A Closing Thought on Regulatory Considerations When Doing eSource Data Integration


The current edition of Applied Clinical Trials is featuring articles on paperless clinical trials, electronic Informed Consent, BYOD apps, eSource and risk-based monitoring. ACT asked us to write “A Closing Thought“ on the topic, which we entitled Regulatory Considerations are Key in eSource Data Integration. Here is a quote from a colleague after he read the article: “Thanks for sharing, and excellent article. I think it’s important to emphasize the eloquent comment you made about leveraging FDA cleared devices, which most folks have a tendency to overlook.“


In terms of “putting our money where our mouth is,“ we are pleased that one of our international clients obtained FDA approvalof a de novo 510(k) device where the clinical trial sites, all major medical centers in the US, used direct data entry (DDE) at the time of the clinic visit. In addition, there is an NDA currently under review with 7 studies, all using DDE, and where >90% of the data were entered in real time. All-together, 8 clinical sites had flawless FDA pre-approval inspections, as was the FDA inspection of Target Health. If you want to do a study or want more metrics, please let us know.


Here are some highlighted quotes from the ACT article:


1. We must also separate the “toys from the tools.“ Just having a “neat app“ won’t fly in the regulated ecosystem we all must live in.


2. It’s critical to involve regulators when the use of these devices impacts the management of subject safety and the evaluation of primary and secondary endpoints.


3. As potentially non-regulated devices are used or regulated devices are used “off-label,“ we must be ever-vigilant on the software validation process, the impact of app performance when used with various operating systems and devices, as well as the impact of system upgrades on the validated state of the software.


4. As we collect continuous data, such as ECG readings, number of steps taken during wake time, or number of awakenings when participating in a nocturia trial, the software should have validated algorithms to summarize the outcomes rather than requiring the pharma or device company to do the analysis from scratch. This will be one of the main advantages of using FDA-cleared devices presenting with validated software.


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 or Ms. Joyce Hays. 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



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Source: Wikipedia Commons



Dr. William Wolff and Dr. Hiromi Shinya pioneered the development of the colonoscope. Their invention, in 1969, was an advance over the barium enema and the flexible sigmoidoscope because it allowed for the visualization and removal of 1) ___ from the entire large intestine. Wolff and Shinya advocated for their invention and published much of the early evidence needed to overcome skepticism about the device’s safety and efficacy.


Colonoscopy is a test that allows your doctor to look at the inner lining of your large intestine (rectum and colon). He or she uses a thin, flexible tube called a colonoscope to look at the 2) ___. A colonoscopy helps find ulcers, colon polyps, tumors, and areas of inflammation or bleeding. During a colonoscopy, tissue samples can be collected in a procedure called a 3) ___and abnormal growths can be taken out. Colonoscopy can also be used as a s creening test to check for cancer or precancerous growths in the colon or rectum (polyps).


The colonoscope is a thin, flexible tube that ranges from 48 in. (125 cm) to 72 in. (183 cm) long. A small video 4) ___ is attached to the colonoscope so that your doctor can take pictures or video of the large intestine (colon). The colonoscope can be used to look at the whole colon and the lower part of the small intestine. A test called sigmoidoscopy shows only the rectum and the lower part of the colon. Before this test, you will need to clean out your colon (colon prep). Colon prep takes 1 to 2 days, depending on which type of prep your doctor recommends. Some preps may be taken the evening before the test. For many people, the prep is worse than the test. The bowel prep may be uncomfortable, and you may feel hungry on the clear liquid diet. Plan to stay home during your prep time since you will need to use the bathroom often. The colon prep causes loose, frequent stools and diarrhea so that your colon will be empty for the test. If you need to drink a special solution as part of your prep, be sure to have clear fruit juices or soft drinks to drink after the 5) ___ because the solution may have a salty or unpleasant taste.


Colonoscopy is one of many tests that may be used to screen for 6) ___. Other tests include sigmoidoscopy, stool tests, and computed tomographic colonography. Which screening test you choose depends on your risk, your preference, and your doctor. Talk to your doctor about what puts you at risk and what test is best for you. Colonoscopy or coloscopy enables the removal of suspected colorectal cancer lesions. Colonoscopy can remove polyps as small as one millimeter or less. Once polyps are removed, they can be studied with the aid of a microscope to determine if they are precancerous or not. It can take up to 15 years for a polyp to turn 7) ___.


