RBM Webinar – InSite (Publication of the Society for Clinical Research Sites)


The recent edition of InSite, The Global Journal for Clinical Research Sites, featured a webinar entitled “The Monitoring Dynamic: An Evolving Process and Relationship with the Site.“ The webinar was jointly presented by Jules Mitchel, President Target Health Inc., Craig Wozniak, VP Clinical Operations Americas Janssen Pharmaceuticals, and Mitchell D Efros, CEO Verified Clinical Trials. The presenters shared their experiences from the Site, Sponsor and CRO perspectives. The needs were clear and cautious optimism prevailed.


Some quotes:


“In Mitchel’s view, the traditional methods of monitoring clinical trials are less intelligent than risk-based monitoring (RBM) because they focus on all aspects of the trials as equally important rather than the things that matter most in the trial.“


According to Wozniak, “We’re doing the risk assessments, the central monitoring and analytics. There’s more of a shift now to anticipating and identifying where we have the risks, focusing on them, and trying to identify those in an ongoing, systematic way,“


“We feel like we’re doing a lot of work that the monitor should be doing when they are on site,” Efros said. “However, the use of direct data entry systems versus paper data entry has tended to reduce these problems.“ “We have done real-time data entry and it does work. And in this age of science and technology and research I don’t understand why that doesn’t take place more often, if not all the time,”


A Gift From Our Colleagues From the Chinese SFDA


Several weeks ago Target Health made presentations to representatives of the SFDA from Shandong Province.  Shandong has played a major role in Chinese history from the beginning of Chinese civilization along the lower reaches of the Yellow River and served as a pivotal cultural and religious site for Taoism, Chinese Buddhism, and Confucianism. Shandong’s Mount Tai is the most revered mountain of Taoism and one of the world’s sites with the longest history of continuous religious worship.


Our colleagues were kind enough to share a gift of a calligraphy based on the following saying from Confucius “With virtue there is no solitude, only companionship.“ Chapter 4, Analects of Confucius.




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


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.


Joyce Hays, Founder and Editor in Chief of On Target

Jules Mitchel, Editor



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Urban Emergency Medicine; Is Gun Violence a Public Health Disease?


Emergency medical team responders (Wikipedia)



Editor’s note: We believe that gun violence in the United States, should be non-partisan, and instead, considered a public health issue with solutions approached as such.


If we had a disease that was killing as many people as our guns in our country, we would devote a lot more resources to make sure we had the best data, the best research to know what is most affected. The public would be clamoring for a 1) ___. Daniel Webster, directs the Johns Hopkins Center for Gun Policy and Research in Baltimore, and believes that gun violence is best viewed as an urgent public 2) ___ problem, one deserving of as much scrutiny and research as any infectious disease. We now have a shooting somewhere in the U.S. each of the 365 days a year.


This past Wednesday morning, a group of doctors in white coats arrived on Capitol Hill to deliver a petition to Congress. Signed by more than 2,000 physicians around the country, it pleads with lawmakers to lift a restriction that for nearly two decades has essentially blocked the Center for Disease Control and Prevention from conducting research on 3) ___ violence. Joined by a handful of lawmakers, the doctors spoke about the need to view gun violence as a 4) ___ health epidemic and research ways to solve it – as the country would with any disease causing the deaths of thousands of Americans each year. “It is disappointing that we have made little progress over the past 20 years in finding solutions to gun 5) ___,“ said Nina Agrawal, a New York physician and member of the advocacy group Doctors for America, according to the group’s Twitter feed. “We should all be able to agree that this debate should be informed by objective data and scientific research,“ said Rep. David Price (D-N.C.). Congressional lawmakers “control the purse strings. They could change this today, if they wanted to,“ Daniel Webster told the Washington Post at the time. Webster wasn’t optimistic that change would come anytime soon. But like the doctors who made their plea to lawmakers on Capitol Hill early Wednesday, hours before gunfire rocked San Bernardino, California, he hoped it would come sooner than later. “It just affects the basic things we care about in public health – the mortality, the life expectancy, morbidity, mental health. It affects all of those things in pretty profound ways,“ Webster said of gun violence. “If we had a disease that was killing as many people as our guns in our country, we would devote a lot more resources to make sure we had the best data, the best research to know what is most affected.“


