Perspective on Screening for Sickle Cell Trait in Student Athletes

Today I watched a video, The Student-Athlete with the Sickle Cell Trait, sponsored by the National Collegiate Athletic Association (NCAA) on its website. The 12-minute presentation provides some helpful background on what it means to have sickle cell trait and how awareness of that condition might influence a student’s (or coach’s?) behavior during rigorous conditioning and competitive sports.

“The more medical information we know about our student athletes, the better equipped we are to help keep them safe,” says Mark Richt, Head Coach at the University of Georgia, at around 3 minutes into the clip.

A new NCAA policy mandates screening all Division I college sports participants for sickle cell trait. Not coincidentally, the Sept 9 issue of the New England Journal of Medicine opens with a noteworthy perspective* on this topic. The screening recommendation, effective at the start of this academic year (i.e. now) directly affects more than a few young adults in the U.S.: among nearly 170,000 athletes who’ll be tested this year, it’s expected that several hundred “carriers” will be identified.

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New NY State Law on Information for Women Undergoing Mastectomy

A few days ago, NY State Governor Paterson quietly signed a new public health law* on information and access to breast reconstructive surgery. From the details provided on my state’s Open Legislation website, it seems this took place on August 13.

The purpose of the new law is to assure that all women undergoing mastectomy in NY are told about reconstructive surgery options and that insurance will cover those additional procedures.

What’s curious are two things – first, why so little coverage of this event? It is end-of-summer, I suppose.

But maybe editors and people like me who are educated in medicine and read newspapers are out-of-touch with the fact that many women who have breast cancer – over 200,000 each year in the U.S. – still don’t really know about breast reconstruction during or after cancer treatment. In my community, people read books and ask multiple doctors in second and third opinion before deciding whether to undergo a trans-flap or have implants inserted and then, once electing for implants, attempt a careful review the not-so-current literature on silicone vs. saline…

The reality is that many women, particularly poor women without newspapers or internet access in their homes, don’t know about any of this. They don’t know their insurance covers pretty much all of these options, by law. Now they will, or should as of Jan 1, 2011. Good.

The other curiosity is that a Montefiore Medical Center-affiliated plastic and reconstructive surgeon is said to have authored this bill, which was sponsored by State Senator Ruth Hassell-Thompson. The doctor’s intentions were surely good; he advocated its passage based on the sad case of a single mom who, after undergoing mastectomy and seeing several physicians, still wasn’t aware that she might undergo breast reconstruction. Nonetheless, it’s not surprising that a plastic surgeon in the Bronx cares about this legislation.

There is a dark side to this, unfortunately. Even among the women with good insurance and purportedly top docs, the results of reconstructive breast surgery are sometimes devastating to the women who undergo these procedures. These are no boob-jobs, and there’s widespread misconception about that. So I hope the law, also, might eventually protect women from botched attempts at reconstruction, an under-reported problem that might also be newsworthy.

*addendum – first link above adjusted because the previous url, http://www.cnbc.com/id/38743477 is no longer available, ES 2/14/11

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On Sergey’s Search (for a Cure for Parkinson’s Disease)

This week I brushed up on Parkinson’s disease. What drew me into this mini-review is an informative article, “Sergey’s Search,” that appeared in the July (print) issue of Wired and is now available on-line. The feature, by Thomas Goetz, offers insight on what it’s like to know that you’ve got a genetic disposition to Parkinson’s, details on some enzymes implicated in the illness and, further, considers what might be done to help future patients.

I recommend this article to any of my readers who are interested in genetics, Parkinson’s and/or what some even consider as a new era for health-related research.

There’s a lot to take in –

The Wired story starts with Google co-founder Sergey Brin. A Moscow native and, more recently, a California swimmer, Brin’s got his reasons for concern. He’s got a strong family history, for one thing: the illness has affected both his mother and aunt. It turns out Brin has a genetic disposition to develop the condition because he shares the disease-associated G2019S mutation with his mom. As Goetz explains, this alteration in the DNA segment of the gene encoding LRRK2, a leucine-rich repeat kinase, involves a single-nucleotide switch of an adenine for a guanine.

