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In This Issue:
Alan Franciscus, Editor-in-Chief
Lucinda Porter, RN
Diet and Hepatitis C
HCV & Lipids
Alan Franciscus, Editor-in-Chief
Depression and HCV Therapy
Alan Franciscus, Editor-in-Chief
HCV Advocate Eblast
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—Alan Franciscus, Editor-in-Chief
The liver processes almost everything we take into the body. One of the most important functions of the liver is to convert medications into safe levels to treat diseases. This is accomplished by certain enzymes within the liver—different drugs are processed by different enzymes. This can be a problem when people take too much of one medication or an unsafe combination of medications or herbs that are processed by the same enzyme or chemical pathway within the liver. The result can be that too much medicine can be absorbed, which could lead to a fatal overdose. But this over-absorption can be used to an advantage when you want to ‘boost’ the level of another specific drug without increasing the dose of the medicine that is being used to treat the condition. This is important because higher doses of the drug to treat the condition may produce severe side effects. Another benefit of using a boosting agent is that you can increase the levels in the blood or plasma concentrations of the second drug without a corresponding increase in the side effects and at the same time decrease chances for the development of drug resistance.
An HIV protease inhibitor, ritonavir, is just such a drug. Ritonavir is metabolized in the liver by an enzyme called P450 3A (CYP3A). It was discovered that, when a second HIV protease inhibitor medication was combined with ritonavir, the plasma concentrations of the second drug were increased. The boosting properties of ritonavir were found to greatly enhance overall successful treatment outcomes, but it also helped to reduce some of the side effects that would develop if higher doses of the second drug were given. Also, because there were higher plasma concentrations of the second drug in the bloodstream, the chances for developing drug resistance were lower.
But ritonavir boosting is not without problems or potential side effects. This could prove more of a problem in people with liver disease such as hepatitis C. For instance, ritonavir has been shown to increase the incidence of certain metabolic disorders such as fat and carbohydrate (sugar) metabolism and increase cholesterol levels. Hepatitis C is already known to increase the chances of metabolic disorders so adding an agent that would further increase the chances of developing metabolic disorders could be a problem. Another potential problem is that the P450 3A (CYP3A) enzyme metabolizes other drugs, and may inadvertently be triggered to boost these as well, which could lead to higher levels that could be unsafe. Careful and frequent monitoring of all medications would be needed in people with hepatitis C who use a boosting agent.
The use of ritonavir is now being studied in combination with HCV protease inhibitors. Roche’s development program of ITMN191, Pegasys and ribavirin, and Schering’s (now Merck) SCH900518 are both using ritonavir as a boosting agent in some clinical trials. The pharmaceutical company that markets ritonavir, Abbott, also has a very active early stage HCV drug pipeline that could eventually be used with ritonavir.
At the Sixteenth Conference on Retroviruses and Opportunistic Infection recently held in Montreal, Canada there were studies presented on two new boosting agents that are being developed by Gilead Sciences and Sequoia Pharmaceuticals that may work as well as ritonavir, but could (hopefully) produce fewer side effects.
Gilead has developed a boosting agent, GS 9350, that does not have antiviral properties against HIV. In test tube and small human studies it was found to have boosting properties similar to ritonavir, but with less of the effect on fat and carbohydrate metabolism that has been found with ritonavir. In the human studies the drug was found to be generally well-tolerated.
Sequoia’s boosting agent, SPI-452, has been found to have no antiviral properties against HIV. In human testing of HIV negative patients it was found to increase the levels of a second drug (HIV medication) with dose proportional effects, but without the type of metabolic side effects typically seen with ritonavir. The drug was also generally well-tolerated.
Both boosting drugs are in early development so it remains to be seen if they are safe and effective. Down the road after the safety and efficacy issues have been resolved, the next logical step would be to combine the new boosters with the newly developed HCV inhibitors. To this end, Sequoia announced that another boosting agent, SPI-425, is in development as a possible boosting drug for HCV medications.
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Lucinda K. Porter, RN
Hepatitis C (HCV) doesn’t just affect the infected. Although not passed casually, HCV touches the lives of those around us. This is especially true for patients with advanced disease who are pre or post-liver transplant. Those who live with HCV patients during their treatment may find themselves thrust into caregiver roles. November is designated as National Family Caregivers Month. This month, let us honor and support those who love us, live with us, care for us, or want to throttle us.
