Is red palm oil as “miraculous” as Dr. Oz says?

Ask the Experts: Red Palm Oil

by Berkeley Wellness  |  July 26, 2013

Q: Is red palm oil as “miraculous” as Dr. Oz says?

A: Hardly. Like so many of Dr. Oz’s endorsements, this one is supported by amazingly little scientific evidence. He claims that red palm oil can fight heart disease, as well as battle belly fat and stop aging “inside and out.” It’s also supposed to prevent dementia, liver disease, bone loss and so on. Red palm oil “may very well be the most miraculous find of 2013,” he declared on his TV show.

Red palm oil, also available in capsules, is simply minimally processed palm oil, derived from the fruit of Southeast Asian and African palm trees. It has the same fatty acid profile as refined palm oil, meaning that it’s high in both saturated and monounsaturated fats. But unlike refined palm oil, red palm oil is rich in carotenoids, including alpha carotene, beta carotene and lycopene, which give it the orange-red color. (The refining of the oil removes these compounds.)

According to a paper published this year in the International Journal of Food Sciences and Nutrition, red palm oil also contains vitamin E and heart-healthy sterols, while other recent papers have noted its phenolic compounds and high antioxidant capacity. Some research has shown that consuming red palm oil increases blood carotenoid levels and improves antioxidant status.

But that’s true of many plant foods. Moreover, none of this proves that red palm oil has medical benefits and will, for example, reduce the risk of heart disease. In fact, a 2003 study in Biomedical and Environmental Sciences found no changes in blood cholesterol, for good or bad, in Chinese men who consumed the oil for six weeks. Overall, there are too few human studies on the effects of palm oil (red or refined) to know if it is detrimental, neutral or beneficial to the heart (or anything else).

There is no need to supplement your diet with red palm oil. There are better ways to get carotenoids (colorful fruits and vegetables) and vitamin E (whole grains, seeds and nuts). Plus, there is growing concern that palm oil production is leading to deforestation and destruction of orangutan habitats in Malaysia and Indonesia. You’d be wise to be skeptical about all of Dr. Oz’s so-called miracles.

 

http://www.berkeleywellness.com/healthy-eating/diet-weight-loss/article/ask-experts-red-palm-oil

First successful laboratory model for studying hepatitis C

Mount Sinai researchers develop first successful laboratory model for studying hepatitis C

System represents major advance in studying virus

By differentiating monkey stem cells into liver cells and inducing successful infection, researchers from the Icahn School of Medicine at Mount Sinai have shown for the first time that the hepatitis C virus (HCV) can replicate in monkeys, according to research published in the journal Gastroenterology. The new findings may lead to the first new animal model and provide new avenues for developing treatments and vaccines for this disease, which impacts more than three million people in the United States.

Scientists have tried for decades to develop animal models to study HCV, but the virus was incapable of infecting any species except for humans and chimpanzees. With a recent National Institutes of Health-imposed moratorium restricting chimpanzee research, the Mount Sinai research team turned to a close relative of chimpanzees and humans—macaques. Led by Matthew Evans, PhD, and Valerie Gouon-Evans, PhD, of Mount Sinai, the research team sought to find out why previous attempts to infect macaques with HCV failed.

Dr. Gouon-Evans, who is Assistant Professor of in the Department of Developmental and Regenerative Biology at Mount Sinai, worked with a team at the Fred Hutchison Cancer Research Center in Seattle to differentiate macaque stem cells into liver cells. Dr. Evans, who is an Assistant Professor in the Department of Microbiology, and his team then attempted to infect these cells with HCV in a petri dish. They found that these differentiated cells were able to support HCV infection and replication, although not as effectively as in human liver cells.

"Now that we know that HCV infection in macaque cells is possible, we wanted to find out why it only worked in liver cells that were derived from stem cells," said Dr. Gouon-Evans. "By identifying where in the viral life cycle the infection is dysfunctional, we can develop an effective animal model of HCV."

Dr. Evans and his team found that HCV was less efficient at entering macaque cells to initiate infection compared to human cells because changes in the macaque form of a certain cell surface receptor rendered it less functional than the human version. This cell entry block could be overcome by expressing the human version of this receptor in macaque cells. Furthermore, HCV infection of normal macaque cells was greatly enhanced by changes to the virus that loosened its requirements for that receptor.