(I’ll add this, just in case you’re interested: the gene encoding LRRK2, or dardarin, resides at human 12q12 – that’s the long arm of chromosome 12. The G2019S nomenclature indicates that the mutation results in a change at the 2019th amino acid position along the protein’s encoded structure, so that a glycine, normally present, is replaced by a serine molecule at that spot. A fascinating tidbit, news to me today, is that when the gene was first cloned in 2004 the researchers, who’d studied several affected families of Basque origin, called it dardarin, derived from the Basque word dardara, meaning tremor.)

The G2019S mutation is relatively common among Ashkenazi Jews. Still, not all of those who carry the mutation develop the disease, and not all who have the disease have this particular mutation. Other genetic variants have been identified, and it’s not clear exactly how these wreak havoc with LRRK2’s function. Enzymes like LRRK2, a kinase, usually transfer ATP molecules from one protein to another. The presumption is that in Parkinson’s, abnormalities in this enzyme’s function – whether they’re caused by this particular mutation or another – somehow lead to loss of dopamine-producing cells in the brain.

Back to Sergey’s story –

“Brin didn’t panic,” Goetz reports (a point I’d emphasize too). Rather, he was reassured by his mother’s experience and high level of functioning with the disease. She still goes skiing (among other things one’s mother might do), he reasons.

What Brin is doing, along the lines of Goetz’s Decision Tree approach, is cutting his risk as best he can. He exercises regularly, doesn’t smoke, and funds research.

Like other rock star informaticists before him (think of Netscape founder James H. Clarke, who launched Healtheon and Steve Case, who started Revolution Health – these are my examples), Brin is struck by the slow pace of medical investigation:

“Generally the pace of medical research is glacial compared to what I’m used to in the Internet,” Brin says. “We could be looking lots of places and collecting lots of information. And if we see a pattern, that could lead somewhere.”

If only medical research could be more like Google…

Some clinical background:

Parkinson’s, a progressive and often debilitating neurological condition, affects a half million or so people in the U.S. As a practicing as a physician, I cared for many patients who had this illness. Although I would see them for other reasons, it was hard not to notice, and know, the characteristic tremor, rigidity and shuffling walk of those affected. The onset of symptoms is usually insidious, slow and unnerving.

As Goetz indicates, most of what doctors understand about Parkinson’s comes from observing patients in the clinic. Illness emerges, it’s thought, as the number of dopamine-producing cells in the brain diminishes. Dopamine is a neurotransmitter, a molecule that transmits messages between cells or groups of cells within the nervous system. Since around 1967, when the drug Levodopa was first marketed, doctors have prescribed this and other pills for people who have Parkinson’s. While these meds can ameliorate symptoms, these don’t reverse the unstoppable deterioration of body and, ultimately, the mind.

One problem with Parkinson’s research and treatment is that once the disease becomes evident, it’s hard – probably too late – to reverse the loss of dopamine-producing cells. Most people don’t develop symptoms until dopamine production is around 20 percent of normal levels. Now, with the advent of genetic markers and potential to “catch” this disease early on, there’s an opportunity for early intervention.

One promising area for Parkinson’s research:

LRRK2 is a kinase, a kind of enzyme that’s over-active in some cancers. Already, pharmaceutical companies have developed specific kinase inhibitors; a dozen or so are already FDA-approved for treatment of particular cancers, and many more are in the pipeline.

What excites me, in all of this, is the possibility that these drugs might be effective in patients with Parkinson’s disease. And because the same enzyme – LRRK2, or dardarin – is implicated in cases without the particular G2019S mutation, it may be that these drugs would work even in cases that lack this particular genetic feature. (There are examples in oncology, in terms of tumor genetics and responsiveness to targeted drugs, that would support this contention, but that’s just theory for now.) The bottom line, as I see it, is that these new drugs should be carefully tested in clinical trials.

Sergey’s view:

One of the key ideas in Goetz’s piece has to do what he considers and may well be a revolutionary approach to medical research.