Colonoscopy is similar to sigmoidoscopy – the difference being related to which parts of the colon each can examine. A colonoscopy allows an examination of the entire colon (1200-1500 mm in length). A sigmoidoscopy allows an examination of the distal portion (about 600 mm) of the colon, which may be sufficient because benefits to cancer survival of colonoscopy have been limited to the detection of lesions in the distal portion of the colon. A sigmoidoscopy is often used as a screening procedure for a full colonoscopy, often done in conjunction with a fecal occult blood test (FOBT). About 5% of these screened patients are referred to colonoscopy.


Virtual colonoscopy, which uses 2D and 3D imagery reconstructed from computed tomography (CT) scans or from nuclear magnetic resonance (MR) scans, is also possible, as a totally non-invasive medical test, although it is not standard and still under investigation regarding its diagnostic abilities. Furthermore, 8) ___ virtual colonoscopy does not allow for therapeutic maneuvers such as polyp/tumor removal or biopsy nor visualization of lesions smaller than 5 millimeters. If a growth or polyp is detected using CT colonography, a standard colonoscopy would still need to be performed. Additionally, surgeons have lately been using the term pouchoscopy to refer to a colonoscopy of the ileo-anal pouch.


Conditions that call for colonoscopies include gastrointestinal hemorrhage, unexplained changes in bowel habit and suspicion of malignancy. Colonoscopies are often used to diagnose colon cancer, but are also frequently used to diagnose inflammatory bowel disease. In older patients (sometimes even younger ones) an unexplained drop in hematocrit (one sign of anemia) is an indication that calls for a colonoscopy, usually along with an EGD or 9) ___, even if no obvious blood has been seen in the stool (feces). Fecal occult blood is a quick test which can be done to test for microscopic traces of blood in the stool. A positive test is almost always an indication to do a colonoscopy. In most cases the positive result is just due to hemorrhoids; however, it can also be due to diverticulosis, inflammatory bowel disease (Crohn’s disease, ulcerative colitis), colon cancer, or polyps. However polypectomy has become a routine part of colonoscopy, allowing for quick and simple removal of polyps without invasive 10) ___.


ANSWERS: 1) polyps; 2) colon; 3) biopsy; 4) camera; 5) prep; 6) cancer; 7) cancerous; 8) virtual; 9)esophagogastroduodenoscopy; 10) surgery


History of Colon Therapy


The Ebers Papyrus (c. 1550 BCE) from Ancient Egypt; Source: Wikipedia Commons



The value of tissue and body cleansing through colon lavage (irrigation or washing out of an organ) has been practiced for more than three thousand years. As early as 1500 BCE, the ?Ebers Papyrus’, an ancient Egyptian medical document, described the many benefits of colon cleansing. In ancient times, the practice of cleansing the colon was administered in a river by using a hollow reed to induce water flow into the rectum. The ancient Egyptians believed that toxins formed as a result of decomposition within the intestines, (as found in the Ebers Papyrus. by Levin and Munksgaard) and moved from there into the circulatory system, causing fever and the development of pus. The Ancient Greeks adopted and expanded the idea, applying their belief in the four humors. In the 19th century, studies in biochemistry and microbiology seemed to support the autointoxication hypothesis, and mainstream physicians promoted the idea. Historically, “purging was one of the few procedures that a physician could perform with visible, often impressive results and without immediate or obvious dangers“.


Centuries later, the benefits of colon lavage continued to be popular. Colon irrigation was commonly used among European populations to assist with maintenance and promotion of overall health. Enemas were frequently used for abatement of fever, anxiety and illness. In the early 1900’s, improvements in colon hydrotherapy devices allowed for a more complete cleansing of the large intestine. Implementation of these technological advancements brought on times of colonic popularity and also times of rejection. Unfortunately, advanced colon irrigation was, at times, administered by the unskilled and poorly trained. This proved to be detrimental for the support of the general population and medical profession. Despite the difficulties in the early 1900’s, the value of colon hydrotherapy continued to be recognized by several medical doctors. Most noteworthy were James A. Wiltsie M.D., Joseph Waddington M.D., and John H. Kellogg M.D.


