Junkfood Science: November 2007

November 30, 2007

More on medical records privacy

News this past week is giving more hints of possible abuses and misuses of government electronic medical record databases and of our personal health information ... in the name of public health and safety.

As we know, the U.S. Department of Health and Human Services is working on policies for how the government can collect, use and sell our electronic medical records without our informed consent. We’ve also seen how little the HIPAA (Health Insurance Portability and Accountability Act) actually protects the privacy of our medical records, including pharmacy records, and how our personal information can be used by the government for just about any purpose it decides.

This knowledge will probably give a more cautious perspective for most readers of this first story, as compared to the uncritical account reported by CNN.

Patients prescribed medications

Dr. Mark McClellan, former commissioner of the FDA and former administrator for the Centers of Medicare and Medicaid Services, spoke this week to biotech executives. He talked about the new bill passed by Congress in September — the FDA Amendment Act of 2007 — that will create a vast new database of pharmaceutical drug patients by 2012. A much larger database he said is needed to help detect safety issues with prescription drugs. As CNN Money reported:

McClellan said major health care organizations such as eHealth Initiative, Partners Healthcare and Kaiser Permanente will coordinate with insurers like Unitedhealth Group and Wellpoint, Inc. to gather and collate the data from patients....

“If [all members of the American health care system] work together and follow the same rules (in how they define adverse events and how they use the data) then you've got tens of millions (of people) in the database," said McClellan

What other types of databases might governmental agencies create for purposes of public health and welfare? Besides the HIV-positive and diabetes databases we’ve already examined, there appear growing movements to create databases of citizens’ mental health information. The slippery slope begins with justifying these as necessary for public safety and law enforcement.

Adults diagnosed with mental health problems

Yesterday, ABC News revealed that 32 states have voluntarily turned over to the Justice Department the mental health records on their citizens without their permission or knowledge, and another 10 states are considering legislation to allow them to share mental health information with the government without court orders. The records are for the “Mental Defective File” of the FBI, under its National Instant Criminal Background Check System.

As ABC reports, it’s “part of efforts to keep mentally disturbed people from purchasing firearms” and prevent another Virginia Tech incident, which may sound laudable at first glance. The database has grown to nearly 400,000 people and includes anyone who’s ever been deemed to be mentally troubled, including veterans who may have once suffered with post-traumatic stress disorder. The Chicago Tribune reported today that citizens and veterans groups are opposing this Mental Defective File because there is no ability or due process for someone to challenge or get their name removed from the list.

This legitimate concern is significant for any government medical database. Mistakes are common in medical records, Dr. Carolyn McClanahan said today in the Lansing, Michigan news. Stress over a specific situation could be noted on your chart, for instance, as ‘anxiety’ and be seen by an outside entity as a mental health issue, and that mistake could result in being denied insurance or charged higher premiums. Or, a problem that’s been resolved could follow you forever.

Growing children and young adults

Even more difficult to follow, a November 7th press release from SAMHSA (the Substance Abuse and Mental Health Services Administration of the HSS) revealed that Congress is now looking at child mental health as a societal and public health issue.

It is recommending the development of an “assessment and accountability system” for purposes of identification, prevention and treatment of child mental health issues, addictions and substance abuse. A 67-page report, Promotion and Prevention in Mental Health: Strengthening Parenting and Enhancing Child Resilience, was prepared by Center for Mental Health Services (CMHS) at the request of a Senate subcommittee. SAMHSA Administrator Terry Cline, Ph.D., said the report’s recommendations “advance the growing medical consensus that mental health needs must be aggressively addressed early in life in order to fully promote the Nation’s public health interests.

As Psychiatric Services reported, the rationale for the public health tactic focuses on factors that may lead to a child’s “resilience.” The report identifies programs to address parents, adults, schools, neighborhoods, friends and other factors on behalf of those national public health interests. The report concludes with eight broad-based recommendations for federal, state and local collaboration to facilitate screening and prevention programs. These include communicating the economic and social benefits of prevention, family and workforce interventions, and a broad assessment and accountability system.

The following week, another SAMHSA press release announced a new report finding that young people with depression are at higher risk for “initiating substance use including cigarette smoking, and use of alcohol or illicit drugs.” The findings were based on the largest national database of its kind on substance use and health, one few consumers probably realize even exists. According to the press release:

[This report defined] a major depressive episode as a period of two weeks or longer during which there is depressed mood or loss of interest or pleasure and the presence of at least four other symptoms that reflect a change in functioning. These include problems with sleep, eating, energy, concentration and self-image. This definition is consistent with the one used by the American Psychiatric Association.

This could easily describe many teenagers at some point and time, meaning a zealous public health screening initiative could put countless young people into the government database, label them with a mental health problem, monitor their behaviors, and subject them to interventions or prevention programs that may or may not be needed, desired or best for them as determined by their healthcare provider and parents, or of proven efficacy. The report went on to say:

The report is also notable because of the size of the database -- nearly 135,000 interviews with persons aged 12 or older, including almost 45,000 young adults – and it was conducted during the course of the 2005 and 2006 NSDUH [National Survey on Drug Use and Health] surveys. This database is one of the largest and most detailed of its kind.


Wednesday, the American Psychiatric Foundation issued a press release announcing that, as part of its efforts to”advance effective employer approaches to mental health,” its Partnership for Workplace Mental Health has launched Employer Innovations Online, a web-based, searchable database that profiles employers’ policies, programs and practices for addressing mental health, including screening and interventions.

As the American Psychiatric Association President Carolyn Robinowitz, M.D., explains, “The Partnership focuses on helping employers understand the business case for addressing mental health at the workplace.”

The Partnership coordinator said that “not addressing mental health is costly.” Employers now appear another entity with a “need to know” and building a case for access to mental health records.

Under HIPAA, our personal health information can be gathered into government databases under all sorts of pretenses and used in countless ways. Calling HIPAA a Privacy Protection Act doesn’t make it so. However, unlike the web, there are few reports in mainstream media of drawbacks or potential problems of a national health databases, or of the objections of consumers and medical professionals.

We are predominately given one side: the “Benefits of Electronic Health Records,” as the Wall Street Journal headlined yesterday, saying:

A sizable majority of Americans believe electronic medical records have the potential to improve U.S. health care and that the benefits outweigh privacy risks, according to a new Wall Street Journal Online/Harris Interactive poll.

Opinion polls are, of course, the most common marketing tactic used by public relations firms to sell an idea and shape public opinions by trying to convince us of something’s popularity. How questions are worded and ordered, who is polled and how the answers are interpreted can create any bandwagon effect a pollster may desire. This Harris Poll is an online poll conducted for marketing clients and the participants are members who sign up and get points and cash rewards for answering the surveys. In this case, the question concerning “if benefits outweighed the risks” was asked at the end of the survey, after multiple questions raising possible benefits of electronic databases, without mention of potential drawbacks. Even so, most of those who answered favorably used electronic medical records.

That very same poll, however, even as the questions were asked and answered, could also have been interpreted as revealing that electronic medical records aren’t popular or used by the vast majority of Americans, that only 2% of adults use electronic medical records and only 1 in 5 doctors maintain electronic patient records.

There is, however, a large movement in England getting media coverage with a very different perspective on electronic databases, their potential misuses and privacy concerns. Nearly two-thirds of family doctors there are boycotting the government’s plan to put the medical records of 50 million NHS patients on its national database, the Guardian reported last week. Growing numbers of general practitioners are unwilling to upload any file without their patient’s specific consent. The report goes on to say:

Family doctors to shun national database of patients' records

...Three-quarters of family doctors said medical records would become less secure when they are put on a database that will eventually be used by NHS and social services staff throughout England. Half thought the records would be vulnerable to hackers and unauthorised access by officials outside the NHS. A quarter feared bribery or blackmail of people with access to the records and 21% suspected that social services staff would not adhere to the confidentiality rules.

The poll of more than 1,000 doctors was conducted by Medix, a healthcare online research organisation previously used by the Department of Health to test medical opinion. It found GPs are increasingly concerned about the department's plan to automatically upload the records of everyone who does not register an objection....

This high level of scepticism came in spite of months of campaigning by Connecting for Health, the NHS's IT procurement agency, to persuade doctors that the “summary care record" scheme would save lives.... One GP told the pollsters: “Patients' confidential records will undoubtedly be at risk in the brave new world ...Another said: “Our current record confidentiality has been breached by a local primary care trust manager and we only found out by accident. I cannot trust the security of a national scheme." ....

If consumers and healthcare professionals were given all sides of the issue, how many would really want the government, insurers and their employers to know everything about them?

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November 29, 2007

Starting them young... on the road to eating disorders?

A new board game for preschoolers has come out just in time for Christmas gift giving. It’s a toy being marketed for 4-year olds to teach kids ‘healthy eating’ and exercise. Instead, it is one of the most troubling examples of educational toys to address 'childhood obesity.' Not only does it reinforce with little ones prejudicial stereotypes of fat children, it shows them how to think like anorectics and compulsive exercisers.

Players come away learning that foods, especially “bad” foods, make them fat. The message being illustrated is that when a food is eaten, they must purge by expending a certain number of calories in exercise to avoid getting fat. Calorie counting before they can count.

The creator of Hungry Hank™ says it “helps young children make the connection between eating, exercise and weight.” [A myth that JFS readers well understand.] Every time the players land on a space on the board game with a food on it, Hungry Hank eats, “burps, grunts and his belly expands.” When they land on an exercise space, they have to do the required exercise to burn off the calories.