…Brin is after a different kind of science altogether. Most Parkinson’s research, like much of medical research, relies on the classic scientific method: hypothesis, analysis, peer review, publication. Brin proposes a different approach, one driven by computational muscle and staggeringly large data sets. It’s a method that draws on his algorithmic sensibility—and Google’s storied faith in computing power…

In what may indeed be a “fourth paradigm” of science, as attributed to the late computer scientist Jim Gray, there’s an inevitable evolution away from hypothesis and toward patterns.

As I understand it, Brin seeks to invert the traditional scientific method by applying Google-size data-mining power to massive and very imperfect data sets in health. Already, he and his colleagues have accomplished this by Google’s Flu Trends, which several years ago beat the CDC to an epidemic’s discovery by two weeks.

You should read this article for yourself, as I’m afraid I can’t adequately describe the potential powers of computational health and science analyses that might be applied to well, pretty much everything in medicine. This goes well beyond a new approach to finding a cure for Parkinson’s disease.

This story, largely based in genomics and computational advances, reflects the power of the human mind, how the gifted son of two mathematicians who fell into a particular medical situation, can use his brains, intellectual and financial resources, and creativity, to at least try to make a difference.

I hope he’s successful!

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Mind over Matter? Don’t Kid Yourself (on Stress and BC)

I learned of a new study implicating stress in reduced breast cancer survival by Twitter. Three days ago, a line in my feed alerted me that CNN’s health blog, “Paging Dr. Gupta,” broke embargo on the soon-to-be-published paper in the journal Clinical Cancer Research. It seems the story – that women who undergo a stress relief program live longer after breast cancer recurrence – couldn’t wait.

“Less stress helps breast cancer patients” is the title of the rushed post. What the researchers, based at Ohio State’s Comprehensive Cancer Center, report is that psychological intervention helps to increase the quality of life and survival among women with recurrent breast cancer.

The intervention at issue is this: weekly, small-group meetings of BC patients for 4 months after their initial surgery and diagnosis. Led by clinical psychologists, the women met 18 times and discussed strategies to reduce stress, improve mood, strengthen social networks, eat better, exercise and adhere to medical treatments.

The current report is an extension of previous findings among an initially larger group of women at the time of BC diagnosis. Then, the researchers randomized 227 patients after surgery, all with stage II or III disease, either to receive the intervention, or not, after an initial psychological assessment and blood tests to check their immune function. The women were overwhelmingly Caucasian, mostly with stage II tumors, well-educated and, for the most part, had ER/PR+ tumors. What the researchers noted was that:

…As predicted, patients receiving the intervention showed significantlowering of anxiety, improvements in perceived social support,improved dietary habits, and reduction in smoking…

In 2008, the same Stress and Immunity Cancer Project investigators reported in the journal Cancer that the psychological intervention reduces BC recurrence and prolongs survival. Here’s where the results become both exciting and suspicious. In 2007, with a median follow-up of 11 years, 62 women (29%) in the initial study had recurrent disease. The proportion among those who’d received the intervention was indeed lower, confirming the authors’ hypothesis that the intervention would help prevent BC from coming back. But the p-value for this difference was 0.034, barely meeting the threshold for statistical significance. Similar results were observed for overall survival among the women who’d attended the group sessions: they had a reduced risk from death with a minimally-significant p-value (0.028) for the difference.

Now, the Ohio group reports on the 62 patients who relapsed. Before going further, I should say that it’s a bummer of a result from a medical perspective and from mine as a BC survivor out at seven years. Group support aside, 44 (71%, yikes!) of the patients with recurrent disease have died with a median time until death (after recurrence) of 2.8 years (range: 0.9 – 11.8 years).

What the authors conclude is that the psychological intervention improved survival after BC recurrence. How the data flowed is this: among the recurrences, there were 33 women who’d been randomized to the assessment only, “A” arm of the original trial and 29 who’d been randomized to the intervention, “I” arm. These numbers were whittled down to 18 patients who could be followed for continued study on the “A” arm and 23 women on the “I” arm. So the total number of women evaluated in this new report is small: just 41 women.