Healthcare disparities, special populations, urban violence, drug and alcohol abuse, and much more, all converge to form what has been called “Urban Emergency Medicine.“ Unfortunately, the 6) ___ battlefield presents special clinical challenges that emergency physicians, nurses, nurse practitioners, physician assistants, as well as out-of-hospital providers, face daily. Most programs in emergency medicine, are three years in duration, but some academic programs are now offering four-year programs. There are several combined residencies offered with other programs including family medicine, internal medicine and pediatrics. The US is well known for its excellence in emergency medicine residency training programs. This has led to some controversy about specialty certification. There are three ways to become board-certified in emergency medicine:


The American Board of Emergency Medicine (ABEM) is for those with either Doctor of Medicine (MD) or Doctor of Osteopathic Medicine (DO) degrees. The ABEM is under the authority of the American Board of Medical Specialties.


The American Osteopathic Board of Emergency Medicine (AOBEM) certifies only emergency physicians with a DO degree. It is under the authority of the American Osteopathic Association Bureau of Osteopathic Specialists.


The Board of Certification in Emergency Medicine (BCEM) grants board certification in emergency medicine to physicians who have not completed an emergency medicine residency, but have completed a residency in other fields (internists, family practitioners, pediatricians, general surgeons, and anesthesiologists).


A number of ABMS fellowships are available for Emergency Medicine graduates including pre-hospital medicine (emergency medical services), critical care, hospice and palliative care, research, undersea and hyperbaric medicine, sports medicine, pain medicine, ultrasound, pediatric Emergency Medicine, disaster medicine, wilderness medicine, toxicology, and critical care medicine. In recent years, workforce data has led to a recognition of the need for additional training for primary care 7) ___ who provide emergency care. This has led to a number of supplemental training programs in first hour emergency care, and a few fellowships for family physicians in emergency medicine.


There are a variety of international models for emergency medicine training. Among those with well-developed training programs there are two different models: a “specialist“ model or “a multidisciplinary model“. Additionally, in some countries the emergency medicine specialist rides in the ambulance. For example, in France and Germany the physician, often an 8) ___, rides in the ambulance and provides stabilizing care at the scene. The patient is then triaged to the appropriate department of a hospital, so emergency care is much more multidisciplinary than in the Anglo-American model. In countries such as the US, the United Kingdom, Canada and Australia, ambulances transport patients to emergency departments and there is more dependence on paramedics and EMTs for on-scene care. Emergency physicians are therefore more “specialists“, since all patients are taken to the emergency department. Most developing countries follow the Anglo-American model: 3 or 4 year, independent residency training programs in emergency medicine are the gold standard. Some countries develop training programs based on a primary care foundation with additional emergency medicine training. In developing countries, there is an awareness that Western models may not be applicable and may not be the best use of limited health care resources. For example, specialty training and pre-hospital care like that in developed countries is too expensive and impractical for use in many developing countries with limited health care resources. International emergency medicine provides an important global perspective and hope for improvement in these areas.


The first Army Emergency Medicine Physician Assistant Residency doctoral class – four United States Army Captains (two females and two males) – graduated on December 17, 2007. Their average age was 39, and the average time from graduating from the Interservice Physician Assistant Program to graduation with their DSc was 7 years. The first graduates were assigned to Army emergency departments throughout the United States, deployed to Iraq, or placed in positions to teach other PAs, with the potential for further academic research. The doctor of science in PA studies in emergency medicine program is different from other training programs because of the combination of didactic learning, clinical rotations, and clinical research it contains. This program only matriculates experienced Army PAs and provides 18 months of specialty training in emergency medicine. The research component is significant and includes original scholarly work. Graduates are tactically and technically proficient in emergency medicine and trauma and have the ability to conduct medical research in a hospital setting or in a war zone. The doctoral degree that is awarded recognizes the unique set of knowledge that these PAs have learned and that sets them apart because of the complexity of their skill set. The proficiency level has been increased to ensure core competency to save lives on the battlefield or wherever trauma occurred. The military EM PA requires a skill set that exceeds that of a civilian emergency medical provider. For example, the San Bernardino shootings required training similar to emergency medicine used in urban 9) ___, like Iraq.