The loser is the player who lands on a food space and causes Hungry Hank to explode.

The Orange Country Register promoted it in a recent article:

Formerly obese guy tries to develop board game for kids

Hungry Hank hiccups. He grunts. He burps. Michael Moore – not that Michael Moore – sits at his kitchen table in Irvine gazing at Hank with unblinking, unconditional love. After all, Hank’s his baby – 14 years in the making The 8-inch-tall, cartoonish figure has a massive, eggplant-shaped nose and arsenal of rude noises. Hank was going to be a star....

What’s needed, Moore says, is a little education – a philosophy at the heart of the Hungry Hank game. But before the educational stuff, Moore says, the game had to be fun – something kids and their parents would want to play together, regardless of their food issues.... Players (from two to four) roll a dice to make their way around a circular board, landing on food and exercise spaces. Every time a player lands on a food space, he or she presses a big green button by Hungry Hank’s feet. For example, landing on a bowl of cereal and a banana for breakfast is one pump – two donuts and chocolate milk are three pumps. Each pump causes Hungry Hank’s belly to grow. His arms flap and he burps or grunts....

“We all have to do more on the early part of the age education to reinforce healthy eating habits,’’ says Moore...

The game comes with no warning labels for parents.

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November 28, 2007

JFS Exclusive: CDC admits there is no obesity epidemic!

Well, sort of. They appear to be doing their darndest to not let you know what they’ve known for years.

Today, the National Center for Health Statistics at the U.S. Centers for Disease Control and Prevention released the latest obesity figures, from the National Health and Nutrition Examination Surveys (NHANES). The NCHS Data Brief was titled: “Obesity Among Adults in the United States — No Change Since 2003–2004.”

The key finding: “There was no significant change in obesity prevalence between 2003–2004 and 2005–2006 for either men or women...No significant difference in obesity existed between men and women.”

But there's more to this story.

The public, trying to learn the facts, has to pick through the intense spin in the 8-page report, filled with graphs and claims that “obesity continues to be a public health concern” and that there remain "alarmingly high rates of obesity in all population groups." As with all of the CDC reports on NHANES, generalizing the results of the representative samples to the entire population involved a calculated margin of error that made any tiny differences from year to year not statistically significant. That fact, however, is hard for most readers to discern, especially with some press stories handwringing that the untenable variations might mean something “worrisome.” The rest of the CDC report didn’t reveal any other new information. Middle age adults weigh more than younger or older people; hispanic and black women are generally heavier than white women; and there are no racial/ethnic weight disparities of BMI among men.

To realize the bigger significance of this story, though, we have to piece together the latest NHANES reports. As JFS has posted repeatedly, back in 2004, in the June issue of the Journal of the American Medical Association, the CDC had reported that there had been no significant increases in the numbers of U.S. adults or children considered “overweight” or “obese” from 1999-2000 through 2001-2002.

In other words, today’s report could more accurately been titled: “Obesity Among Adults in the United States — No Change Since 1999-2000.” There has been no statistically significant change in obesity rates for the past 7 years. That’s “obesity.” Not just those a few pounds “overweight.”

The media headlines should, at the very least, be shouting:

“Obesity Epidemic Over!”

Instead, the media across the country has only been able to bring itself to headline with things like: “U.S. Obesity Rates Seem to Have Leveled — Government Says Obesity Rates in the U.S. Have Leveled Off, At Least Temporarily.”

Some, like Dr. Sanjay Gupta at CNN, are already suggesting that their anti-obesity healthy lifestyle initiatives may be working — except their programs were started years after obesity rates had already stabilized. In fact, as has been reported at JFS, years before the marketing of an “obesity epidemic” went into high gear, the government's own data was already showing no significant changes or increases in rates of overweight or obesity among the U.S. population.

The war on obesity has been built on a scare campaign, albeit a profitable one for countless of interests, but harmful for all too many consumers. Knowing the facts makes the hysterical claims about the obesity crisis sound just plain absurd, doesn’t it?

How likely is it that the government will suddenly stop spending billions of our taxpayer dollars on a fictitious “obesity epidemic” — monies and limited resources that could be spent on real healthcare needs — and shut down its countless programs, now that the truth is out that there isn’t and never was an epidemic when they launched them?

Or, will they try to downplay this report, as they did the 2004 one? Or, will they try to redefine “epidemic” now, too?

The definition of epidemic: The unusually rapid increase and spread in the number of cases of a disease in a given location over a limited period of time.

There is no way the CDC’s own figures since 1999 can support its own claim that obesity is an epidemic.

Nor can its own figures support its claim that overweight and obesity is a public health crisis. While in reality, we’ve seen modest increases in actual heights and weights among the population for half a century, during that same period, life expectancies have increased to the longest in our history, and age-adjusted rates for chronic diseases have dramatically fallen.

Sadly, the only thing the CDC’s own figures can support is that we’ve been hoodwinked.

© 2007 Sandy Szwarc. All rights reserved.

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The good-bad salt debate gets a hearing at the FDA

The FDA is convening a public hearing tomorrow to decide if salt should be regulated as a potentially dangerous food additive and whether to revoke salt’s status as “generally recognized as safe.” Is this a sign that we should be concerned? Is this hearing in response to troubling new science showing that the population is at risk from salt, necessitating government intervention? Has evidence come out showing that salt reductions would benefit everyone?

No, no and no.

Reading the Federal Register Docket (No. 2005P-0450), we learn it is only in response to the latest petition from CSPI (Center for Science in the Public Interest). As CSPI’s press release said yesterday, it has been urging the FDA for years “to do something—anything” to get people to eat less salt.

In its Docket, the FDA reviewed those regulatory and legal efforts that began in 1978:

In 1978, CSPI submitted a citizen petition requesting that FDA establish limits for sodium in processed foods and reclassify salt as a food additive....The 1978 CSPI citizen petition also requested that FDA require sodium content labeling on packaged foods and require a special symbol on the labels of high-sodium foods.... In a letter dated August 18, 1982, FDA denied the petition....

In 1981, CSPI submitted a citizen petition requesting that FDA require warning labels on packages of salt weighing half an ounce or more. FDA denied that petition in a letter dated October 7, 1982. In that denial letter, FDA considered an isolated warning appearing on the label of one class of food products to be inappropriate given that many foods contribute to an individual's sodium intake.

In 1984, CSPI sought review of FDA's actions in the United States District Court of the District of Columbia...The district court concluded that FDA's decision was consistent with its regulations and the act and rejected the argument that FDA had unreasonably delayed reconsideration of the GRAS status of salt. CSPI did not appeal.

In 2005, CSPI sought a writ of mandamus, in the United States Court of Appeals for the District of Columbia, compelling FDA to publish in the Federal Register a proposed rule either affirming or denying the GRAS status of salt and providing an opportunity for comment on the proposal. The court dismissed CSPI's petition for lack of jurisdiction,

In a petition dated November 8, 2005, CSPI requested that the agency take certain regulatory actions regarding salt. Specifically, CSPI requested that FDA initiate rulemaking to revoke the GRAS status for salt, amend prior sanctions for the use of salt, require food manufacturers to reduce the amount of sodium in all processed foods, require a health message on retail packages of salt one-half ounce or larger, and reduce the DV [daily value] for sodium from its current level of 2,400 mg/d to 1,500 mg/d. CSPI also requested that FDA take regulatory action to reduce the amount of sodium in processed foods sold directly to restaurants...

Tomorrow’s hearing will examine two issues:

The first, is whether to revoke salt’s status as generally recognized as safe and if it should be regulated as an additive. As readers may know, back in 1959 the Federal Food, Drug and Cosmetic Act was passed which defined food additives subject to government regulation, excluding commonly used substances that are “generally recognized, among experts qualified by scientific training and experience to evaluate their safety as having been adequately shown through scientific procedures (or, in the case of a substance used in food prior to January 1, 1958, through either scientific procedures or through experience based on common use in food) to be safe under the conditions of their intended use.” Among the substances listed in the FDA’s GRAS list were common food ingredients such as salt, pepper, vinegar and baking powder.

Even so, during the 1970s, the FDA initiated a comprehensive review of GRAS substances to ensure their safety. As such, it contracted with the Federation of American Societies for Experimental Biology (FASEB) for a committee of scientific experts to summarize the available scientific literature regarding substances presumed to be GRAS, including salt. In the FDA’s 1982 policy notice, it outlined the findings of the FASEB’s report on salt and labeling recommendations. Concerning the safety of salt for the vast majority of the population, the FASEB concluded: “The evidence on sodium chloride is insufficient to determine that the adverse effects reported are not deleterious to the health of a significant proportion of the public when it is used at levels that are now current and in the manner now practiced.”

The FDA said it had considered and rejected the request to revoke salt as GRAS in 1982 for several reasons. The FDA would “have to establish a limitation for each technical effect for which salt is used in each food category, and it would be extremely difficult to prescribe and enforce ‘fair use’ limitations for salt that would be safe and effective for all consumers.” Salt also has many functions in foods and in different steps in food preparation that would be impossible to regulate separately, and the regulatory burden, and costs to consumers, would be extraordinary.

The FDA also said in 1982 that to revoke salt’s GRAS status and take regulatory action, it “would have to show that salt in food is a ‘poisonous or deleterious substance.’” No such evidence at levels consumed exists. Therefore, it concluded that the informational labeling in place would be most responsive to any health concerns about sodium that individual consumers might have.