"Our discovery shows that by manipulating either host or viral genetics we can efficiently infect macaque cells," said Dr. Evans. "These findings may open doors for the field of HCV research, lead to new animal models, and hopefully vaccines and therapies."

Next, Dr. Evans plans to take these experiments out of petri dishes by attempting to infect macaques in vivo with the mutant HCV that can use the receptors this animal naturally expresses. If successful, this work would provide a new, much-needed animal model for HCV studies and vaccine development.

###

This work was supported by the Pew Charitable Trust.

The Mount Sinai Hospital / Mount Sinai School of Medicine

Association of Visceral Obesity with High Viral Load and Histological Findings in Elderly Patients with Genotype 1 Chronic Hepatitis C

Internal Medicine
Vol. 52 (2013) No. 15 p. 1665-1673

Association of Visceral Obesity with High Viral Load and Histological Findings in Elderly Patients with Genotype 1 Chronic Hepatitis C

Hironori Tsuzura1), Takuya Genda1), Shunsuke Sato1), Katsuharu Hirano1), Yoshio Kanemitsu1), Yutaka Narita1), Tetsu Kikuchi1), Katsuyori Iijima1), Ryo Wada2), Takafumi Ichida1)
1) Department of Gastroenterology and Hepatology, Juntendo University Shizuoka Hospital, Japan 2) Department of Pathology, Juntendo University Shizuoka Hospital, Japan Released on J-STAGE 20130801

Keywords: chronic hepatitis C, visceral obesity, viral load, steatosis, fibrosis, adiponectin

 

...visceral obesity was found to be associated with high viral load, steatosis , and age-dependent fibrosis progression in patients with  genotype 1 chronic hepatitis C.....

Download Full Text PDF [222K]

Objective Genotype 1 chronic hepatitis C (G1CHC) is generally accompanied by metabolic disturbances related to visceral obesity, such as insulin resistance, steatosis, or dyslipidemia. Because these abnormalities negatively influence the clinical course of G1CHC, we sought to clarify the effect of visceral obesity on the pathophysiology of G1CHC.

Methods We evaluated 180G1CHC patients for the presence of visceral obesity on the basis of computed tomography findings. Multivariate analysis was performed to estimate the relationship between visceral obesity and demographic, viral, and biochemical characteristics of patients. The associations of visceral obesity with histological findings and serum adipokine levels were also analyzed.

Results Multiple logistic regression analysis revealed that visceral obesity was independently associated with metabolic syndrome, platelet count, high-density lipoprotein level, and serum viral load in elderly patients (≥65 years). Multiple linear regression analysis confirmed the association between visceral obesity and high viral load. However, visceral obesity was not correlated with viral load in non-elderly patients (<65 years). Histological data (160 patients) demonstrated the significant association between visceral obesity and steatosis. Furthermore, patients with visceral obesity showed increase in the severity of fibrosis with advancing age. However, age-associated fibrosis progression was not evident in patients without visceral obesity. The serum adiponectin level was significantly low in patients with visceral obesity, whereas those of leptin, tumor necrosis factor-α, and interleukin-6 were not affected significantly.

Conclusion Visceral obesity was associated with high viral load and histological damage in elderly patients with reduced adiponectin levels.

Visceral obesity
Type: Term
Definitions:
1. a form of obesity due to excessive deposition of fat in the abdominal viscera and omentum, rather than subcutaneously, associated with dyslipidemia (increased plasma triglyceride, low high-density lipoprotein cholesterol); perhaps due to accelerated lipolysis and mobilization of abdominal fatty acids by way of the portal vein; poses greater risk of diabetes mellitus, hypertension, metabolic syndrome, and cardiovascular disease than peripheral obesity does.

Full Text Available Here, Download PDF Here.

Healio Updates: Statins may protect cirrhotic patients from infection

Statins may protect cirrhotic patients from infection

August 2, 2013

Veterans with cirrhosis who used statins were at reduced risk for developing severe infection compared with nonusers, according to recent results.
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Rifaximin improved outcomes of lactulose therapy for hepatic encephalopathy

August 1, 2013

Patients with overt hepatic encephalopathy experienced better results and less mortality when treated with lactulose and rifaximin than those who received...
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Healio Minute, August 2, 2013

Cyclospora, mental illness, plantar fasciitis
Salad mix linked to cyclospora, economics worsen mental illness and painful condition targets foot soldiers.