A caregiver is anyone who provides assistance to those who need it. Caregivers are often family members (83%), but friends and others in the community may provide assistance. This service is usually unpaid and often round-the-clock. Caregivers may lose income from work or incur out-of-pocket expenses as a direct result of giving assistance.
The emotional side of care giving often includes feeling powerless or hopeless. It means giving up dreams of the future if caring for someone who is dying, demented, or chronically ill. Ask a loved one if they would rather have HCV or care for someone who has it, and you may find that they would rather be the patient than the caregiver.
Care giving is stressful and caregivers’ health may diminish as a result. Many of us have heard stories of caregivers who have died during the course of supporting an ill partner. Care giving is hard work. It may mean getting up in the middle of the night, engaging in physically demanding tasks, possibly setting aside one’s own needs and wants.
Although HCV can lead to death, most of us will not die from it. The majority of those with HCV don’t know they have it. Most are functioning well enough to not need care giving. However, this may change soon because of three factors.
First, we are headed towards a rise in the number of cases of HCV-related cirrhosis. This is because those who contracted HCV during its peak transmission period in the 1980’s have now had it for 30 or more years. Second, as Baby Boomers age, we are at a natural risk for other medical problems. Third, in the course of managing other medical problems, some of those undiagnosed patients will be identified and may opt for HCV treatment. Caregivers may be called on to help in these circumstances.
The line between patient and caregiver can blur. I witnessed this in the patients I worked with who were undergoing HCV-treatment. Many took care of aging or dying parents. One cared for his chronically ill wife. Another cared for her husband who died unexpectedly during the fifth month of her HCV treatment.
Care giving is demanding, regardless the circumstances. Most who are thrust into the role don’t give it a thought. It’s like learning to swim after being thrown into deep water. However, just as there are other ways to learn how to swim, there are care giving tools to help with the work.
Many caregivers don’t feel they have time to devote to mastering care giving. After taking care of their loved one, they barely have time to take care of themselves. This leads to the most important point in the art of care giving—in order to have time for yourself, you must take the time. If you don’t, you risk your own health, resulting in needing someone to care for you and the person you are caring for.
The expression caregiver burnout describes a person who is overwhelmed with the responsibility and may be headed towards illness. The symptoms of burnout are much like those for stress and depression: irritability, exhaustion, feeling down, changes in appetite or sleep patterns, and problems with memory or concentration.
The following are suggestions on how to avoid or relieve caregiver burnout:
- Join a support group.
- Put yourself first. If you don’t take care of your health, you cannot be an effective caregiver.
- State your needs. Compose a list of everything you need, such as more sleep, someone to talk to, time off, help with meals, help with errands, etc.
- Identify a support network. List everyone who may be willing to help. Include everyone who has offered to help or those who might be good listeners.
- Ask for help and delegate responsibilities. Ask someone to pick up groceries for you. Ask your kids to mow the lawn or help with household chores.
- Take short-cuts. The house doesn’t have to be sparkling clean and meals don’t need to be complicated. You don’t have to change the car’s oil yourself and you can let it go for another few hundred miles.
- Minimize stress, especially during the holidays.
- Learn time management techniques.
- Screen for depression and seek help should you have it.
Practice stress management, meditation and other mind-quieting techniques. Excellent information is provided by the Benson-Henry Institute at University of Massachusetts. www.massgeneral.org/bhi/
As for putting your own health first, this is critical. When on an airplane, we are told to put our own oxygen masks on before helping others and this applies to care giving. Put at the top of your list:
- Eat sensibly.
- Be physically active.
- If sleep is a problem, get some help. You may need to sleep in a different room or have someone stay with your loved one so you can go somewhere to rest.
- Get regular medical care, including a flu shot or other immunizations.
- Take time every day to do something to recharge. Read a book, watch a sporting event, go for a walk, meditate, pray, play with the dog, do a Sudoku puzzle, or take a class.
Another issue is coping with feelings. You may fantasize that your loved one slips on a banana peel and dies. It’s normal to have these thoughts, so skip the guilt if these thoughts creep in. However, if you start leaving banana peels on the floor, then you are in trouble. Get some help.