The second issue that will be examined in tomorrow’s hearing is the food labeling changes requested. As the FDA states:

Our regulations currently require declarative statements on the label about the sodium content of processed food, define nutrient content claims for foods based on their salt content, provide for a health claim regarding low sodium diets and reduced risk of hypertension, and stipulate maximum sodium concentrations for foods that are to be labeled as ‘healthy.’ In addition to the goal of providing information to consumers, these labeling initiatives are also intended to encourage food manufacturers to reduce the salt content of foods and to provide incentives to manufacturers to produce lower sodium foods. CSPI argues that these measures have not ultimately served to reduce salt intake and that further, more aggressive regulatory action is needed.

The core to the FDA’s decisions to date has been the science. Is there good evidence to support CSPI’s beliefs that salt is dangerous and in need of governmental regulation? And, is there good evidence that cutting salt consumption in half, population-wide, to the lowest in the world, will benefit public health and reduce premature deaths?

Let’s look at the three main scientific papers CSPI used to support its petition that were outlined in its paper, “Salt: The Forgotten Killer,” last updated in May.

1. CSPI says: “Reducing sodium consumption by half would save an estimated 150,000 lives per year.” It supported this claim by referencing a 2004 article published in the American Journal of Public Health.

This paper, however, was not a study, but a “Commentary” and “Call for Action” in support of the government’s Healthy People 2010 objectives headed by the National Heart, Lung and Blood Institute (NHLBI) and its National High Blood Pressure Education Program Coordinating Committee. This commentary was authored by Dr. Stephen Havas at the University of Maryland School of Medicine and two others with the NHLBI. Their estimation was based on associations of hypertension among those having heart attacks and strokes, and a calculation of what could happen if salt reduced levels of hypertension. Potential risks were not included in their calculation, nor were the effects on the majority of people in the population who don’t have clinical hypertension.

2. CSPI says: “Reducing salt intake in children quickly lowers their blood pressure. If their blood pressure remains lower, those kids could experience lower rates of heart attack and stroke as they age.” This claim was supported by the study led by professor Graham MacGregor, founder of CASH (Consensus Action on Salt and Health).

JFS reviewed that study thoroughly last December. Essentially, it was only speculations based on no clinically meaningful evidence.

3. CSPI says: “One recent study found that people who are pre-hypertensive and cut back on sodium, reduced their chances of developing cardiovascular disease by 25% and their risk of dying from it by 20%.” In support of this claim, CSPI referenced the study led by Nancy Cook, associate professor at Harvard Medical School in Boston. That study and others, including a Cochrane Review, were reported here.

To summarize, the Cook study was a follow-up of the Trial of Hypertension Prevention (TOHP) trials which had been conducted during the late 1980s to look at the blood pressure effects of salt reduction and weight loss among more than 3,000 people with hypertension (and who were mostly obese). Even extreme salt-restricted diets reduced blood pressures in this cohort by a mere 1.2/0.6 mmHg. While hypertension can be an indicator of cardiovascular disease, salt restrictions have been shown in the scientific literature to reduce blood pressure in about one-third of the population and then only modestly, while it can increases blood pressures for another quarter of people.

Citing relative risks, as CSPI did, makes the effects of salt-reduction sound much more significant than they really are. After 5 to 10 years, the Cook researchers found that the difference in the number of cardiovascular-related deaths between the intervention and control groups was only 5 people. These differences were so insignificant that the authors made no assertions that salt reduction lowered mortality among the study populations. In fact, they also specifically cautioned that high blood pressure is not a cardiovascular event (a clinical outcome), but a surrogate endpoint, and not sufficient evidence to call for large scale sodium reductions.

What about more recent studies?

Walker et al. The most recent analysis of the evidence examining if dietary salt restrictions provided protection from cardiovascular events or deaths was published last month in the Journal of Interactive Cardiovascular and Thoracic Surgery. Led by Dr. Jay Walker of the Department of Cardiothoracic Surgery, James Cook University Hospital, Middlesbrough, UK, the researchers identified 14 studies which presented the best evidence, included among them were the TOHP studies.

Their paper was aptly titled: “Does reducing your salt intake make you live longer?” That’s really what matters, isn’t it?

Most studies to date, they observed, have looked at the effects of low-sodium diets on blood pressure or blood pressure medication use among people with hypertension, and only a few examined mortality. An NHANES (National Health and Nutrition Examination Surveys) study of 9,485 people followed for 19 years after a 24-hour sodium questionnaire found no difference in clinical risks among the ‘normal’ weight patients and among the ‘obese,’ and only a 3% difference in any clinical outcome (heart disease and mortality) between the lowest and highest salt intakes.

The most recent analysis the Walker researchers examined was the one of the TOHP trials on hypertension by Cook and colleagues. While the Cook authors had reported that cardiovascular events were 25% lower among the patients given counseling on salt reductions as compared to the control patients, this is another example of how we can be misled by relative risks versus actual (absolute) numbers. “On looking further into this study” and actual incidences, Dr. Walker and colleagues cautioned, “this difference was 7% compared to 9% over 10 years for cardiovascular events (of which there were 200 across over 3000 patients).” The bottom line, they concluded, while salt restrictions may reduce blood pressures, “the ability of dietary sodium restriction to reduce the incidence of cardiovascular events is more controversial.”

Grobbee et al. Another major peer-reviewed study was also published last month, this one in the European Journal of Epidemiology, examining sodium and potassium intakes and their relationship to cardiovascular disease and mortality. We didn’t hear much about this study in the news, either, so let’s look briefly at what it found.

Researchers from Wageningen University in The Netherlands followed a general population sample of people 55 years and older for five and a half years. Clinical exams were done at the beginning of the study, including body measurements, blood pressure, blood tests and 24-hour urine samples to measure sodium and potassium levels. Dietary data was obtained from food-frequency questionnaires.

They found no association between any of the levels of sodium, potassium or sodium/potassium ratios and cardiovascular or all-cause mortality, nor was there a tenable relationship among the overweight study participants. “The absence of a relationship between salt intake and mortality in our study corroborates the findings from the large Scottish Heart Health Study among almost 12,000 middle-aged subjects with 24-h urine samples,” they wrote. Also, “follow-up data of the MRFIT trial neither showed a relationship between dietary sodium intake estimated by 24-h recall and cardiovascular events or mortality.”

They concluded: “The effect of sodium and potassium intake on CVD morbidity and mortality in Western societies remains to be established.”

In fact, while there have been more than 17,000 studies published on salt and blood pressure since 1966, none has shown population-wide health benefits from low-sodium diets, only some select subgroups of people appear to respond. According to Dr. David Klurfeld, Ph.D., professor and chairman of the Department of Nutrition and Food Science at Wayne State University, editor-in-chief of the Journal of the American College of Nutrition, “the better controlled studies fail to show a significant benefit on blood pressure for large groups with sodium restriction.”

The other side of the coin

If there is no support that salt reduction among the general population, versus people with specific medical issues, will save lives and help ensure that everyone will enjoy longer, healthier lives; any evidence that such reductions might harm vast numbers of the population becomes even more critical to consider. Yet, the possible adverse effects of salt reductions aren’t mentioned by CSPI and rarely in the media.

Far from being totally benign, the European Society of Cardiology Guidelines for the Management of Arterial Hypertension, for instance, reported recent research showing low-salt diets can have negative effects: activating the rennin-angiotensin system and the sympathetic nervous system, increasing insulin resistance and hypodehydration (especially with the elderly). This, they concluded, could lead to increased risks for cardiovascular disease.

A cardiologist once explained one of the concerns very simply, when commenting that some of the longest living people in the world also have the highest salt consumptions. When most of us eat a lot of salt, we get thirsty and drink water, and our bodies excrete the excess sodium chloride while maintaining the balance of sodium in our blood and our blood pressures. Our bodies are designed to compensate for excess salt without hurting us. When people eat less salt, though, blood levels of sodium can drop below normal. Should you get sick, go out in the hot sun or exercise, when you drink more water, it dilutes the sodium even more, resulting in greatly increased risks for heat stroke or circulatory collapse. Now, that’s not good for your health.

Salt also improves the flavor of many nourishing foods, helping to prevent nutritional deficiencies especially among vulnerable populations, such as children and elderly. It does more than make many of the foods we love taste good. Salt has served invaluable roles in food preparation and preservation, baking, culturing cheese, and making our food safer to eat since the earliest days of mankind. Salt reductions could jeopardize these benefits, at costs to health, safety and enjoyment of foods.

A recent randomized clinical trial of patients with hypertension, published in the American Journal of Hypertension, confirmed the connection with insulin resistance, as noted by the European Society of Cardiology. It found that increasing sodium in their diet appeared beneficial and concluded: “An abundant sodium intake may improve glucose tolerance and insulin resistance, especially in diabetic, salt-sensitive, and or medicated essential hypertensive subjects.”

The authors of the NHANES II follow-up study of a representative sample of U.S. residents were especially cautious about establishing dietary guidelines based on currently available evidence. This study, led by Dr. Hillel W. Cohen, MPH, DrPH, of the Department of Epidemiology and Population Health at Albert Einstein College of Medicine, Bronx, NY, said that guidelines calling for reductions are based on the modest blood pressure changes associated with low-sodium diets in short term clinical trials. “However, these trials could not assess the long-term cardiovascular morbidity and mortality consequences.”