Among those, the women who received the psychological intervention were more likely to survive, with what’s called a hazards ratio of 0.41. Here again the p-value is valid but marginal (p= 0.014). The authors show a very limited amount of data regarding test-tube based studies of natural killer (NK) and T lymphocytes in the different patient groups, and suggest in the paper’s abstract that “immune indices were significantly higher for the intervention arm.”

What would have killed this paper (pardon the verb) had I been a reviewer is this: among the 41 women with recurrent disease, there was a major difference in the treatments they received. According to the “Patients and Methods” section of the paper, in the section on “adherence, chemotherapy dose intensity,” the authors indicate that just 6 of the “A” patients received chemo in the 12 months following the recurrence, while 13 of the “I” patients got chemo in the same period.

My math: only 6 of the 18, or 33 percent of the “A” group (assessment-only) patients received chemo, while 13 of the 23 (56 percent) of the “I” (intervention) patients got chemo in the year after recurrence. That’s a huge difference in medical treatment among a very small number of patients.

My point: the small difference in survival after recurrence among those women who received structured psychological support, years earlier, may be attributable to the prompt chemotherapy they received upon relapse of the cancer. This seems a more plausible explanation than that group therapy-type sessions make a difference in tumor biology or treatment resistance. (Neither outcome is proved by this study.) The difference may also derive from better overall health in the women who initially received the intervention that included advice and support regarding diet, exercise, smoking cessation and medication compliance.

My opinion:

I think there can be tremendous value in psychological support for people with illness of any kind, whether that’s provided casually by supportive families and friends, one-on-one psychotherapy, medication and/or group meetings. And it’s easy to envision that meetings in which women with similar disease situations and concerns get together and discuss coping mechanisms, how to stay healthy, eat better and exercise could have positive effects on overall survival.

But the immune benefits of stress relief, like those presented in David Servan-Schreiber’s like-minded Anti-Cancer, are bogus. There’s no scientific evidence that the sort of NK or T cell changes tested in this study help or hurt breast cancer growth. It’s possible that a revved-up, stress and steroid-driven immune system might help kill cancer cells, or might favor their expansion. It could go either way. The effects of stress steroids on tumors vary and are complex. Prednisone and similar steroids, for example, which resemble the body’s natural stress steroid cortisol, are well-established and effective components of most lymphoma treatment regimens and once were a mainstay of breast cancer treatment. My point is not that the immune system doesn’t affect tumor growth. (I think it can and does.) But the effects are complicated and differ among individuals and according to the specific tumor type.

On linking stress and breast cancer: this argument, which is all that it is in the absence of better data, is patronizing and demeaning to women. It’s the kind of advice we offer children, that if they think and do the right things the outcome will be favorable. Oncology doesn’t work that way. If a woman’s breast cancer comes back, it’s not because she didn’t go to support groups or relax sufficiently. Tumors grow due to inherent, malignant properties of the cancerous cells and other biological factors in the body, such as other illnesses that may, indeed, weaken the immune system or limit a person’s capacity to receive effective treatment.

I’m all for stress reduction, as an aim in itself. But it’s not a cure for cancer.

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About Those Skipped Heart Test Results

Harlem Hospital Center stands just three miles or so north of my home. I know the place from the outside glancing in, as you might upon exiting from the subway station just paces from its open doors. The structure seems like one chamber of its neighborhood’s heart; within a few long blocks’ radii you’ll find rhythms generated in the Abyssinian Baptist Church; readings at the Schomburg Center and artery-clogging cuisine at the West 135th Street IHOP.

So I was saddened to hear about the missed heart studies. Or should I say unmissed? No one noticed when nearly 4,000 cardiac tests went unchecked at the Harlem center, a public hospital managed by the city’s Health and Hospitals Corporation. The skipped beats began sometime in 2007.

According to the Times report, that’s when hospital administrators, hurting perhaps for doctors sufficiently skilled in reading echocardiograms, OK’d a process by which technicians scanning the images would alert the responsible physicians if they noticed abnormalities. Otherwise they stored the results – pictures of the heart’s contractions, wall thickness and size, valves and some large vessels – for review, later.