If you are caring for someone who is undergoing HCV treatment, here are a few specific suggestions:
- Learn about HCV and its treatment. Understand that the medications may affect moods, sexual interest, and other behaviors.
- Side effects of HCV medications are not permanent, but it will take some time after the drugs are stopped before the patient returns to previous moods.
- Set limits on unacceptable behavior. If your loved one has anger management issues, you do not have to tolerate outbursts.
- Suicide, harmful threats, or aggressive or abusive behavior are not normal. If you or your loved one is in harm’s way, seek immediate help.
- If you have HCV-related concerns about your loved one, ask if you can go along to their medical appointments.
Taking care of someone is hard work, especially if that person is moody. Perhaps George Burns knew of someone on HCV treatment when he said, “Happiness is having a large, loving, caring, close-knit family in another city.”
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Diet and Hepatitis C
In the past, when less was known about hepatitis C and its treatment, strict dietary modification was considered an important aspect of disease management, especially for people with advanced liver fibrosis or cirrhosis.
Today, hepatology experts increasingly recognize the importance of the metabolic aspects of chronic hepatitis C, and pay more attention to managing obesity and blood sugar and fat abnormalities.
The Liver as Food Processor
The liver plays an important role in digestion and processing of food, including filtering out toxins, regulating sugar and fat metabolism, converting food into usable forms of energy, and storing nutrients for later use. Therefore, it is not surprising that what we eat can have major effects on the liver, and vice versa.
Blood sugar, or glucose, levels increase after eating. The liver converts some of this glucose into glycogen, which is stored for later use. Conversely, when energy is needed, the liver converts glycogen back into glucose, a process called gluconeogenesis.
Liver enzymes called aminotransferases (ALT and AST) process amino acids from digested food, which are then used to build compounds including fatty acids, cholesterol, hormones, neurotransmitters, and immune and clotting factors. When the body does not get enough sugar, the liver can convert fatty acids into ketones, which provide an alternative source of energy. In addition, the liver stores nutrients including vitamin A, vitamin D, and iron.
When Liver Function Goes Awry
As the liver becomes increasingly damaged by HCV infection, heavy alcohol use, or other causes, it loses it ability to carry out crucial metabolic functions. People with cirrhosis are less able to process proteins and eliminate toxic by-products such as ammonia. Elevated ammonia levels can lead to impaired brain function known as hepatic encephalopathy, which may progress to hepatic coma.
For this reason, cirrhotic patients have traditionally been advised to limit the amount of protein in the diet – a legacy of the days when there were few other therapies for encephalopathy. But clinical trials do not support this approach, and today other therapies are preferred (e.g., lactulose, neomycin).
In the July 2004 Journal of Hepatology, Juan Cordoba and colleagues from Barcelona reported results from a study of dietary protein in 30 cirrhotic patients hospitalized with episodic hepatic encephalopathy. Participants were randomly assigned to receive either a normal-protein (1.2 gm/kg/day) or a low-protein diet for 14 days; they were also treated with standard measures to reduce blood levels of ammonia.
Encephalopathy outcomes did not differ significantly between the two groups. The groups also exhibited similar levels of protein synthesis, but the low-protein group had greater protein breakdown. “Diets with a normal content of protein, which are metabolically more adequate, can be administered safely to cirrhotic patients with episodic hepatic encephalopathy,” the researchers concluded. “Restriction of the content of protein of the diet does not appear to have any beneficial effect for cirrhotic patients during an episode of encephalopathy.”
The milder cognitive impairment – or “brain fog” – commonly reported by people with hepatitis C who do not have advanced liver damage is not thought to be related to toxic metabolic by-products, and protein restriction is not recommended for this group.
Cirrhosis also interferes with the liver’s ability to synthesize blood proteins such as albumin, which helps regulate the body’s fluid balance. Reduced albumin levels, in conjunction with portal hypertension due to impaired blood flow through a heavily scarred liver, can lead to ascites, or build-up of fluid in the abdominal area. Sodium, or salt, worsens this condition, as well as edema or swelling in the feet and legs, so patients are often be advised to limit dietary sodium.