They said that caution was especially advised with making conclusions based on observational studies, as “no single observational study can confirm a causal inference.” We recently saw that when that World Cancer Research Fund Expert Report said that many of the claims of salt being associated with health problems and higher rates of premature deaths are due to confounding factors not considered in observational studies. For example, they noted that “salt is inversely related to the availability of refrigeration in a population, and so to socioeconomic status.”

Dr. Cohen and colleagues added:

[B]asing a lower sodium recommendation primarily on intermediate effects such as blood pressure reduction is also unsatisfactory. Unintended health consequences can result from seemingly reasonable expectations.... In the case of sodium, extrapolations from positive effects on blood pressure may be offset by extrapolations from potentially adverse effects on the sympathetic nervous system, the renin-angiotensin system, insulin resistance, and the potential that other important nutrients might be decreased when free-living individuals alter diets to decrease sodium...

The data here cannot sustain a conclusion that lower sodium is harmful. However, these findings, along with the inconsistent results of other epidemiologic studies, and the propensity for substantial variability among individuals, do not lend support to any universal prescription for salt intake.

In sum, the inverse associations of sodium to CVD mortality observed in this large, nationally representative sample, raise questions regarding the likelihood that a survival advantage will necessarily result from a universal recommendation for a lower dietary sodium intake.

An Associated Press story today mentioned none of this, however. It quoted the director of CSPI, Michael Jacobson, as saying the “current levels of salt in the diet are one of the biggest health threats to the public.” Dr. Havas (who authored that Call to Action mentioned above) was then quoted: “This is truly urgent. We need to act.”

Is salt a killer and a public health crisis? The FDA will hear all sides tomorrow. Whether we’ll hear all sides in the news coverage is another story.

© 2007 Sandy Szwarc

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November 27, 2007

Role models of positive body images for young women?

Two articles this week have alerted readers to risks associated with pro-anorexia websites. One investigative report by People UK revealed to parents the alarming extremes of starvation encouraged by troubled young women on these unmoderated sites, the “thinspiration” photos they post of themselves and celebrities they are emulating, and life-threatening weight loss ideas they share. Included in the undercover dossier was one girl who slashed her wrists on a livejournal pro-ana chatroom and no one tried to get help for her as she bled to unconsciousness. People UK contacted livejournal.com and gave them detailed documentation of what was going on and urging them to discontinue the pro-anorexia forums. There was no response. The livejournal mission statement, according to the report, says it believes “in letting users create their own content with complete freedom of expression.” This is not to advocate to censorship, but to serve as an added warning to family and young people about things on the internet that can be harmful.

The second article by Mama Vision warned girls of the dangers of posting their photos online at pro-ana sites, jeopardizing their futures in ways they might never have imagined.

Both articles and the accompanying photos [click on headlines to read full articles] are disturbing, and so are popular syndicated television shows airing this month as part of “Body Image” campaigns — depicting extreme weight loss, idolizing gaunt celebrities, and suggesting dangerous and unsound diet techniques....

Generation Anorexia Revealed

An anorexic schoolgirl cut her wrists while logged on to a live internet chatroom, we can reveal today. The shocking suicide drama was exposed by an alarming People investigation which will horrify parents everywhere. We infiltrated a well-meaning self-help website which has been hijacked by pro-anorexia extremists and found youngsters:

Bragging about eating nothing for days at a time... Swapping starvation tips on how to survive on just 150 calories a day... Boasting how to hide their killer condition from desperate families and doctors...Daubing the internet site with “thinspirational" photos of stick-thin celebs ...Yet the site claims it is there to HELP youngsters....

“I don't think I have even eaten 800 cals the whole week put together but get the feeling I have put on weight." She added: “If I have put on, I will just feel fat. Help me!" ...The forum - which regularly gets hundreds of messages a day - is linked to information on support groups for victims. But concerned experts claim the tie-ins are just a cover for the real purpose of the website - to encourage anorexia....

Pro Ana Privacy, part 2

...A talented young woman recently applied for a job just after she graduated from college. A dream job really, everything she ever wanted. Mom and Dad were so proud. Little did she know that some pictures that she uploaded to the web many years prior would come back to haunt her....

No job. Worst of all? No way to remove them - ever. This thing is permanent girls. It’s called the world wide web and once you CHOOSE to serve yourself up for the taking, you are gone, your privacy is gone, and your future opportunities are at stake....

Access Hollywood, the NBC syndicated celebrity gossip newsmagazine, has been airing special features as part of its “Body Image Month.” The focus isn’t on helping women develop positive, healthy body images, but mostly about achieving the thin body of celebrities. Viewers are treated to tips on how supermodels stay so thin, “healthy” ideas from a “Biggest Loser,” Star Jones talking about slimming with bariatric surgery, and tips from celebrity trainers on slimming down and foods you should never eat. Viewers can work out with Jennifer Aniston’s Yoga Instructor to get fit, with a video depicting underweight women.

The article, “Marlee’s Get Fit Challenge: Junk food intervention,” says that the already slim Marlee Matlin is unfit at 129 pounds because she weighs 30 pounds more than she did as a teenager — at 99 pounds! So, she is put on a “junk food intervention” and intense exercise regimen by a celebrity trainer to lose weight. He goes through her kitchen and throws out her peanut butter, juice, cream cheese, butter, ice cream and chicken tenders. She is told none of these foods are up to the diet code. When you click on the link to learn what foods she is possibly allowed to eat, up pops nothing.

Access Hollywood offers other resources in a drop down menu, such as the Cabbage Soup diet and the Master Cleanse. Information on the Master Cleanse, courtesy of a “nutritionist” with the Today show and author of a food cures book, describes it as “the quick way to lose weight.” While saying it’s unhealthy, being a liquid starvation diet consisting of only drinking water, lemon juice, maple syrup, and cayenne pepper; she still gives the exact recipe for the bogus concoction. JFS readers know that there is no medical support for any fad diet, be it the water diet or lemonade made with maple syrup, as safe and effective weight loss interventions. Even lemon is a weak acid that doesn’t begin to approach the acidity already in our stomachs, so it holds no magical properties.

With such extreme thinness and unsound fad diets promoted on mainstream television, for many young viewers, the lines blur between the pro-anorexia mindsets they learn in media and those on livejournal. And we wonder why our young girls are getting caught up in being thin at all costs.

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November 26, 2007

Even gold can be tarnished

A riveting pharmaceutical clinical trial melodrama has been playing this past week. It’s a story filled with conspiracy theories of cover-ups and secret manipulations of clinical trial data and clinical trial design that’s leaving cardiologists and medical ethicists rankled. Most consumers are unaware of these debates, however, as there’s not been a peep on network news or in our local newspapers. But this incredible tale gives us a glimpse as to why even published clinical trials, the gold standard of research, deserve close scrutiny.

The firestorm began last Monday when Merck/Schering-Plough Pharmaceuticals issued a press release to medical professionals announcing that an independent review panel had been convened by the company the previous Friday to advise them on how to analyze the data of its ENHANCE trial. As a result, the company had decided to change the primary endpoints to expedite their analysis. They also said that only some of the original primary results would be released. They hoped to present their report of the trial at the American College of Cardiology meeting in March 2008. The significance of this may not be immediately clear, so let’s get caught up.

This trial had begun in 2002 on 720 people with very high cholesterol, and the study ended in April 2006. Cardiologists had been expecting to learn the results last November. That didn’t happen. Then, they were promised them in March of this year. Again, they never materialized. The delays are concerning cardiologists because millions of people have been being prescribed Zocor (simvastatin) with Zetia (ezetimibe), believing they prevent heart attacks and strokes.

The only problem, no study has ever shown Zetia to be effective in improving clinical outcomes (such as reducing cardiovascular events or deaths), despite bringing in $5 billion a year in sales for Schering-Plough. It turns out the Zetia had been approved by the FDA on the basis of trials showing it could lower LDL-cholesterol, a surrogate endpoint, by 15-20%.

The ENHANCE trial was designed to see if Zetia with Zocor works better than Zocor alone. Again, however, it wasn't using actual clinical outcomes as its primary endpoints, but surrogate endpoints of arterial obstruction as measured by carotid intima-media thickness at three locations and femoral artery IMT.

What makes this trial especially critical for the pharmaceutical makers is that Zocor’s patent expired, so it has been combined with Zetia to make a “new” drug, Vytorin, that can be patented. Multi-billions of dollars are at stake in protecting their interests from generic drug companies.

This exemplifies what Dr. Marcia Angell, M.D., former Editor-in-Chief at The New England Journal of Medicine and author of The Truth About the Drug Companies: How They Deceive Us and What to Do About It, had warned. Most drugs brought to the market aren’t new drugs or improvements over drugs already available. Most don’t even contain new chemical compounds, but are old drugs in new combinations or formulations, often created just as patents are about to expire. “The idea is to grab a share of an established, lucrative market by producing something very similar to a top-selling drug.” As she wrote:

Of the seventy-eight drugs approved by the FDA in 2002, only seventeen contained new active ingredients, and only seven of these were classified by the FDA as improvements over older drugs. The other seventy-one drugs approved that year were variations of old drugs or deemed no better than drugs already on the market. In other words, they were me-too drugs.

More would come out about this trial as the days went on...