Since the inception of the postgraduate Army Emergency Medicine PA specialty training program in 1991, the amount of core emergency medicine knowledge, and the skill sets required to practice it, has increased dramatically. The competency requirement for an Army emergency medicine physician assistant to practice effectively and safely alongside residency trained and board-certified emergency medicine physicians was seen as both challenging and a necessity. It should come as no surprise that at NASA, the medical specialty most represented in the cadre of astronauts and flight surgeons is 10) ___ medicine. Currently at NASA, Drs. Tom Marshburn, Kjell Lindgren and Serena Aunon are all training in earnest for the International Space Station missions, and all are emergency physicians. There are nine flight surgeons who support the space program and are boarded emergency physicians. In addition to being EPs, all have additional training in aerospace medicine, human factors engineering, or hyperbarics. Some were trained via a second residency in aerospace medicine, while others trained via the military’s aerospace medicine training courses. Sources: nih.gov; cdc.gov; Washington Post; Wikipedia


ANSWERS: 1) cure; 2) health; 3) gun; 4) public; 5) violence; 6) urban; 7) physicians; 8) anesthesiologist; 9) warfare; 10) emergency


The Hybrid Physician, Dr. Michael Neeki, First Responder


Dr. Michael Neeki


Lines of heavily armed officers held their weapons at a tense ready. Wounded people were brought to a triage center. Some were on stretchers. Some were rushed to the hospital. Elsewhere in San Bernardino, California, another shooting scene erupted. Officers following a tip had gone looking for male shooter Farook at his residence in nearby Redlands. The gunman and his partner, female shooter, Malik, drove by. Police pursued them as the couple sped back to San Bernardino. As Malik drove, Farook fired out the window at police. The gunbattle ended with police riddling the SUV and the shooters with bullets.  But not before they had killed 14 people and wounded many more.


Dr. Michael Neeki is a board certified emergency medicine doctor in Colton, California. He received his medical degree from Ohio University College of Osteopathic Medicine and has been in practice for 13 years. Before his local SWAT team arrived on the scene of the San Bernardino shooting massacre, Dr. Neeki was already there, arriving just minutes after the shooting began, to join the other agencies on the scene. “The call came in on the radio: There’s an active shooter scenario in San Bernardino,“ said Neeki, an emergency room doctor at Arrowhead Regional Medical Center’s trauma center in Rialto, California. “I just hop in the car with my tactical equipment and go to the scene. Often I don’t have time to notify anybody, I just go.“ Pulling up in front of the Inland Regional Center, Neeki immediately began suiting up in his military boots, helmet and Kevlar vest, and checked his assault rifle, eerily similar to the one being used by the shooters. Without waiting for the rest of his SWAT team, he grabbed his medical pack and headed into the unknown.




San Bernardino shooting: Inside the ER 


“At the time that you go in it is still an active situation, so you don’t know what you will encounter,“ Neeki said. “It was one of the most organized scenes I had ever seen but you could feel that energy of worry. They [police on the scene] were worried if the shooters were [still] in the building and are they going to hurt more victims.“ Unfortunately, on this day 21 people were wounded, and 14 people died. “There were a lot of head injuries, chest injuries, and they didn’t have a good chance of surviving,“ Neeki said. “We are very sad. There is no good news when you find out that your fellow citizens have died for no good reason.“


Neeki is a new kind of doctor, a hybrid of healer and solider, an increasingly necessary type of medic trained to be able to defend as well as save lives. As assault rifles have replaced handguns as the weapon of choice in gang, street and mass shootings, the injuries and treatment needs have changed. “So, we are now going to this assault rifle injury-type pattern which rips and shreds apart organs in your body, tissues in the body, vessels as they’re going through,“ Neeki explained. “So you have to be ready to put in a tourniquet to avoid the bleeding, or quickly staple a wound in the field. Or use an Israeli bandage, which is a compression dressing. I also have a clotting factor you could put in a lesion.“ If this sounds like battlefield medicine, that’s because it is. Neeki said much of what doctors know today about treating assault rifle wounds has come from the wars in Iraq and Afghanistan. And because wounds like these shorten survival time for victims, it also means physicians need to be on the scene immediately, just like medics in foreign combat zones.