In addition, impaired bile synthesis and flow may result in reduced ability to digest fat and absorb certain vitamins, and altered metabolism and storage can lead to various nutrient deficiencies.
Fatty Liver and the Metabolic Syndrome
Steatosis, or fat accumulation in the liver, is increasingly recognized as a manifestation of the metabolic syndrome – a constellation of conditions including high blood pressure, insulin resistance, elevated blood lipids, systemic inflammation, and abdominal obesity that are associated with increased risk of cardiovascular disease.
A growing body of evidence indicates that insulin resistance (decreased ability of cells to respond to insulin, which they need to absorb and use glucose), diabetes, and obesity are associated with accelerated steatosis and fibrosis progression, as well as poorer response to interferon-based therapy.
Furthermore, a study presented at the European Association for the Study of the Liver (EASL) meeting this past April indicated that insulin resistance, high body mass index, and elevated cholesterol were the strongest predictors of liver-related mortality in people with hepatitis C.
The effect of HCV on blood lipids is less clear, but considerable research indicates that it appears to actually lower blood fat levels, which may mask cardiovascular disease risk.
In the October 2009 issue of Hepatology, K. Corey and colleagues found that people with HCV had significantly lower total and harmful low-density lipoprotein (LDL) cholesterol than uninfected control subjects. In a retrospective analysis, treated hepatitis C patients who achieved sustained virological response had larger increases in total and LDL cholesterol from baseline than patients without viral clearance. After treatment, one-third of patients who cleared HCV had elevated total cholesterol levels warranting lipid-lowering therapy.
“A significant portion of successfully treated patients experience LDL and cholesterol rebound to levels associated with increased coronary disease risk,” the researchers concluded. “We suggest that serum lipid levels should be assessed in follow-up among patients undergoing successful antiviral therapy, as clearance may reveal some patients with previously unappreciated coronary risk.”
a Healthy Diet?
A healthy diet for people with hepatitis C closely follows the type of diet recommended to the general population for optimal health and lowering cardiovascular risk. Such a diet is low in fat, sodium, and processed sugar, and rich in fruits, vegetables, and complex carbohydrates like those found in starches and whole grains. The new Food Guide Pyramid is a good basis for a healthy diet.
People with chronic illness are at greater risk for malnutrition, and it is important to consume an adequate amount of calories and protein for bodily maintenance and repair and to avoid wasting. As noted, research generally does not support severe protein restriction, although some clinicians still recommend low-protein diets for patients with hepatic encephalopathy. Although there is little controlled research on the topic, many experts favor protein from non-animal sources – or from chicken or fish instead of red meat – which contains less ammonia and is more easily processed by the liver.
Most people can get an adequate amount of nutrients by eating a well-balanced diet, but others may benefit from nutritional supplementation. However certain vitamins and minerals – including vitamin A, vitamin D, niacin, and iron – can be toxic to the liver at high doses, so consult a healthcare provider before taking supplements or starting unusual diets.
In addition to food, it is important to drink enough water or other liquids. A common recommendation is eight glasses of water per day, though this varies based on a person’s weight. The Institute of Medicine advises that average-sized men should drink about 13 cups and women should drink about nine cups of total fluids each day. Some experts recommend avoiding caffeine, which has a dehydrating effect, though some studies suggest coffee and tea are associated with reduced fibrosis and it is well-known that people with liver disease should avoid alcohol.
Overall, current dietary guidelines for people with hepatitis C are based on “common sense” and general recommendations for the population as a whole, but some research has looked specifically at the link between diet and liver disease.
In the July 2009 issue of Hepatology G. Ioannou and colleagues reported that in a study of more than 9,000 initially non-cirrhotic participants (not limited to those with HCV) followed for an average of 13 years, people who ate a diet high in protein were at higher risk for hospitalization or death due to cirrhosis or liver cancer, while those who reported a diet high in carbohydrates were at lower risk. Total fat consumption was not significantly linked to cirrhosis or liver cancer, but cholesterol consumption significantly increased the risk; blood cholesterol, however, was not a risk factor.