On Monday, Matthew Herper wrote in Forbes’ business section that the delays were raising suspicions among cardiologists that the ENHANCE trial results weren’t favorable, because with so much money at stake if the news was good, the company would rush to report the results. Two other sources of suspicion were revealed: the pharmaceutical companies hadn’t listed the trial on the government website, clinicaltrials.gov, where all clinical trials are supposed to be recorded; and credible clinical trial protocols standardly recommend that the drug company sponsors not have control over the study data and how it is analyzed. “In this case, that database is held by Schering-Plough,” he wrote.

After the Forbes article was published, the Merck/Schering-Plough press release came out announcing they were changing the primary endpoints. That fueled an article on Wednesday by Alex Berenson in the New York Times. As he reported, scientists consider for a clinical trial to be valid that its goals must be clearly defined at the start and not changed later, otherwise it’s easy to change the goals to match the data the trial actually came up with. Two other worrisome facts were made clear in that story. The lead investigator didn’t have access to the raw study data or any control over its analysis, as that was all in the hands of the drug company sponsors. The drug companies were also not disclosing the “experts” they’d convened, who’d advised the primary endpoints be changed.

Was everyone just being paranoid and getting caught up in conspiracy theories, as some wondered?

The next day, an article appeared on Heartwire (a news service of WebMD), trying to counter speculations that the results were bad and the companies were delaying their release. Reiterating the companies’ press release, the lead investigator said that the study was late in reporting because of technical difficulties with nearly 40,000 images to process. “That’s an incredible amount of data to deal with,” he told Heartwire. “Maybe we were a little ambitious on the timeframe required to process so much data. That is why there has been some delay. The suggestion that the results are being suppressed because they are negative is simply wrong.” He said the data was still blinded but the companies’ expert panel felt that the secondary endpoint would be better as the primary endpoint and the primary endpoints would now be secondary. When asked why the company made this unusual move after the trial was completed, he admitted:

These are very important data for the company. The drug has huge sales, and this study will be the first real indication as to whether it is working. Everybody is understandably nervous. My opinion was that everything was fine the way it was and we should just continue, but they wanted some additional reassurance from outside experts and they got it. I didn't like it very much, but it was necessary to settle their minds.

According to Heartwire, he said the whole debacle has highlighted the tensions that exist between the lead investigator of a study and the sponsor. Readers could feel the unease in this situation, when he said:

The other experts supported me, but maybe we have had more difficulties with this study because the sponsor has control over the database. If the investigators have control, then we get to do the analysis our way. In future, I will try very hard to get this.

Most of the discussions of this situation have been among bloggers. Dr. Aubrey Blumsohn suspected that the study data had been secretly unblinded, and may be why the endpoints were changed, as the unblinding codes are presumably held by the same entity holding the raw data. “That same entity has a huge financial stake in the outcome,” he said. However, it’s also “easy to fiddle the results of a randomized trial given a blinded study database even without unblinding codes,” he said. Zetia has enough side effects that it could easily be distinguished from placebo, he said.

But the harshest critic of these drug trials may be Dr. Scott K. Aberegg, M.D., M.P.H, Assistant Professor of Medicine at Ohio State University in Columbus, Ohio. Writing on his blog, Medical Evidence, he made three interesting observations about this situation.

While the drug companies aren’t releasing the findings even nearly two years later, saying that analyzing the IMT data is taking longer that they anticipated, they could greatly allay concerns by simply releasing the more easily compiled data on mortality and safety endpoints, which are monitored for safety on all clinical trials. “It doesn’t take very long to add up deaths,” he said.

He also pointed out concerns about the endpoints, saying that by pre-specifying multiple endpoints (carotid IMT at three locations and femoral IMT), their chances of meeting one of them by chance alone was increased. But changing their primary endpoints after the trial is completed breaks the most hallowed position on endpoints. If you fail to prove your hypothesis, you lose, you don’t move the endposts. Worse, the sponsors are now not even planning to release all of their former primary endpoint data at all.

Discussing the design of the ENHANCE trial, he said it compares full 80-mg doses of Zocor to 80-mg of Zocor and 10-mg of Zetia, but isn’t looking at any clinically meaningful endpoints. To test the drug’s effectiveness with hard clinical endpoints (heart attacks, strokes and death), Shering-Plough has launched the IMPROVE-IT trial, due to be completed in 2011. But the company is up to some tricks to save Zocor from generic death with this trial, he wrote. They designed the study to compare half doses of Zocor and Zetia to half doses of Zocor alone, so there will be no way for clinicians to know what works better, he said. Doctors won’t have the important information they need to know if Zetia is superior to an alternative (going generic soon) at maximum dose, or if its addition to maximum dose Zocor offers any additional benefit. They didn’t use full doses, he said: “Such trials are too risky for the company — they may show that there is no point to prescribing [Zetia] because it is either less potent than max dose [Zocor] or that it has no incremental value over max dose [Zocor].” He went on to say:

You see, this trial was designed primarily for the purpose of maintaining patent protection for simvastatin [Zocor] in the combination pill. Its potential contribution to science and patient care is negligible. So much so in fact, that I think this trial is unethical. It is unethical because patients volunteer for research mainly out of altruism (although in this case you could argue it's for free drugs). The result of such altruism is expected to be a contribution to science and patient care in the future. But in this case, the science sucks and the main contribution patients are making goes to the coffers of Schering-Plough.

Such harsh criticism is reminiscent of concerns raised by Dr. Angell when advocating for scientific integrity and pointing out the abuses of science and the inferior research that is increasingly the norm. As she’s said, the medical profession needs to break its dependence on the drug industry and the inappropriate control sponsors have over the evaluation of their own products. As she wrote:

Clinicians know privately that results can be jiggered. You can design studies to come out the way you want them to. You can control what data you look at, control the analysis, and then shade your interpretation of the results. Even the most careful research can be fraught with murky results that require sifting and weighing, a measure of judgment that the researcher hopes will bring him closer to the truth.

The ENHANCE trial appears to be a worse case scenario of how pharmaceutical company sponsors can manipulate and control the design, completion, data analysis and reporting of a clinical trial of its products, blurring the lines between scientific research and marketing. For doctors and patients, this makes it hard to even guess where the valid science lies and what to believe.

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Low cholesterol levels and premature babies

Amidst all the media attention on keeping our cholesterol levels low and the promotions for widespread use of statins — leading many to believe they’re as safe as aspirin — we seldom hear about studies suggesting risks associated with low cholesterol. A study published last month in the journal Pediatrics highlighted a special concern for girls and women of childbearing age and for the health of newborn babies.

JFS has looked at some of the research showing why many doctors are recommending women of child-bearing age avoid statins. Not only have such cholesterol-lowering drugs been shown to have little efficacy for preventing heart disease deaths in women, but they are beginning to be associated with incidences of birth defects. Yet, a surprising number of doctors are unaware female patients shouldn’t be on statins, said Dr. Malcolm Kendrick. “Cholesterol is essential for the development of neural tissue,” he explained. So if a mother is taking a drug that inhibits cholesterol synthesis at a time when the fetus is developing, there could be increased risks for developmental abnormalities of the brain or nervous system.

A recent University of Pittsburgh Medical Center study cautioned that many women aren’t being warned about possible risks to their unborn babies when taking certain prescription medications, such as statins, making it important for women to be proactive in seeking information.

This latest study wasn’t about statins, but tried to examine cholesterol levels themselves and the relationships to premature and underweight babies. While this was an epidemiological study and, like all such preliminary studies, its results need to be viewed with caution and confirmed in further research, compared to the avalanche of daily epidemiological studies in the news, it received surprisingly little attention, especially given its possible significance.

Researchers, led by Dr. Robin J. Edison, M.D., MPH, at the National Human Genome Research Institute of the National Institutes of Health at Bethesda, Maryland, said that optimal cholesterol levels for women of childbearing age are not known, nor are potential risks to pregnancies. What is known, they reported, is that LDL-cholesterol is the chief substrate for placental progesterone biosynthesis, that cholesterol is critical for implantation and uteroplacental vascularization, and that low cholesterol levels in mothers have been reported associated with intrauterine growth retardation in the developing fetus. They hypothesized that low maternal cholesterol levels during early pregnancy may be associated with adverse pregnancy outcomes.

They examined the health records of nearly 10,000 women who had had routine prenatal care at western South Carolina prenatal clinics during 1996-2001 and given birth to live babies. To isolate cholesterol from other known confounding factors associated with pregnancy-related problems, they excluded teens and older ages, smokers, women with serious illnesses or substance use, twins, and (pre-pregnancy) diabetics. Overall, their cohort of 1,058 women, age 21-34 years of age, was healthier, of lower risk for pregnancy-related problems, and experienced considerably fewer preterm deliveries than the general population. In excluding mothers under age 21 and smokers, they also eliminated most of those with low cholesterol levels, meaning this study’s findings are likely underestimations and cannot be generalized.

The researchers also tried to carefully isolate the mothers’ inherent cholesterol levels from the natural increases in LDL-cholesterol and total cholesterol levels that occur during the second and third trimesters. They used the mean levels at 17.6 weeks gestation and performed three levels of analysis.

Their findings?

Even among this low-risk cohort, prevalence of preterm delivery among mothers with low blood total cholesterol levels was 12.7% to 16.2% (<10th percentile and <3rd percentile, respectively) compared with 5.0% among the control group with mid-range cholesterol levels. Low serum cholesterol was associated with triple the risk for premature babies.