In the early 1900’s Dr. John H. Kellogg M.D. used forms of colon therapy on several thousand of his patients. In a 1917 edition of the Journal of American Medical Association (JAMA) Dr. Kellog reported that in over forty thousand gastrointestinal disease cases, he had used surgery in only twenty cases. The rest were helped as a result of cleansing the bowels, diet and exercise. 


Dr. Ilya Ilyich Mechnikov (1845-1916) became the strongest supporter of the idea of colon cleansing; he thought that toxins could shorten the lifespan. Over time, the concept broadened to “auto-intoxication“, which supposes that the body cannot fully dispose of its waste products and toxins, which then accumulate in the intestine. In some cases, the concept led to radical surgeries to remove the colon for unrelated symptoms. Auto-intoxication enjoyed some favor in the medical community in the late 19th and early 20th centuries, but clinicians discarded it as advances in science failed to support its claims. A 1919 paper entitled “Origin of the so-called auto-intoxication symptom“ in the Journal of the American Medical Association marked the beginning of the rejection of the auto-intoxication hypothesis by the medical community. Despite a lack of scientific support, “auto-intoxication“ persists in the public imagination. The practice of colon cleansing has undergone a resurgence in the alternative-medical community, supported by testimonials and anecdotal evidence and promoted by manufacturers of colon-cleansing products.


In the United States, the FDA regulates the production of equipment used in colon hydrotherapy in the USA, but does not regulate their use, or the supplements used in oral colon-cleansing regimens and manufacturer claims do not require verification or supporting evidence. The contents of the products are also not verified or tested. The FDA has issued several letters warning manufacturers and suppliers of colon hydrotherapy equipment about making false claims of effectiveness, safety issues and quality control violations.



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Eye Study Shows Long-Lasting Benefits of Diabetes Control


Diabetic retinopathy affects about 7.7 million Americans and is the leading cause of vision loss among working-age Americans. Diabetic retinopathy can cause blood vessels to swell and leak fluid, sometimes distorting vision. Proliferative diabetic retinopathy, an advanced stage of the disease, occurs when abnormal blood vessels appear on the surface of the retina. These abnormal blood vessels are prone to bleeding and lead to the formation of scar tissue, sometimes causing retinal detachment and permanent vision loss.


ACCORDION is a follow-up assessment of diabetic retinopathy progression in 1,310 people who participated in ACCORD, which tested three treatment strategies to reduce the risk of cardiovascular disease among people with longstanding type 2 diabetes. ACCORD tested maintaining near-normal blood sugar levels (intensive glycemic control); improving blood lipid levels, such as lowering LDL “bad“ cholesterol and triglycerides and raising HDL “good“ cholesterol; and lowering blood pressure. Results, published in Diabetes Care (2016; 39:1-12), showed that type 2 diabetics who intensively controlled their blood sugar level during the landmark Action to Control Cardiovascular Risk in Diabetes (ACCORD) Trial Eye Study were found to have cut their risk of diabetic retinopathy in half in a follow-up analysis conducted four years after stopping intensive therapy.


The treatment phase of the glycemic control portion of ACCORD had been planned to last 5.6 years but was stopped at 3.5 years due to an increase in death among participants in the intensive glycemic control group. The blood pressure and blood lipid portions of ACCORD continued. Tight control successfully reduced glycemia to an average 6.4-percent A1C — a measure of average blood glucose — compared to 7.7 percent among participants on standard glycemic control therapy. Although the study failed to reduce cardiovascular disease risk, such as heart attack and stroke, it was observed that the therapy had cut retinopathy progression by about one-third by the end of ACCORD. Investigators considered progression to have occurred if a participant required laser surgery for diabetic retinopathy, required a vitrectomy — a procedure used to remove the gel-like fluid of the eye — or advanced three or more steps on the Early Treatment Diabetic Retinopathy Study (ETDRS) Severity Scale. The ETDRS Severity Scale uses photographs of the retina to rate disease severity from 1 (no disease) to 17 (high-risk for progression in both eyes).