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HCV decline associated with needle and syringe programs
Jenny Iversen and colleagues present the results of a 724-patient cohort study.
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Temperature increase after HCV treatment linked to response
Yaron Rotman, MD, MSc, discusses the results of his study of 60 treatment-naive patients.
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FDA Warns of Rare Acetaminophen Risk-linked to rare fatal skin reactions

Good Morning Folks,
Yesterday the FDA warned consumers that Tylenol and other medicines to treat colds, coughs, headaches, and sleep aids that contain the ingredient acetaminophen can cause a potentially deadly skin rash known as Stevens-Johnson Syndrome, see the warning below, and Medscape article here.

As a reminder to the HCV community in 2012 Vertex Pharmaceuticals revised the INCIVEK® (telaprevir) label to include a Boxed Warning stating that fatal and non-fatal serious skin reactions were reported in patients taking INCIVEK. According to a statement from Vertex, "Fatal cases of serious skin reactions have been reported in patients with progressive rash and systemic symptoms who continued to receive Incivek combination treatment after a serious skin reaction was identified."

Serious skin reactions include; drug rash with eosinophilia (a higher than normal level of white blood cells called eosinophils) and systemic symptoms (or DRESS) and Stevens-Johnson Syndrome (SJS). Read the FDA Drug Safety Communication/Data Summary here.

Consumer update;

FDA Warns of Rare Acetaminophen Risk

Acetaminophen, a fever and pain reliever that is one of the most widely used medicines in the U.S., can cause rare but serious skin reactions, warns the Food and Drug Administration (FDA).

On this page:
Ingredient Linked to Several Conditions
Evidence of Link

Although rare, possible reactions to acetaminophen include three serious skin diseases whose symptoms can include rash, blisters and, in the worst case, widespread damage to the surface of skin. If you are taking acetaminophen and develop a rash or other skin reaction, stop taking the product immediately and seek medical attention right away.

Used for decades by millions of people, acetaminophen is the generic name of a common active ingredient included in numerous prescription and non-prescription medicines. Tylenol is one brand name of the pain reliever sold over the counter, but acetaminophen is also available as a generic under various names. It is also used in combination with other medicines, including opioids for pain and medicines to treat colds, coughs, allergy, headaches and trouble sleeping.

"This new information is not intended to worry consumers or health care professionals, nor is it meant to encourage them to choose other medications," says Sharon Hertz, M.D., deputy director of FDA's Division of Anesthesia, Analgesia and Addiction. "However, it is extremely important that people recognize and react quickly to the initial symptoms of these rare but serious, side effects, which are potentially fatal."

Other drugs used to treat fever and pain, such as nonsteroidal anti-inflammatory drugs including ibuprofen and naproxen, already carry warnings about the risk of serious skin reactions. Advil and Motrin are among the common brand names that include ibuprofen as an active ingredient. Aleve and Midol Extended Relief are among the best-known brand names that include naproxen as an active ingredient.

FDA is requiring that a warning about these skin reactions be added to the labels of all prescription medicines containing acetaminophen. FDA will work with manufacturers to get the warnings added to the labels of over-the-counter (OTC) medicines containing acetaminophen.

On OTC medicines, the word "acetaminophen" appears on the front of the package and on the Drug Facts label's "active ingredients" section. On prescription medications, the label may spell out the ingredient or use a shortened version such as "APAP," "acet," "acetamin" or "acetaminoph."

Ingredient Linked to Several Conditions

Stevens-Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN) are the two most serious skin reactions linked in rare cases to acetaminophen. They usually require hospitalization and can cause death.

Problems usually begin with flu-like symptoms followed by rash, blistering and extensive damage to the surfaces of the skin. Recovery can take weeks or months, and possible complications include scarring, changes in skin pigmentation, blindness and damage to internal organs.

A third skin reaction, acute generalized exanthematous pustulosis (AGEP), usually resolves within two weeks of stopping the medication that caused the problem.

A serious skin reaction can occur at any time, even if you've taken acetaminophen previously without a problem. There is currently no way of predicting who might be at higher risk.

If you've ever had a skin reaction when taking acetaminophen, don't take the drug again and discuss alternate pain relievers/fever reducers with your health care professional.