The risks were strikingly higher for white mothers. Prevalence of preterm babies among white mothers with low total cholesterol levels was 21% to 28.6%, compared to 5% in midrange cholesterol levels. Low cholesterol levels among white mothers was associated with nearly 6- to 8-fold higher risks for preterm babies compared to controls. [OR=5.63 for total cholesterol < 10th percentile; OR=7.69 for cholesterol levels < 3rd percentile].

The risks for preterm babies associated with the highest maternal cholesterol levels were elevated over controls, but paled in comparison to those associated with low cholesterol.

These researchers were admirably cautious and careful in their analyses, noting untenable associations. In doing so, their other hypotheses were not confirmed:

· Low cholesterol levels were consistently associated with low birthweight babies, however the risks were only statistically significant among the lowest cholesterol levels (<3rd percentile) with a nearly a 3-fold increased risk. And among the mothers with the highest cholesterol levels, there was an insignificant 10% lower risk for SGA babies. “Low maternal weight was the most significant predictor of low birthweight for gestational age,” they wrote.

· Microcephaly was over 2.5 times more prevalent among babies born to mothers with low cholesterol levels, and 3.4 times as high among the white mothers. But these findings were not confirmed statistically, they wrote. There were no increased risks at all for microcephaly among the mothers with the highest cholesterol levels. Overall, low cholesterol levels “were no more likely than control pregnancies to produce an infant with a congenital anomaly.”

They concluded that low total cholesterols were strongly associated with preterm delivery among otherwise low-risk white mothers in this pilot study. They proposed future research of questions raised in their study:

Although low serum cholesterol level is known to be correlated with poor nutritional status, there was no correlation between maternal total cholesterol and maternal weight in this cohort. However, micronutrient deficiencies may be more common among the low-total cholesterol risk group studied here and could account for the observed adverse outcomes. Many such nutritional deficiencies have been studied as predictors of preterm delivery or low birthweight. Why any of these potential mechanisms might manifest among white but not black mothers would be critical to address should these findings be replicated. By contrast, the extremely high risk ratios observed among mothers with total cholesterol below the third population percentile suggests a severe and persistent dyslipidemia, which might exert complex effects throughout pregnancy.

So, low cholesterol levels proved to be strongly associated with premature babies in this study, but these correlations don’t tell us what the real causes for low cholesterol-related risks might be. Regrettably, they made the common mistake of equating mothers' body weights with diet and nutritional status, and while they didn’t examine nutritional status or eating behaviors among the women, they did note that low cholesterol levels have been correlated to poor nutritional status in other studies. Since they didn’t explore that, let’s look at a few earlier studies that might help lead to an explanation.

Israeli researchers attempting to determine the etiology of low serum cholesterols (total, LDL and HDL-cholesterol levels) found that they were associated with chronic anemias, notably anemias with high-erythropoietic activity. While they suggested a role of genetics for these disorders, could diet-induced anemias also adversely affect cholesterol levels? Iron deficiency is one of the most common causes of anemia.

Undernutrition in American women is found among the high risk populations they excluded from their study (smokers, ill, substance abuse, etc.) and the poorest. But among low-risk populations, it’s most common among those intentionally restricting their food intake trying to lose weight, regardless of whether they’re fat or thin. Black women have generally been more accepting of their bodies and less apt to engage in dieting as much as white women, although that is beginning to change over more recent years since this study, and may perhaps explain why the Black women in their low-risk cohort had fewer preemies compared to the white women.

Iron deficiency is the most common dietary deficiency, most affecting girls and women of childbearing age. Those trying to watch their weight are at highest risk, by eating insufficient calories and avoiding iron-rich foods they believe are fattening.

A 2001 study in the Annals of Clinical & Laboratory Science examined serum lipid profiles and iron depletion among 427 teenage girls and found that total cholesterol levels in the severely anemic girls were two-fold lower than those who weren’t iron deficient. With iron supplementation, the girls’ lipid levels returned to normal.

But iron supplements can’t overcome dieting. Researchers at the Western Human Nutrition Research Center, Presidio of San Francisco, California, found that dieting itself diminishes iron status — even among obese women getting adequate iron in their foods and from supplements while dieting. They conducted a 21 week calorie-restricted diet study, where all of the foods were prepared for the obese women and the women consumed twice the U.S. Recommended Dietary Allowance for iron (half from food sources and half from an oral supplement). Despite even an iron-rich diet, restricting calories itself, and possible shortfalls of a range of nutrients, significantly reduced their iron status and hematological measures. (The women’s cognitive function and memory also significantly declined, giving further support for the mental decline seen among dieters.)

The research suggests that low cholesterol levels related to dieting and calorie-restrictive eating among women of child-bearing age and the relationship to adverse birth outcomes deserves more attention.

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November 25, 2007

Not today, not ever

What could possibly be harmful about telling young people the importance of ‘healthy’ eating, exercising and maintaining a ‘healthy’ weight? This is often voiced by those who wrongly believe most children are eating poorly, sedentary, ‘too fat’ and heading for an early grave.

A mother addressed this with one of the most heartwrenching, powerful essays I’ve ever read. One I hope everyone will read in its entirety. Her perspective illustrates why children do not need or benefit by more health concerns, no matter how well-intentioned they might seem.

All parents trying to bring up their daughters and sons in an environment that doesn’t promote fixations with body image, food issues and eating disorders, will share the pure terror Harriet Brown felt when her youngest daughter said she was too fat and that her mother didn’t understand. Mrs. Brown does understand, it’s this culture that doesn’t....

Mom, I’m too fat!

These are the words to strike terror into a mother's heart, especially if you've ever dealt with anorexia or bulimia in your house. Every child or teen with an eating disorder says these words at one time or another. They reflect the delusion at the heart of an eating disorder, the distorted perceptions of her/his own body and the anguish caused by those distortions. I heard them many times in the year my older daughter was sick with anorexia. But this time, this weekend, they were uttered by my younger daughter....

I do know that seventh grade girls diet. A lot. And that they talk about their diets. And they talk, as young women (and some young men) do, about how fat they are. They talk about how fat their butts and thighs and stomachs are. I know these kids.... They look no different from kids of my generation, except that maybe they're a little taller....

To those advocating ‘healthy eating’ and other initiatives in the name of childhood obesity, the reality for our children is far from healthy.

They're bombarded at school with hysteria warnings about body fat and obesity and unhealthy eating. They are forced to watch Supersize Me. They are weighed and their BMIs calculated, in front of other children. Their body fat is “measured" (however inaccurately) with calipers, all in front of other children. They are taught that there's good food and bad food, that some foods are unhealthy, that some bodies are unacceptable. They're taught that you can never strive hard enough to be thin, to exercise, to avoid certain foods....

Maybe if they grew up in a culture that wasn't obsessed by issues of weight and body size and shape, [some of them] would pass through the dangerous time of adolescence without ever developing an [eating disorder]. If they grew up in a culture where it was OK to be who you are — fat or thin, intellectual or street-savvy, funny or serious — they would come out of adolescence loving themselves, not hating who they are.

She goes on to write about the still-fresh memories of what her older daughter went through and all of the things she’ll now be watching like a hawk in her youngest, with the “determination to do whatever it takes to save her if she is in fact in danger.” She wishes for a culture that supported parents like her, rather than fought them. "But in this culture and time, to advocate for, as Ellyn Satter says, a 'joyful relationship with food,'" she writes, is to be perceived as a nutcase by mainstream.

It takes a strong child advocate to say: “I don't care what the powers that be think. I care only about my children, and other people's children.”

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November 23, 2007

Crystal balls and “forward looking statements”

This past week, the financial news reported that retirement investors had sadly been taken in by the “forward looking” statements** released by a drug company projecting enormous profit potentials for a revolutionary weight loss drug in development.

The press statements, like the glowing media reports taken from them, were marketing, of course. A critical look at the actual clinical trial evidence on the drug, the medical literature and the history of every diet drug to date, demonstrated a far less optimistic picture. This is another tragic illustration of why it is important to look critically at the health information we hear, to understand science and go to the original sources to examine the actual study data for ourselves. Basing decisions on the interpretations presented in an abstract, medical meeting or press release can cost more than our savings, but possibly even jeopardize our lives and well-being.

More recent developments are leading to this drug being considered as a treatment for diabetes, heart disease and ‘metabolic syndrome,’ with far more enormous potential profits at stake. The promotions have already begun in the media and literature, making an understanding of the clinical evidence of special importance.

Concerning those investors, the lawyers and courts will battle their case out. They have a law firm, Coughlin Stoia Geller Rudman & Robbins LLP — one with 180 lawyers who’ve successfully won more than $45 billion in aggregate recoveries on behalf of investors — and have filed a class action lawsuit against Sanofi-Aventis, the third largest pharmaceutical company in the world. The complaint filed on November 13 with U.S. District Court, southern district of New York, states that:

[Sanofi] made false and misleading statements and engaged in a scheme to deceive the market and a course of conduct that artificially inflated Sanofi’s stock price and operated as a fraud or deceit on class period purchasers of Sanofi stock by misrepresenting the company’s business.

Their case charges that they weren’t told that Acomplia® (rimonabant, aka Zimulti, Slimona) increases depression. After the FDA Endocrinologic and Metabolic Drugs Advisory Committee’s decision to not recommend Acomplia for approval on June 13, 2007, the company's stock price dropped like a rock.