ACCORDION re-assessed diabetic retinopathy about four years after the intensive glycemic control portion of the study had ended — eight years after enrollment in ACCORD. By then, average A1C was nearly the same: 7.8% for the intensive therapy group and 7.9% for the standard therapy group. However, diabetic retinopathy had advanced in only 5.8% of participants in the intensive therapy group since enrollment in ACCORD, compared to 12.7% in the standard therapy group. Other clinical trials have reported the phenomenon, also known as the legacy effect. Participants with type 1 diabetes who received intensive glycemic therapy in the 10-year-long Diabetes Control and Complications Trial on average had 50% less progression of diabetic retinopathy three decades later. A similar trend was seen in the United Kingdom Prospective Diabetes Project, a study of people with newly diagnosed type 2 diabetes.


Results from ACCORDION suggest that lowering blood glucose can reduce progression of retinal disease relatively late in the course of type 2 diabetes and that even short-term changes in glucose have an effect. The findings add to mounting evidence that tight glycemic control has positive, long-lasting effects on small blood vessels. Other follow-up studies of ACCORD participants have observed a legacy effect similar to ACCORDION in kidney and peripheral nerve health, which also involve small blood vessels. But the benefits of intensive glycemic therapy must be weighed against the potential risks — most notably the increased risk of death observed in ACCORD. Investigators have been unable to determine a cause for the increase, which was not seen in other trials.


Results also point to a possible role for ongoing use of fenofibrate to treat diabetic retinopathy, if taken regularly. The blood lipid and blood pressure portions of ACCORD concluded at 5.6 years. Neither strategies reduced cardiovascular disease. However, fenofibrate, a drug that raises HDL cholesterol, decreased diabetic retinopathy progression by about one-third during ACCORD. ACCORDION investigators found fenofibrate had no lasting benefit 3 years after the drug was discontinued. But based on ACCORD findings, fenofibrate might be worth taking to control diabetic retinopathy progression. Other countries, including Australia, have approved fenofibrate for treating diabetic retinopathy but not the U.S. The NEI-funded Diabetic Retinopathy Clinical Research Network is currently planning a clinical trial to further explore ongoing use of fenofibrate to control diabetic retinopathy.


View an NEI video about how diabetic retinopathy can be detected through a comprehensive dilated eye exam.



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Proper Maternal Folate Level May Reduce Child Obesity Risk


Obesity in children and adults is a serious health issue in the United States, contributing to such conditions as heart disease, stroke and type 2 diabetes. During pregnancy, maternal obesity also increases the risk for a range of pregnancy complications, such as stillbirth, birth defects and preterm birth. Furthermore, babies born to obese mothers have long-term health risks, including a higher risk of obesity in childhood.


Folate, an essential B vitamin, reduces the fetus’ risk for neural tube defects, which are malformations affecting the brain, spine and spinal cord. The U.S. Centers for Disease Control and Prevention recommends that women of childbearing age take 400 micrograms of folic acid (a synthetic form of folate) daily to reduce their children’s risk for neural tube defects. However, the role of maternal folate levels on a child’s future obesity risk was not known, especially among those born to mothers who are obese during pregnancy.


According to an article published online in JAMA Pediatrics (13 June 2016), proper maternal folate levels during pregnancy may protect children from a future risk of obesity, especially those born to obese mothers. The study investigated the health outcomes of mothers and children (ranging from 2 to 9-years of age) in the Boston Birth Cohort, a predominately low-income, minority population with a high prevalence of maternal and child obesity. The study team analyzed health records from more than 1,500 mother-child pairs, including information that was collected before, during and after pregnancy. To gauge a mother’s folate level during pregnancy, the authors measured folate from stored plasma samples that were collected two to three days after delivery. Results showed a wide range of maternal folate levels, but observed an “L-shaped“ relationship between maternal folate levels and child obesity. In other words, the lowest levels of folate correlated with the highest risk of child obesity. When folate levels reached approximately 20 nanomoles per liter (nm/L), which is within the normal range for adults, further increases in folate levels did not confer additional benefits, indicating a threshold or ceiling effect. According to the authors, this threshold is higher than the standard cutoff for diagnosing folate deficiency (less than 10 nm/L).


