on the asparagus potatoes. ©Joyce Hays, Target Health Inc.

 

Simple lunch of baked salmon with ginger, plus the asparagus potatoes. ©Joyce Hays, Target Health Inc.

 

Another simple tasty lunch: red cabbage salad with goat cheese & dates  –  and the asparagus potatoes. ©Joyce Hays, Target Health Inc.

 

Both chilled white wines, above, went well with these Smashed Potatoes with Asparagus Sauce, sprinkled with rosemary pistachio chopped nuts. ©Joyce Hays, Target Health Inc.

 

 

From Our Table to Yours

Bon Appetit!