Coincidentally this past week, a review of the clinical trials looking at Acomplia’s efficacy and safety, was published in the journal Lancet. In this article, Danish researchers, led by Robin Christensen of the Parker Institute, Musculoskeletal Statistics Unit, Frederiksberg, looked at the data on the four randomized, controlled trials that had compared the full dose of Acomplia (20-mg) to placebo. They found that the patients on Acomplia were 2.5 times as likely to have depression and 3 times as like to have anxiety (as measured on the Hospital Anxiety and Depression Scale) that was so severe they had to be taken off of the trial by the investigators.

In an editorial in this same issue of Lancet, doctors at the University of New South Wales wrote that these findings “provide compelling evidence that rimonabant is associated with development of severe adverse psychiatric events.”

These findings are especially striking since people who had a history of serious depression or other psychiatric illnesses had been excluded before study entry,” the editorial noted. Part of the clinical trial protocols mandated that patients, who had been carefully selected before they were eligible to participate, be taken off the trial if they developed a need for antidepressant treatment.

Sanofi’s latest press statement contended that in this review, “extrapolation of certain data appears to us to be the sole result of the authors’ opinions.”

These authors’ conclusions, however, were far more than their opinions. The full dose of Acomplia has been shown in every published clinical trial sponsored by the drug company — as well as several meta-analyses and expert reviews — to be consistently associated with increased risks for serious psychiatric side effects, suicide ideation, depression and anxiety compared to those taking a placebo, as well as having a clear biological explanation. Similarly, the potential health benefits seen to date haven’t been much to write home about, either. The findings of this latest analysis, however, don’t begin to tell the full story.

So, let’s start from the top.

Brief background overview

Last December, as you may remember, the media was saturated with stories of this new “miracle weight loss drug.” Dr. Lou Aronne, M.D., one of the primary investigators for RIO-North America, featured prominently on CBS. It was part of the company’s marketing efforts in anticipation of FDA approval this spring and where JFS picked up the story as a new blog. But the saga began years earlier.

Sanofi-Aventis had submitted an Investigational New Drug application to the FDA Division of Metabolism and Endocrinology Products (DMEP) in May 1999 to begin exploring use of Acomplia in humans.

As a selective cannabinoid CB1 receptor antagonist, it was initially pursued as a treatment for nicotine dependence and other addictive behaviors in humans, as it appeared to suppress cravings for nicotine and food in rodents. Three randomized controlled clinical trials on humans were conducted, examining its efficacy for nicotine dependence and smoking cessation: the STRATUS studies (Studies with Rimonabant and Tobacco use): STRATUS-US and STRATUS-EU were 10-week studies and STRATUS-WW was a one-year study. The results have never been published, even years later, but were only presented as abstracts, posters or oral presentations at scientific meetings. However, in a review of Acomplia for the American Heart Association, published last year in the journal Circulation, Kishore M. Gadde, M.D., David B. Allison, Ph.D., concluded: “Abstinence rates in these RTCs [randomized controlled trials] were not highly impressive.” On February 17, 2006, Sanofi reported that the FDA had issued a nonapproval letter for use of Acomplia for smoking cessation.

With that dead end, Sanofi submitted a New Drug Application in April 2005 for Acomplia as a weight loss drug, as well as a treatment for type 2 diabetes, dyslipidemia and metabolic syndrome. According to the FDA, this application was accompanied by data from 36 Phase I studies, 5 Phase II studies, and 8 Phase III studies. [The phases of studies were explained here.] Only four completed Phase III trials were submitted. These were the ones that have been conducted on Acomplia for weight loss to date: the RIOs (Rimonabant In Obesity) — RIO-North America, RIO-Europe, RIO-Lipids and RIO-Diabetes.

The FDA Endocrine and Metabolic Drugs Advisory Committee met on June 13, 2007 to review the safety and efficacy data and make recommendations to the FDA before its final ruling on Acomplia for weight loss, scheduled for the following month. The FDA advisory panel did not recommend Acomplia for approval, citing safety concerns that the risks for adverse psychiatric effects outweighed its benefits for weight loss. In fact, the FDA Advisory Committee also said, based on the efficacy data from the RIO trials, they did not believe that the data “should be viewed as supporting a specific indication for rimonabant as a primary treatment of type 2 diabetes, dyslipidemia, or the metabolic syndrome,” either.

Sanofi quickly withdrew its FDA application before the FDA final ruling. By withdrawing their application, they could avoid outright rejection of the drug by the FDA and would be able to modify their application and come back and try again. In fact, they are currently working to develop a case for rimonabant as a treatment for diabetes, cardiovascular disease and metabolic syndrome. There are Phase III trials underway involving cardiovascular disease (CRESCENDO, AUDITOR, STRADIVARIUS, VICTORIA and ADAGIO-Lipids) and type 2 diabetes (SERENADE, ARPEGGIO and RAPSODI).

JFS looked at RIO-North America as an example, but all of the RIO trials shared similar methodological concerns that are important to understand so that we can more accurately understand why the risks reported by several meta-analyses and expert reviews — including the American Heart Association, Cochrane, the FDA, and the Europe Medicines Agency — actually went so far as to note that the studies likely underestimate the adverse effects and overstate the benefits. Let’s take a critical look at the RIOs.

A few of the major design and methodological concerns

1. Short-term trial period. The duration of any weight loss study needs to be long enough to demonstrate effectiveness for weight loss, meaning go beyond the period of inevitable weight regain. A study also needs to be long enough to determine if the associated changes in health indices (seen during any type of weight loss) hold and to enable reviewers to weigh the long-term complications seen after weight rebound. Most studies, however, stop before these adverse outcomes manifest themselves. As all experts and scientific reviews of the clinical evidence of weight loss products and diets — including the National Institutes of Health, U.S. Preventive Service Task Force, National Academies of Science and the Federal Trade Commission — have concluded, weight regain by year five is the rule, not the exception, and any weight loss intervention under five years cannot be taken as credible evidence for effectiveness.

The RIO trials were only one and two years.

As the FDA Advisory Committee said:

[T]he FDA now seeks demonstration of long-term efficacy with the recognition that patients regain weight quickly after stopping these drugs and that no significant long-term health benefits may be achievable with short-term treatment of obesity.

The Cochrane review of the randomized clinical trials evaluating full dose Acomplia for weight loss compared to a placebo, published on October 18, 2006, found that Acomplia “caused significant more adverse effects both of general and serious nature, especially of nervous system, psychiatric or gastro-intestinal origin.” It also concluded that the reported effects on weight, blood lipids (cholesterol) and blood pressure were not “clinically relevant.” It added:

The observed results should be interpreted with some caution, since the evaluated studies presented some deficiencies in methodological quality. Studies with longer follow-ups after the end of treatment and of more rigorous quality should be done before definitive recommendations can be made regarding the role of this new medication in the management of overweight or obese patients.

2. Extraordinarily high drop-out rates and numbers lost in followup. When a clinical trial has high attrition rates, it is easier to make the treatments appear more effective and with fewer side effects. Most people participating in clinical trials are highly motivated — this would be especially true for a drug promising miracle weight loss, as most obese people have desperately tried every weight loss treatment imaginable — and most who drop out of trials do so because the treatment isn’t working and/or the side effects are so unpleasant they can’t continue. Many researchers will also employ “last observed carried forward” in their statistical analysis, which is especially flawed in weight loss studies as it enables them to show patients maintaining weight loss and their initially improved health indices, rather than the inevitable rebounds with long-term follow-up.

In RIO-North America, for example, the Sanofi researchers started with 1,222 patients in the arm receiving the full 20-mg dose, yet only were able to report on 323 of them left at year two. That’s a mere 26% who completed the study arm!

Similarly, only 67% completed the full-dose arm of RIO-Diabetes at one year.

Overall, only 44.7% of the 2,2176 participants in the full dose arms in all of the RIO trials completed the studies.

There is another reason that attrition and how the RIO results were reported would make the psychiatric and other adverse effects reported likely to be underestimations. The Lancet meta-analyses explained that those on the full dose were 2.5 times more likely to discontinue because of depression and 3 times more likely to stop because of anxiety than a placebo. BUT, these refer only to the serious adverse reactions for which a reason was recorded by the investigators. These “Adverse Events” were those where the researchers took the participants off of the study because, most often, the severity of their side effects made them ineligible to continue per the trial protocol — such as needing treatment for depression or psychiatric problems. These adverse events with known explanations made up less than half (47.7%) of all those who dropped out of the RIO trials.

Of the others in the treatment group who didn’t complete the RIO trials:

33% requested to leave (the investigators didn’t reveal the participants’ reasons)

7% were “lost in follow-up”

6% stopped taking the trial drug (the investigators didn’t reveal their reasons)

4% left because it wasn’t working

2% other reasons (not described)

The big unanswered question is why over half of the participants in the RIO trials dropped out. Several independent reviewers have been highly critical of these trials because no efforts were made to follow-up and evaluate the long-term weight changes, health indices or determine why so many didn’t complete these studies. “It is a mystery to me why they don’t make a more concerted effort to measure the people who dropped out,” said Dr. Denise Simons-Morton, Director of the Clinical Applications and Prevention Program, Division of Epidemiology and Clinical Applications at the U.S. National Heart, Lung, and Blood Institute.

3. Designing a trial that isn’t a “fair test” of the intervention. As in most pharmacological weight loss studies, the drugs are almost always tested in combination with diet and exercise. So, it’s impossible to reliably estimate the changes due to the drug versus caloric restrictions or exercise. As the American Heart Association Acomplia reviewers noted, “in the absence of these ancillary interventions and the structure of a clinical trial, one would suspect that these drugs might be even less effective in real-life clinical practice settings than in clinical trials.”