Obese mothers in the study tended to have lower folate levels than normal weight mothers. However, when the authors examined obese mothers only, they found that children of obese mothers with adequate folate levels (at least 20 nm/L) had a 43% lower risk of obesity compared to children of obese mothers with lower folate (less than 20 nm/L). The children in the latter group had higher body mass index-for-age z-scores (BMI-z)-a measure of body fat in children. According to the authors, establishing an “optimal“ rather than “minimal“ folate concentration may be beneficial for women planning a pregnancy, especially obese women.


FDA Clears New Obesity Treatment Device


The FDA has approved a new obesity treatment device that uses a surgically-placed tube to drain a portion of the stomach contents after every meal. The AspireAssist device should not be used on patients with eating disorders, and it is not intended to be used for short durations in those who are moderately overweight. It is intended to assist in weight loss in patients aged 22 and older who are obese, with a body mass index of 35 to 55, and who have failed to achieve and maintain weight loss through non-surgical weight-loss therapy.


To place the device, surgeons insert a tube in the stomach with an endoscope via a small incision in the abdomen. A disk-shaped port valve that lies outside the body, flush against the skin of the abdomen, is connected to the tube and remains in place. Approximately 20 to 30 minutes after meal consumption, the patient attaches the device’s external connector and tubing to the port valve, opens the valve and drains the contents. Once opened, it takes approximately five to 10 minutes to drain food matter through the tube and into the toilet. The device removes approximately 30% of the calories consumed.


The FDA reviewed results from a clinical trial of 111 patients treated with AspireAssist and appropriate lifestyle therapy, and 60 control patients who received only the lifestyle therapy. After one year, patients using AspireAssist lost an average of 12.1 percent of their total body weight compared to 3.6 percent for the control patients. Clinical trial results also suggested that both patient groups had small improvements in conditions often associated with obesity, such as diabetes, hypertension and quality of life. These improvements may be attributable to the lifestyle therapy, which includes nutrition and exercise counseling.


Patients require frequent monitoring by a health care provider to shorten the tube as they lose weight and abdominal girth, so that the disk remains flush against their skin. Frequent medical visits are also necessary to monitor device use and weight loss and to provide counseling on lifestyle therapies. The device also has a safety feature that keeps track of the number of times the drain tube is connected to the port and automatically stops working after 115 cycles (approximately five to six weeks of therapy); patients must return for a medical visit to get a replacement part for the device in order to continue the therapy. This safety feature helps ensure patients use the device properly during therapy.


Side effects related to use of the AspireAssist include occasional indigestion, nausea, vomiting, constipation and diarrhea. The endoscopic surgical placement of the gastric tube is associated with risks, including sore throat, pain, abdominal bloating, indigestion, bleeding, infection, nausea, vomiting, sedation-related breathing problems, inflammation of the lining of the abdomen, sores on the inside of the stomach, pneumonia, unintended puncture of the stomach or intestinal wall and death. Risks related to the abdominal opening for the port valve include abdominal discomfort or pain, irritation, hardening or inflammation of the skin around the site where the tube is placed, leakage, bleeding and/or infection around the site where the tube is placed and device migration into the stomach wall. All have the potential to necessitate removal of the device. After device removal, there may be a risk of persistent fistula, an abnormal passageway between the stomach and the abdominal wall.


AspireAssist is contraindicated in those with certain conditions, including uncontrolled hypertension, diagnosed bulimia, diagnosed binge eating disorder, night eating syndrome, certain types of previous abdominal surgery, pregnancy or lactation, inflammatory bowel disease or stomach ulcers. AspireAssist is also contraindicated in patients with a history of serious pulmonary or cardiovascular disease, coagulation disorders, chronic abdominal pain or those at a high risk of medical complications from an endoscopic procedure.


The AspireAssist System is manufactured by Aspire Bariatrics located in King of Prussia, Pennsylvania.


Vitamin B6 Benefits of Chickpeas


Source: Wikipedia Commons


Half a cup of chickpeas supplies about half a milligram of this cancer-fighting B vitamin, which doesn’t sound like much. But you only need slightly north of 3.5 milligrams daily for healthy benefits. And in a recent study, people from many different walks of life seemed to benefit from ample B6. No one will get pellagra with chickpeas in their diet. The chickpea is one of the earliest cultivated legumes: 7,500-year-old remains have been found in the Middle East.