Evidence of Link

Prior to deciding to add a warning about skin reactions to products containing acetaminophen, FDA reviewed medical literature and its own database, the FDA Adverse Event Reporting System (FAERS).

A search of FAERS uncovered 107 cases from 1969 to 2012, resulting in 67 hospitalizations and 12 deaths. Most cases involved single-ingredient acetaminophen products; the cases were categorized as either probable or possible cases associated with acetaminophen.

A small number of cases, just over two dozen, are documented in medical literature, with cases involving people of various ages.

FDA has examined—and continues to examine—acetaminophen for safety issues, just as it does with all approved drugs. The warning comes two years after FDA took new steps to reduce the risk of liver injury from acetaminophen. In that case, FDA asked all makers of prescription products to limit acetaminophen to 325 milligrams per tablet or capsule. FDA also required all prescription acetaminophen products to include a Boxed Warning—FDA's strongest warning, used for calling attention to serious risks.

The agency continues to consider the benefits of this medication to outweigh the risks.

"FDA's actions should be viewed within the context of the millions who, over generations, have benefited from acetaminophen," says Hertz. "Nonetheless, given the severity of the risk, it is important for patients and health care providers to be aware of it."

This article appears on FDA's Consumer Updates page4, which features the latest on all FDA-regulated products.
August 1, 2013

Related Aug 2
Acetaminophen Linked to Fatal Skin Reactions
“This new information is not intended to worry consumers or health care professionals, nor is it meant to encourage them to choose other medications. However, it is extremely important that people recognize and react quickly to the initial symptoms of these rare but serious, side effects, which are potentially fatal,” said Dr. Sharon Hertz, the deputy director of FDA’s Division of Anesthesia, Analgesia and Addiction in a statement.

For More Information 

Acetaminophen Information5

FDA limits acetaminophen in prescription combination products; requires liver toxicity warnings6

Acetaminophen Awareness Coalition’s Know Your Dose Campaign78

FDA Drug Safety Communication: FDA warns of rare but serious skin reactions with the pain reliever/fever reducer acetaminophen9

Questions and Answers: FDA warns of rare but serious skin reactions with the pain reliever/fever reducer acetaminophen10

The Safety of Chemotherapy for Breast Cancer Patients with Hepatitis C Virus Infection

J Cancer. 2013 Jul 24;4(6):519-23. doi: 10.7150/jca.6231. Print 2013.

 

The safety of chemotherapy for breast cancer patients with hepatitis C virus infection.

 

Miura Y, Theriault RL, Naito Y, Suyama K, Shimomura A, Iwatani T, Miura D, Kawabata H, Kumada H, Takano T.

 

Source

1. Department of Medical Oncology, Toranomon Hospital, Tokyo, Japan.

Abstract

Background: Hepatitis C virus (HCV) infection is one of the major causes of chronic liver disease, and more than 880,000 people are estimated to be infected with HCV in Japan. Little information is available on the outcomes of HCV during chemotherapy for solid tumors, and the impact of HCV infection on toxicity of chemotherapy is unknown.

Materials and methods: We performed a retrospective survey of 1,110 patients diagnosed with breast cancer between January 2006 and March 2011 at our institution. All patients had been screened for hepatitis C serology at diagnosis of breast cancer. We retrospectively investigated the change in HCV load and the toxicities of chemotherapy, based on review of their medical records.

Results: 23 patients were identified as having a positive test for anti-HCV antibodies. Ten of these patients received chemotherapy. Their median age was 66 years. No patient had decompensated liver disease at baseline. Eight patients received cytotoxic agents with or without trastuzumab, and two patients received trastuzumab alone. Four of eight patients who received cytotoxic chemotherapy developed febrile neutropenia and one developed transaminases elevation. Serum HCV-ribonucleic acid (RNA) level before and after chemotherapy was evaluated in six patients. Median serum HCV-RNA level at baseline and after chemotherapy was 6.5 and 6.7 logIU/ml, respectively.

Conclusion: Chemotherapy for breast cancer patients with HCV infection is feasible, and viral load doesn't change during the chemotherapy.

Keywords: HCV, HCV-RNA, febrile neutropenia, Child-Pugh criteria, liver cirrhosis, chemotherapy.