Putting medics into U.S. urban combat zones is a relatively recent phenomenon. The Bureau of Alcohol, Tobacco, Firearms and Explosives started putting paramedics in the field after the deadly shooting at the Branch Davidian compound in February 1993. Now in the second decade of the program, the bureau has about 70 special agents embedded with their special response teams. Another recent shift in law enforcement tactics has been to put officers in emergency medical training. But critics worry they may not develop enough skills to function as well as a fully trained medical practitioner. Thus the notion of training medical professionals to become soldiers.


Doctors now have to be ready to protect themselves on an urban battlefield.


“Shooters ready?“ yells the sergeant. “Yes sir!“ comes the chorus of voices from the men in the training room. “Then move!“ he barks. “Threat!“ The assault rifles blaze. “Threat!“ With each sound-off, the men advance, aiming another blast of ammo at the targets on the wall. Neeki is one of them, training the day after the Waco massacre, next to his SWAT team brothers. “I don’t want to get hurt,“ said Neeki. “If someone has the intention of coming in and just indiscriminately shooting and I’m the first there, I want to be able to defend myself and those civilians. A good guy should be able to defend himself and also help everybody else.“


Neeki, 51, is familiar with self-defense, having been born in Iran and drafted into the Iraqi war at age 18. But after 27 years in his adopted country, he didn’t expect his combat experience would be needed here. “Never in a million years, but now that I’m here this is one of my duties,“ said Neeki. “It’s a privilege to work here and it’s a privilege to be a part of this team, to serve the community out there. It’s the least I could do.


Link Found Between Congenital Heart Disease and Neurodevelopment in Children


Congenital heart disease, in which there are structural defects in the heart, is the most common type of birth defect in the United States, and one of the leading causes of infant death. Nearly 40,000 children are born with congenital heart disease each year, and experts estimate that approximately 1 to 2 million adults and 800,000 children in the U.S. currently live with the disease. Surgery is often performed early in life to repair heart defects, but once children reach school age, many exhibit various attention deficits, including attention deficit hyperactivity disorder, and other neurobehavioral problems.


A study, published online in the journal Science (4 December 2015), has identified the role of a set of gene mutations in the development of congenital heart disease as well as a link between them and some neurodevelopmental abnormalities in children. These abnormalities include cognitive, motor, social, and language impairments. For the study, investigators from the Bench to Bassinet Program’s Pediatric Cardiac Genomics Consortium used a technique called exome sequencing to genetically evaluate 1,220 family trios composed of a child with congenital heart disease and the mother and father. Through this technique, which examines only the protein-coding regions of DNA, it was found that children with moderate-to-severe congenital heart disease had a substantial number of “de novo“ gene mutations. De novo mutations occur within egg, sperm, and fertilized cells, but are not part of the genetic makeup of the mother or father. According to the authors, this finding was especially high in patients who had congenital heart disease and another structural birth defect and/or a neurodevelopmental abnormality. When the consortium examined the specific genes involved, many of them were highly expressed in both the developing heart and brain, suggesting that a single mutation can contribute to both congenital heart disease and neurodevelopmental abnormalities. The authors added that the findings have implications for basic research and clinical medicine and that through further analyses of these mutated genes, new pathways will be uncovered that are critical for the development of the heart, brain, and other organs. The authors added that this information will also contribute basic insights into the causes of many human congenital malformations. Going forward, if the relationship between the de novo mutations and neurodevelopmental abnormalities in children continues to hold, clinical genetic tests could be created for newborns with moderate-to- severe congenital heart abnormalities and that patients found to carry the gene mutations could then be targeted for greater surveillance and early interventions that might address and limit developmental delays and improve their outcomes.


Neurons’ Broken Machinery Piles Up in ALS


More than 12,000 Americans have Amyotrophic Lateral Sclerosis (ALS), also known as Lou Gehrig’s disease, and roughly 5-10% of them inherited a genetic mutation from a parent. These cases of familial ALS are often caused by mutations in the gene that codes for SOD1, an important enzyme located in the neuron’s mitochondria, the cell’s energy-producing structures. This mutation causes the death of motor neurons that control the patient’s muscles, resulting in progressive paralysis.