The name “chickpea“ traces back through the French chiche to cicer, Latin for ?chickpea’ (from which the Roman cognomen Cicero was taken). The Oxford English Dictionary lists a 1548 citation that reads, “Cicer may be named in English Cich, or ciche pease, after the Frenche tonge.“ The dictionary cites “Chick-pea“ in the mid-18th century; the original word in English taken directly from French was chich, found in print in English in 1388 and became obsolete in the 18th century. The word garbanzo came to English as “calavance“ in the 17th century, from Old Spanish (perhaps influenced by Old Spanish garroba or algarroba), though it came to refer to a variety of other beans. The Portuguese (?) arvan?o has suggested to some that the origin of the word garbanzo is in the Greek erebinthos. But the Oxford English Dictionary mentions a possible origination in the word garbantzu, from Basque – a non-Indo-European tongue – in which it is a compound of garau, seed + antzu, dry.


Domesticated chickpeas have been found in the aceramic levels of Jericho along with Cayonu in Turkey and in Neolithic pottery at Hacilar, Turkey. They are found in the late Neolithic (about 3500 BCE) at Thessaly, Kastanas, Lerna and Dimini. In southern France Mesolithic layers in a cave at L’Abeurador, Aude have yielded wild chickpeas carbon dated to 6790+90 BCE. By the Bronze Age, chickpeas were known in Italy and Greece. In classical Greece, they were called erebinthos and eaten as a staple, a dessert, or consumed raw when young. The Romans knew several varieties such as venus, ram, and punic chickpeas. They were both cooked down into a broth and roasted as a snack. The Roman gourmet Apicius gives several recipes for chickpeas. Carbonized chickpeas have been found at the Roman legion fort at Neuss (Novaesium), Germany in layers from the first century CE, along with rice.


Chickpeas are mentioned in Charlemagne’s Capitulare de villis (about 800 CE) as cicer italicum, as grown in each imperial demesne. Albertus Magnus mentions red, white and black varieties. Nicholas Culpeper noted “chick-pease or cicers“ are less “windy“ than peas and more nourishing. Ancient people also associated chickpeas with Venus because they were said to offer medical uses such as increasing sperm and milk, provoking menstruation and urine and helping to treat kidney stones. “White cicers“ were thought to be especially strong and helpful.



Hearty Chickpea Salad with Artichoke Heart, Tomato & Arugula




One 15-oz. can chickpeas, rinsed and drained (if you want to soak & cook your own, do it the day before you make this salad)

One frozen package Artichoke hearts (steam for 8-10 minutes, drain, & towel dry)

1 stalk celery, finely chopped

2 ripe Tomatoes, cut into small pieces

1/2 to 1/3 cup thinly sliced black olives

1 avocado, cut into cubes

2 cloves garlic, juiced (throw the pulp away)

1 Onion, chopped very fine

1/4 cup finely chopped fresh parsley

1/3 cup chopped cilantro

1 teaspoon turmeric

Zest & Juice from 1/2 a lemon (or lime)

2 Tablespoons Olive oil

1 cup baby arugula, stuff them down into the cup (wash these leaves very well, dry with paper towels)

1 cup grated soy Mozzarella or crumbled feta cheese, or crumbled goat cheese

Several grinds Black pepper & (optional) salt




In a small bowl make the dressing. Add the olive oil, garlic juice, chopped onion, turmeric, lemon zest and lemon juice, several grinds of black pepper (salt if desired)

In your salad bowl, toss together chickpeas, artichoke hearts, celery, tomatoes, olives, cilantro and parsley.

Now add to the chickpea mixture the dressing and stir well. Next stir in slowly the arugula, avocado, and the cheese you selected to use. Taste to check the seasoning and add more grinds of pepper, or anything else, if needed.


Serve with warm pita bread and/or a grainy bread and a nice chilled Sauvignon Blanc or Pinot Grigio, or crisp dry Chardonnay or even a dry rose. However, with my brother in law, we’re still enjoying icy Pouilly-Fuisse.



Cheers! ©Joyce Hays, Target Health Inc.



From Our Table to Yours !


Bon Appetit!