In another recent study, published in the September 2, 2009, advance online edition of Journal of Viral Hepatitis, E. Sathiaraj and colleagues found that many patients with acute viral hepatitis in India consumed significantly less calories and protein after becoming ill, which they attributed to perceptions and traditional nutritional practices. Furthermore, individuals who consumed a low-calorie diet required significantly longer hospitalization than those who ate a high-calorie diet (an average of six vs. eight days, respectively).
With regard to treatment, C. Loguercio and colleagues from Italy reported in the December 2008 American Journal of Gastroenterology findings from a study of more than 1,000 chronic hepatitis C patients (432 of them treated with interferon-based therapy) and more than 2,000 uninfected control subjects; about half were overweight. They found that consumption of carbohydrates, lipids, polyunsaturated fatty acids, and alcohol were independent risk factors for liver damage. In addition to heavier alcohol use, levels of unsaturated fatty acids, iron, zinc, vitamin A, and niacin differed significantly between treatment responders and non-responders; steatosis also predicted poorer response.
While dietary restrictions are no longer considered a mainstay of managing liver damage, the contribution of insulin resistance and obesity to liver disease progression and poor hepatitis C treatment response is increasingly recognized.
This has led to an increased emphasis on healthy diet – along with increased exercise, optimal weight, and possibly insulin-sensitizing medications like rosiglitazone (though studies to date have produced mixed results) – as part of a lifestyle modification program to reduce fibrosis progression, optimize treatment response, and improve overall health.
For further information on diet and hepatitis C:
- Cordoba, J. et al. Normal protein diet for episodic hepatic encephalopathy: results of a randomized study. Journal of Hepatitis 41(1): 38-43. July 2004.
- Corey, K. et al. Hepatitis C virus infection and its clearance alter circulating lipids: implications for long-term follow-up. Hepatology. 50(4): 1030-1037. October 2009.
- Ioannou, G. et al. Association between dietary nutrient composition and the incidence of cirrhosis or liver cancer in the United States population. Hepatology 50(1): 175-184. July 2009.
- Loguercio, C. et al. The impact of diet on liver fibrosis and on response to interferon therapy in patients with HCV-related chronic hepatitis. American Journal of Gastroenterology. 103(12): 3159-3166. December 2008.
- Sathiaraj, E. et al. Dietary alterations due to perceptions in acute viral hepatitis lead to sub-optimal calorie intake and increased length of hospitalization. Journal of Viral Hepatitis. September 2, 2009 (epub ahead of print).
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HCV & Lipids
—Alan Franciscus, Editor-in-Chief
It is well-known that the hepatitis C virus causes a pre-diabetic condition called insulin resistance. Insulin resistance occurs when the body does not process carbohydrates effectively. It has also been found that lipids or fats play a critical role in the hepatitis C replication process by helping the hepatitis C virus to enter liver cells. Furthermore, people infected with chronic hepatitis C have lower cholesterol levels compared to those with infected with chronic hepatitis B.
An important question, however, remained unanswered until recently—what happens when HCV is eliminated from the body? Do lipid levels return to ‘normal’ levels? In a first of its kind study, Corey and colleagues set out study the effect of successful HCV treatment and the effect on lipid levels before and after treatment.
There were two parts to this study:
Study 1: 179 people with chronic hepatitis C were compared to 180 people without chronic hepatitis C. The characteristics of the people with and without hepatitis C were well-matched. It was found that those with hepatitis C had significantly lower total cholesterol and LDL levels than those without hepatitis C. The difference in mean levels remained significant even after accounting for sex, race, and body mass index (P<0.0001). The levels of HDL and triglycerides were not different between the two groups.
Study 2: There were 87 patients out of 711 who received HCV treatment who had lipid data available before and after treatment. In total, 39 patients achieved a sustained virological response (SVR); 48 were either nonresponders or relapsers. All of the study participants had lipid levels checked within 1 year before starting HCV treatment and within 1 year after stopping HCV therapy.
Pre-treatment lipid (LDL, cholesterol, triglyceride, HDL) levels did not differ between those who responded to HCV treatment and those who did not.
It was noted that the pre-treatment levels of LDL and/or cholesterol among the participants was lower than is usually recommended for starting lipid lowering medications.
The major findings of the study revealed that:
- There were considerably higher mean cholesterol levels in people in the SVR group compared to the non-SVR group (189.1 vs. 165.2, P = 0.03).