The Lancet reviewers expressed similar concerns, adding that the “intensity and the enforcement of the restriction in calories in the RIO programme was fairly weak, and produced only modest weight loss of less than 2 kg in the placebo groups.” The weight loss attributed to Acomplia would be considerably less in a more calorie-restricted cohort, meaning “the additional weight loss produced by rimonabant would probably be less than that we reported.”

Similarly, the health indice changes attributed to Acomplia, when lumped with a diet and exercise program resulting in temporary weight loss, are also questionable. In RIO-Diabetes, for example, the full dose over placebo showed an absolute (actual) 0.7% fall in HbA1c, in the context of weight loss. This resulted “in the intriguing claim by the researchers that 57% of this improvement (together with an improvement of much the same size in the concentration of HDL cholesterol) was independent of weight loss,” wrote doctors Stephen J Cleland and Naveed Sattar in a Lancet editorial review of the study. However, they cautioned:

the effect of rimonabant over-and-above weight loss merits closer scrutiny, because these data were generated by a statistical model that will be difficult to follow for most readers and which might have made invalid assumptions, including a disregard of weight loss in the run-in period.

The same caveats are likely in order for the other Acomplia diabetes studies. Sanofi press releases have already been reporting, before the SERENADE study has been published, that Acomplia “significantly” lowered HbA1c levels by 0.5% over placebo.

4. Use of false surrogate endpoints versus report actual clinical outcomes or mortality data. There are a number of health indices (serum glucose, cholesterol levels, and blood pressure) that change during weight loss, as they do with serious stresses and illnesses. But, these health indices are also well-known to rebound, often reaching higher levels, after the weight loss intervention has been stopped.

The average weight lost at one year among all four of the RIO trials was 10.3 pounds among those taking the full dose over those on a placebo. (The FDA found the 5-mg dose not effective at all for weight loss.) That’s 0.19 pound a week attributed to Acomplia. But, like all weight loss studies, the RIO trials show striking regains nearly to baseline among the two-year data reported. “No follow-ups were reported after discontinuation of active treatment, thus any [additional] weight regain could not be assessed,” said the Lancet reviewers.

Why the FDA Advisory Committee found no support among the RIO trial data for Acomplia as a treatment for type 2 diabetes, dyslipidemia, or the metabolic syndrome is also clearer when one looks at the actual trial data. As the American Heart Association reviewers noted, not only was the weight loss efficacy no better than the modest effects observed with other anti-obesity drugs; in all four RIO trials, Acomplia “led to a negligible reduction in systolic blood pressure...no reductions in total cholesterol or LDL-cholesterol...The National Cholesterol Education Program guidelines emphasize that lowering LDL-C is of primary importance in reducing cardiovascular morbidity and mortality.”

RIO-Diabetes, for example, enrolled 1,047 diabetics with stable weight (BMIs 27- 40) who had required medications (metformin or sulphonylurea) for at least 6 months. Among the two-thirds who completed the one-year intervention period on the full dose, compared to the placebo group, actual total cholesterols changed 0.06 mmol/L, LDL-cholesterol 0.04 mmol/L, fasting insulin lowered 0.3 µIU/mL, and HbA1c fell 0.7%. There was no change in the numbers diagnosed with metabolic syndrome, with 26% showing improvement and 27% developing metabolic syndrome.

The drug also did not show any benefits on diabetes medication needs, concluded the FDA Advisory Committee. No changes were seen among 75.9% among the intervention group, 11.3% needed increased medications and 11.9% saw dosages lowered.

Adverse effects — how significant are the psychiatric and neurological side effects?

Earlier this year, Acomplia was turned down for reimbursement by health insurance in Germany, the European Union’s largest market. It also failed to get approval for reimbursement as a weight loss drug in France. The European Medicines Agency has allowed Acomplia to be on the market, but their review found it doubled risks for depression “in all types of patients,” leading to the addition of strong warning labels and mandating that it “must no longer be used in patients [taking antidepressants].” In the U.K, since Acomplia’s release in June 2006, 364 psychiatric reactions have been reported, the Department of Health's Medicines and Healthcare Products Regulatory Agency (MHRA) said on July 19th.

The most comprehensive review of the adverse reactions seen in the preclinical and clinical evidence on Acomplia was done by the FDA Endocrinologic and Metabolic Drugs Advisory Committee. Its 88-page Briefing Document concluded:

Among the most significant adverse events throughout the Phase 3 program were those in the primary System Organ Class Psychiatric Disorders, specifically depressive events, anxiety, psychomotor agitation, and sleep disorders. In the pooled RIO studies, for subjects receiving the same treatment during the whole study, 26% of rimonabant 20-mg treated subjects vs. 14% of placebo treated subjects experienced a psychiatric symptom reported as an adverse event. Specifically, 9% of rimonabant 20-mg treated subjects vs. 5% of placebo treated subjects reported symptoms of depression (depressed mood; depression; depressive symptom; or major depression).

Neurological symptoms “appeared commonly” in the clinical studies and were more frequent among those receiving the full dose compared to placebo, noted the FDA. These included sensory changes, motor impairments, and cognitive difficulties, but the trial reports didn’t characterize them well or evaluate them in detail. “Motor impairment occurred with greater frequency in the rimonabant 20-mg group than in the placebo group – 1.7% and 0.12%, respectively – and was driven predominantly by 'tremor' and 'balance disorder.'" Neurological disorders were seen in 14.3% of the Rio treatment participants compared to 9.4% in placebo; and mental impairment and memory problems were reported in 2.1%, compared to 1.3% in placebo. “In RIO-Diabetes and in SERENADE,” the FDA said, “approximately 5% of rimonabant 20-mg treated subjects vs. 1.2% of placebo treated patients experienced paresthesia, dysaesthesia, or hypoaesthesia.”

Sanofi had been asked by the DMEP to submit additional data on specific psychiatric events. Adverse event reports forms don’t record multiple symptoms when they occur, and the additional data proved by Sanofi, said the FDA, “included 155 additional symptoms associated with depressed mood disorders and 208 additional symptoms of anxiety disorders in subjects receiving rimonabant 20-mg versus 49 and 51, respectively in the placebo group. Overall, the number of associated symptoms reported by subjects reporting a psychiatric adverse event was 427 in the rimonabant 20-mg treated group and 118 in the placebo-treated group.”

Overall, in the four RIO trials, the relative risks for both psychiatric adverse events and incidence of suicidality in the full dose versus placebo group were 1.9, concluded the FDA Advisory Committee. Relative risks for neurological adverse events were 3.1 among diabetics.

Because of the lack of follow-up of the roughly half of patients who withdrew from the trials needing anti-depressant medications, “the results of the above analyses should be viewed as incomplete at best and at worse as an underestimate of rimonabant’s risk for suicidality,” said the FDA.

The FDA committee also had access to additional safety and adverse event reports for the ongoing trials not yet published. Data from ongoing trials as of December 18, 2006 found 11 cases of suicidality among the treatment group, including one completed suicide, and 6 cases of suicidability among the placebo groups. Since then, the FDA said it has received two additional reports among the treatment group, one of a suicide attempt and another of psychiatric homicidal ideation. “Subsequent to the sponsor’s submission of the safety update in March 2007,” said the FDA, they’ve received three more cases of suicide attempts or ideations among the CRESCENDO trial and another in the RAPSODI trial.

Thus far, there have been two completed suicide deaths among those taking Acomplia – one in RIO-North America and one in the ongoing STRADIVARIUS study.

Both the Lancet reviewers and the FDA caution that these adverse reactions are significant, especially given these cases represent only a fraction of those with known outcomes. These are additionally notable because they were seen among a carefully screened study population that excluded those with depression or a history of depression or psychiatric illness, and will likely underestimate the risks in a real-life setting.

As the Lancet authors concluded their analysis: “Taken together with the recent US Food and Drug Administration finding of increased risk of suicide during treatment with rimonabant, we recommend increased alertness by physicians to these potentially severe psychiatric adverse reactions.”

© 2007 Sandy Szwarc. All rights reserved.

* [from Sanofi press releases]:

Forward Looking Statements

This press release contains forward-looking statements as defined in the Private Securities Litigation Reform Act of 1995. Forward-looking statements are statements that are not historical facts. These statements include financial projections and estimates and their underlying assumptions, statements regarding plans, objectives and expectations with respect to future operations, products and services, and statements regarding future performance. Forward-looking statements are generally identified by the words “expect,” “anticipates,” “believes,” “intends,” “estimates,” “plans” and similar expressions. Although sanofi-aventis’ management believes that the expectations reflected in such forward-looking statements are reasonable, investors are cautioned that forward-looking information and statements are subject to various risks and uncertainties, many of which are difficult to predict and generally beyond the control of sanofi-aventis, that could cause actual results and developments to differ materially from those expressed in, or implied or projected by, the forward-looking information and statements. These risks and uncertainties include those discussed or identified in the public filings with the SEC and the AMF made by sanofi-aventis, including those listed under “Risk Factors” and “Cautionary Statement Regarding Forward-Looking Statements” in sanofi-aventis’ annual report on Form 20-F for the year ended December 31, 2004 [2005, 2006 or 2007, varying by press release date]. Other than as required by applicable law, sanofi-aventis does not undertake any obligation to update or revise any forward-looking information or statements.

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