A healthy motor neuron needs to transport its damaged components from the nerve-muscle connection all the way back to the cell body in the spinal cord. If it cannot, the defective components pile up and the cell becomes sick and dies. According to an article published in the journal Neuron (15 July 2015), investigators at the National Institutes of Health’s National Institute of Neurological Disorders and Stroke (NINDS) have described how a mutation in the gene for superoxide dismutase 1 (SOD1), which causes ALS, leads cells to accumulate damaged materials. The study suggests a potential target for treating this familial form of ALS.


Since about 90% of the energy in the brain is generated by mitochondria, if the mitochondria aren’t healthy, they produce energy less efficiently, which can also release harmful chemicals called reactive oxygen species that cause cell death. As a consequence, mitochondrial damage can cause neurodegeneration. In healthy neurons, storage containers called late endosomes collect damaged mitochondria and various destructive chemicals. A motor protein called dynein then transports the endosomes to structures called lysosomes, which use the chemicals to break down the endosomes. The authors discovered that this crucial process is faulty in nerve cells with SOD1 mutations because mutant SOD1 interferes with a critical molecule called snapin, which attaches dynein to the endosomes via a part of the protein called the dynein intermediate chain (DIC).


The experiments were performed in mice engineered to have an ALS mutation in their SOD1 genes. Using light and electron microscopes, a buildup of damaged mitochondria was observed in the mutant animals’ motor nerve fibers. This accumulation was present even in early stages of the disease before overt symptoms emerged. In spinal cord motor neurons from the affected mice, it was observed that the altered SOD1 binds to the DIC and prevents snapin from doing so. Increasing the amount of snapin in these neurons during the early, asymptomatic stage of the disease corrected the problem and reduced the buildup of defective mitochondria. This helped the motor neurons to survive longer and slightly increased the animals’ lifespans. It also slowed down the loss of motor coordination, which worsens in animals with the SOD1 mutation as motor neurons die.


According to the authors, there is now a new mechanistic link that explains why mutant SOD1 impairs endosome transport, which can provide a cellular target for future development of early therapeutic interventions when motor neurons may still be salvageable.


FDA Approves Portrazza to Treat Advanced Squamous Non-Small Cell Lung Cancer (NSCLC)


Lung cancer is the leading cause of cancer death in the United States, with an estimated 221,200 new diagnoses and 158,040 deaths in 2015. The most common type of lung cancer, non-small cell lung cancer (NSCLC), is further divided into two main types named for the kinds of cells found in the cancer – squamous cell and non-squamous cell (which includes adenocarcinoma).


The FDA has approved Portrazza (necitumumab) in combination with two forms of chemotherapy to treat patients with advanced (metastatic) squamous NSCLC who have not previously received medication specifically for treating their advanced lung cancer. Portrazza is a monoclonal antibody that blocks activity of EGFR, a protein commonly found on squamous NSCLC tumors.


The safety and efficacy of Portrazza were evaluated in a multicenter, randomized, open-label clinical study of 1,093 participants with advanced squamous NSCLC who received the chemotherapies gemcitabine and cisplatin with or without Portrazza. Those taking Portrazza plus gemcitabine and cisplatin lived longer on average (11.5 months) compared to those only taking gemcitabine and cisplatin (9.9 months). Portrazza was not found to be an effective treatment in patients with non-squamous NSCLC.


The most common side effects of Portrazza are skin rash and magnesium deficiency (hypomagnesemia), which can cause muscular weakness, seizure, irregular heartbeats and can be fatal. Portrazza includes a boxed warning to alert health care providers of serious risks of treatment with Portrazza, including cardiac arrest and sudden death, as well as hypomagnesemia.


Portrazza is marketed by Eli Lilly and Company, based in Indianapolis, Indiana.


Salmon Roll-Ups


If you’ve had your fill of turkey and turkey left-overs, here’s a change that’s easy, quick to make and delicious. ©Joyce Hays, Target Health Inc.