- The LDL levels were significantly higher in the SVR group compared to the non-SVR group (105.8 vs. 89.9, P=0.05).
- The mean increase of 19.7 mg/dL in cholesterol levels occurred in the SVR groups compared to a decrease of 4.5 mg/dL in the non-SVR group (P=0.0045).
- There was a mean increase of 26.4 in LDL in the SVR group compared to a 2.9 mg/dL decrease in the non-SVR group (P=0.0046).
The differences in cholesterol and LDL found in SVR vs. non-SVR groups was still significant even after accounting for age, sex and genotype. No major differences were found in triglyceride or HDL levels between the two groups.
A total of 13% of patients who achieved an SVR had an increase in LDL levels, and 33% had an increase in cholesterol levels that should have necessitated the start of lipid lowering treatment but didn’t.
There were some concerns and comments expressed by the authors including:
- Frequently, people who achieved an SVR were not monitored post-treatment for lipid abnormalities.
- Many of the patients in this study had evidence of increased risk for coronary heart disease, but had not received lipid lowering treatment.
- Lipids levels of people who achieve an SVR should be closely monitored after therapy is completed and people should be started on lipid lowering medications if appropriate.
What Are Lipids?
Lipids are a group of naturally occurring chemical compounds that includes fats, waxes, fat-soluble vitamins, and triglycerides (fatty acids). Lipids are important for many reasons such as cell structure and overall metabolism.
High-density lipoprotein (HDL)—also known as good cholesterol—is made up of particles that transport fats back to the liver and glands to be removed from the body.
Triglycerides are fats derived from food ingested and circulated within the blood.
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Depression and HCV Therapy
Alan Franciscus, Editor-in-Chief
It is well-known that pegylated interferon plus ribavirin can induce or exacerbate depressive symptoms that can affect adherence, early treatment discontinuation and ultimately lower treatment outcomes. A recently published study is adding to the body of knowledge on the association between HCV treatment outcome and depression associated with HCV therapy.1
Data from 394 patients (191 African Americans, 203 Caucasians) was analyzed. Depression was defined as a score of >23 on the Center for Epidemiologic Studies Depression (CES-D) scale. Depression scores were taken before treatment, at weeks 4, 12, and 24 of treatment, and 24 weeks after treatment ended. Baseline social support was measured using the Medical Outcomes Study (MOS) Social Support Survey. The association between patient characteristics prior to treatment and the incidence of depression was measured.
The study found that prior to treatment 47 (12%) of the participants had CES-D scores of 23. Analyses indicated that several patient characteristics were associated with baseline depression, including lower social support (P<0.0001).
On treatment, these patients were more likely to have psychiatric adverse events or start new antidepressants (45% vs. 28%, P=0.02) and stop treatment early (38% vs.13%, P<0.0001); however, sustained virological response (SVR) rates were similar (38% vs. 40%, P=0.79) to those of participants without baseline depression. Twenty-six percent developed depression by 24 weeks of treatment. A total of 1/3 of the patients started on antidepressants. No patients attempted suicide.
Factors associated with new onset of depression included:
- Younger age (P=0.04).
- Lower social support (P<0.001).
- "Feeling depressed, sad, or blue" (P=0.008).
Patients who developed depression during treatment were more likely to have a psychiatric adverse event or begin antidepressants (44% vs. 23%, P<0.001), but were found to have lower rates of treatment discontinuation (6% vs. 15%, P=0.02) and comparable rates of sustained virological response rates compared with patients without depression (47% vs. 38%, P=0.16).
There were no differences in the frequency of pretreatment or new-onset depression between African-American and Caucasian participants in this study.
The authors concluded that there was a correlation between depressive symptoms before and during treatment based on certain patient characteristics, but importantly the sustained virological response rates did not differ between patients who were depressed or not depressed. An important take home message from this study is the need for a solid support system before, during and after treatment.
1Prospective data from the Viral Resistance to Antiviral Therapy of Chronic Hepatitis C (Virahep-C. D.M, Evan et al. Am J Gastroenterol advance online publication, 29 September 2009; doi:10.1038/ajg.2009.528. PMID: 19789525 [PubMed - as supplied by publisher]
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