Introduction Only

Full Article Available Here

Hepatitis C virus (HCV) infection is one of the major causes of chronic liver disease, and more than 880,000 people are estimated to be infected with HCV in Japan (1). The estimated number of HCV carriers increases with age, therefore, carriers aged from 40 to 69 years account for more than 80% of cases (1). Breast cancer is the most common cancer among Japanese women (2). Furthermore, the age-adjusted breast cancer incidence rate has been increasing since 1975, and the incidence rate of breast cancer is highest in the age group of 40-49 years in Japan (2).

Little information is available on the status of HCV during chemotherapy for solid tumors and the influence of HCV infection on toxicity of chemotherapy is also unknown. Although there are guidelines for management of patients with Hepatitis B virus during chemotherapy, there are no data to support the use of chemotherapy to treat HCV-positive patients with solid tumors (3, 4). Some reports have noted the reactivation of HCV in patients with lymphoma who have received rituximab and combination chemotherapy (5, 6). However, there are substantial differences in immunosuppressive mechanisms between rituximab-based chemotherapy for hematologic malignancies and conventional chemotherapy for solid tumor, because rituximab, an anti-CD20 antigen, mainly inhibits B-cell function. Therefore, it may not be appropriate to use the same management during chemotherapy for HCV carrier patients with solid tumors.

The purpose of this study was to evaluate the safety profile and the change in HCV viral load during chemotherapy for HCV-carrier patients with breast cancer

Miura Y, Theriault RL, Naito Y, Suyama K, Shimomura A, Iwatani T, Miura D, Kawabata H, Kumada H, Takano T. The Safety of Chemotherapy for Breast Cancer Patients with Hepatitis C Virus Infection. J Cancer 2013; 4(6):519-523. doi:10.7150/jca.6231.

Full Text Article Available from http://www.jcancer.org/v04p0519.htm

Received 2013-3-11
Accepted 2013-5-23
Published 2013-7-24

 

TheraSphere® Recommended by the National Institute for Health and Care Excellence (NICE) for the Treatment of Primary and Secondary Liver Cancer

TheraSphere® Recommended by the National Institute for Health and Care Excellence (NICE) for the Treatment of Primary and Secondary Liver Cancer 

LONDON, July 30, 2013 /PRNewswire/ --

BTG plc (LSE: BTG), the specialist healthcare company, today announces that the National Institute for Health and Care Excellence (NICE) has issued guidance recommending the use of Selective Internal Radiation Therapy (SIRT)(1), which includes TheraSphere®, for patients with liver cancer across the NHS. The guidance supports the use of this innovative treatment for patients with primary hepatocellular carcinoma as well as for those with intrahepatic cholangiocarcinoma(2) and follows the previous recommendation for its use in patients with colorectal cancer liver metastases(3).

The NHS in England is currently preparing guidelines on how SIRT should be used as a treatment option for patients with liver cancer, including those with colorectal cancer liver metastases and cholangiocarcinoma, after recently issuing an interim policy on how this therapy should be funded(4). It is anticipated that this latest NICE guidance will result in a similar evaluation for patients with primary liver cancer. "NICE's guidance further highlights the growing acceptance and understanding of radioembolization in the treatment of liver cancer," said Peter Pattison, General Manager TheraSphere®. "With over 4,000 new liver cancer cases diagnosed annually in the UK(5), this new guidance will potentially provide patients with access to a broader range of treatment options."

Pattison added: "With many countries looking to the UK for direction on their own reimbursement decisions and processes, this guidance should lead to greater awareness amongst physicians and patients and may also prompt similar guidance in other geographies. In addition to increasing liver cancer treatment options for physicians and patients in the UK, this guidance will assist BTG as we continue to explore other reimbursement opportunities in various regions across the world."

About TheraSphere®

TheraSphere is a form of radioembolization therapy that consists of millions of small glass beads (20 to 30 micrometers in diameter) containing radioactive yttrium-90 (Y-90). The product is injected by physicians into the artery of the patient's liver through a catheter, which allows for a high dose of radiation to be delivered directly to the tumour via blood flow thereby limiting the damage to surrounding healthy tissue and side effects to the patients.

TheraSphere is used in the European Union and in Canada for the treatment of hepatic neoplasia in patients who have appropriately positioned arterial catheters. Since its introduction in Europe, more than 1,000 patients have been treated with TheraSphere.