1/2 cup Panko

1 Tablespoon extra-virgin olive oil

1 Tablespoon whole-grain mustard

1 Tablespoon chopped shallot

1 Tablespoon lemon juice

2 garlic cloves, juiced

1 teaspoon chopped rinsed capers

1/3 cup cilantro, chopped

1 1/4 pounds center-cut salmon fillet, skinned and cut lengthwise into 4 strips (Tell fish guy at Dean & Deluca, or Whole Foods, to skin the center cut salmon fillet, and to cut it into 4 equal strips) If you have the fishmonger do this for you, you save time.

4 teaspoons regular Kraft mayonnaise

Toothpicks to secure the rolled-up salmon (buy at Dean & Deluca or Whole Foods, where seafood is reliably fresh)




Simple ingredients – healthy and fresh. ©Joyce Hays, Target Health Inc.





1. Preheat oven to 400oF. Coat a 9-by-13-inch baking dish with 1-spray of cooking spray.


2. Mix breadcrumbs, oil, mustard, shallot, lemon juice, garlic juice, capers and cilantro in a small bowl until combined. Then with a spatula, scrape this crumb mixture out of the bowl and onto a large flat plate.




Mixing the ingredients for the filling, together. ©Joyce Hays, Target Health Inc.



Working with one at a time, spread 1 teaspoon mayonnaise on a salmon strip. Spread about 3 Tablespoons of the breadcrumb mixture over the mayonnaise. Starting at one end, roll the salmon up tightly, tucking in any loose filling as you go. Insert a toothpick though the end to keep the pinwheel from unrolling. Place in the prepared dish. Repeat with the remaining salmon strips. Distribute any extra crumbs, onto the tops of the salmon roll-ups, just before baking.




Here, I scraped the filling out of the bowl and put it on a large flat plate for easier rolling. This is the first of four strips of very fresh salmon fillet, spread with Kraft mayo and now being rolled, on both sides, in the crumb mixture.



Here is that first strip of salmon, rolled up and secured with a toothpick. ©Joyce Hays, Target Health Inc.



In this photo, all four strips of salmon fillet, have been rolled up, secured with toothpicks, and placed into an oiled baking dish. Any extra crumbs have been added to the top of the salmon roll-ups.



Bake the pinwheels until just cooked through, 15 to 20 minutes. Remove the toothpicks before serving.




Salmon roll-ups served with a couscous/ bean recipe. ©Joyce Hays, Target Health Inc.



We started this meal with a chilled white wine, green and red olives and a new recipe I’ve worked on for a while: red cabbage salad (will share it later) with goat cheese. Then the salmon roll-ups with a side dish of couscous & beans and broccoli sauteed in garlic and olive oil. This salmon was rare and literally melted in our mouths, it was so-o good. Jules gave it 5 stars (1 to 5). Because sweet seasonal citrus fruit is starting to show up in markets, we had Satsuma tangerines for dessert.




We had Cloudy Bay sauvignon blanc with the salmon roll-ups and sweet Satsuma tangerines for dessert. ©Joyce Hays, Target Health Inc.


We had a wonderful weekend, even though the play we saw on Saturday was awful, so won’t even mention the name. We did see Therese Raquin at Studio 54, with a superb cast, starring Keira Knightley. The critics gave this play rave reviews, however, because I had seen the movie version which is so much better than this play, I was negatively critical regarding much in the RoundAbout production, although I did think the acting was excellent. Studio 54 used to be a popular disco which was renovated in 1998 into a beautiful Broadway theater by one of the theater clubs, that we donate to, RoundAbout Theater Company.


THERESE RAQUIN, starring Keira Knightley


“White-knuckle suspense, spooky gothic ambience, a confident Broadway-debut performance from Keira Knightley.“ ?Elisabeth Vincentelli, New York Post


CRITICS’ PICK / FOUR STARS ?Adam Feldman, Time Out New York

“Leaves the audience gasping“ ?Marilyn Stasio, Variety

Roundabout Theatre Company presents a striking new adaptation of Therese Raquin starring Academy Award®, Golden Globe® and Olivier nominee Keira Knightley (Pride and Prejudice, Pirates of the Caribbean film series) in her Broadway debut. Evan Cabnet (Roundabout’s Dream of the Burning Boy) directs.


STUDIO 54: 254 West 54th Street, New York, NY, 10019 | Ticket Services: 212.719.1300



From Our Table to Yours!


Bon Appetit!