Common side effects include mild to moderate fatigue, pain and nausea for about a week. Physicians describe these symptoms as similar to those of the flu. Some patients experience some loss of appetite and temporary changes in several blood tests. For details on rare or more severe side effects, please refer to the TheraSphere package insert/instructions for use at http://www.nordion.com/therasphere.
National Institute of Care Excellence. IPG460 Selective internal radiation therapy for primary hepatocellular carcinoma: guidance. London. 24 July 2013.

National Institute of Care Excellence. IPG459. Selective internal radiation therapy for primary cholangiocarcinoma. London. 24 July 2013.

National Institute of Care Excellence. IPG401. Selective internal radiation therapy for non-resectable colorectal metastases of the liver: guidance. London. July 2012 (updates May 2013).
NHS England. Interim Clinical Commissioning Policy Statement: Selective Internal Radiotherapy (SIRT). June 2013.
http://www.cancerresearchuk.org/cancer-info/cancerstats/types/liver/

About BTG

BTG is an international specialist healthcare company that is developing and commercialising products targeting critical care, cancer and varicose veins. The company has diversified revenues from sales of its own marketed products and from royalties on partnered products, and is seeking to acquire new programmes and products to develop and market to specialist physicians. For further information about BTG please visit our website at http://www.btgplc.com.

http://www.prnewswire.co.uk/news-releases/therasphere-recommended-by-the-national-institute-for-health-and-care-excellence-nice-for-the-treatment-of-primary-and-secondary-liver-cancer-217517801.html

HCC-4 risk score’ IDs hepatitis C patients likely to develop HCC

 
HCC-4 risk score’ IDs hepatitis C patients likely to develop HCC

By: MARY ANN MOON, Family Practice News Digital Network

A risk score derived from four simple test results readily obtained during routine care may help identify the patients with chronic hepatitis C who are most at risk for developing hepatocellular carcinoma, according to a retrospective study published online July 12 in the European Journal of Internal Medicine.

The score could enable physicians to target only the highest-risk patients for annual surveillance for malignant hepatic nodules, which is crucial because current screening methods are too invasive, too expensive, and too low-yield to be applied broadly across all risk groups.

The new risk score also may help identify patients with chronic hepatitis C who are at lowest risk for developing HCC, who can then be reassured that they can safely forgo invasive and expensive surveillance, reported Dr. Juan Carlos Gavilan and his associates at University Hospital Virgin de la Victoria, Malaga (Spain).

A new risk score may help identify the patients with chronic hepatitis C who are most at risk for developing hepatocellular carcinoma.

The investigators reviewed data from a 17-year longitudinal cohort study involving 829 patients with chronic hepatitis C. These subjects were assessed every 6 months for the development of HCC using serum alpha-fetoprotein (AFP) levels and ultrasound imaging to detect new focal hepatic lesions.

A total of 58 subjects (7%) developed HCC during follow-up.

An initial univariate analysis identified numerous clinical and epidemiologic factors associated with elevated risk for HCC. The researchers constructed a formula for predicting risk using the four independent factors that were most predictive of HCC in this cohort: patient age, platelet count, gamma-globulin level, and AFP level at baseline.

By dividing the study population into tertiles, Dr. Gavilan and his colleagues established cutoff ranges for low, medium, and high risk. They then classified each study participant as belonging to one of these three categories, to see how well this risk score correlated with the actual rates of HCC.

The annual incidence of HCC was 0.06% in the group designated as low risk, 0.5% in the group designated as medium risk, and 2.6% in the group designated as high risk, indicating that this "HCC-4 risk score" was indeed highly predictive, Dr. Gavilan and his associates said (Eur. J. Intern. Med. 2013 July 12 [doi: 10.1016/j.ejim.2013.06.010]).

In fact, the score was more accurate at predicting HCC than was the commonly used fibrosis index, they noted.

According to recently published recommendations, surveillance is only justified in populations with an HCC incidence of 1.5% or more per year. Thus, patients found to be high risk using this HCC-4 risk score would be appropriate for such surveillance, while those at medium or low risk would not be.

"These results must be confirmed in other studies," the investigators said.

There was no external funding source for this study, and no financial conflicts of interest were reported.

Photo-Courtesy US. Dept of Veterans Affairs
Source-Family Practice News Digital Network