Usually when a person gets an echocardiogram there’s a reason. Mine, for example, was done before I received a chemotherapy drug, adriamycin that can affect the heart’s function and, another time, before I had a major operation – basically to make sure my heart was strong enough to handle the stress of surgery. Years earlier, I’d had an echo (as doctors sometimes call these tests) to evaluate shortness of breath I experienced while pregnant. I like echocardiograms, as cardiac imaging methods go, although I must admit I find the blobby representations cryptic if not frankly rorschachian. These tests rely on ultrasound, the same technology we routinely use to examine unborn fetuses by projecting and canvassing sound waves. There’s no radioisotope or x-rays. Not even a magnet’s involved.

Echocardiogram reveals 4 heart chambers - adapted from Wikimedia Commons

What generally happens is that after the procedure a doctor, usually a cardiologist, inspects the images and provides a written assessment. Ideally, the test report reflects the reason for doing the procedure. So if a teenage soccer player has an echo to evaluate an episode of fainting on the field, the physician-reviewer would focus on structural heart abnormalities associated with sudden death in some young athletes. Sometimes the studies reveal enlargement of the heart; this can occur in alcoholics, in people with chronic forms of severe anemia like sickle cell disease, and in other conditions. For patients with atrial fibrillation – a disorder in which the heart flutters irregularly – doctors might look to see if there’s clot inside the heart’s walls that might, unmitigated, migrate through the arteries to the brain. Echocardiogram can assess the heart’s condition after a heart attack or in congestive heart failure. They can visualize holes in the heart chamber walls of infants, lapsed valves and more.

The Times story indicates that doctors didn’t review images for over half of the echocardiograms performed at Harlem Hospital since 2007. The medical center, staffed by doctors from Columbia University, had six attending cardiologists and six fellows in 1999, according to the paper. Now the hospital has only three full-time cardiologists and lacks a fellowship program. The hospital runs approximately 2,500 echocardiograms each year. Among those 4,000 patients whose tests went unread, some 200 have died since the time of the procedure. Hospital officials say it’s unlikely that any deaths are attributable to the lapse.

Since the story emerged last week, a squad of doctors has been scrambling to review the images. Heads rolled at Harlem Hospital: the clinical director was fired and the medical director has been demoted. An investigation, led by Dr. John N. Morley of the State Health Department, is underway. The press, or at least my local newspaper, is all over the matter.

So what’s to be learned from this oversight? My take’s two, so far:

1. It appears that at least some physicians working at Harlem Hospital felt it was understaffed and that they were too overworked to meet their clinical responsibilities, and that the administration did not adequately address their concerns. And while Health and Hospitals Corporation has indicated this problem is unique to that particular department – the echo lab – at one hospital, I’m not convinced.

Having worked for years in hospitals where cardiologists, gastroenterologists, hematologists and even pathologists spend much of their time putting out fires, so to speak, it’s scarily easy for me to envision how non-urgent tests could pile up without review. When hospitals operate with money as a bottom line, the difficult work doctors do doesn’t get easier. So we might blame individual physicians for not signing those reports. But I’d take the system to task, and not just at one Harlem hospital.

2. No one’s mentioned the patients’ role in all of this, which seems strange to me. These days, we expect that most patients will enter into discussions with their physicians about what tests they need done. Maybe at a medical center like Harlem Hospital, which serves a relatively poor population, the expectations differ regarding patients’ involvement in medical decisions. But if that is the case, those separate standards reflect another problem – of poor communication between physicians and their patients – equally demanding of our attention.

Lastly, as I’ve said previously here and elsewhere, we waste a lot of medical resources by ordering procedures without thinking. If a person undergoes a medical test there should be a reason for it, sufficient that either the doctor or the patient cares enough to find out the results.

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DNA Comes Home, or Maybe Not

Earlier this month employees at most of 7500 Walgreens pharmacies geared up to stock a new item on their shelves: a saliva sampler for personal genetic testing. On May 11, officials at Pathway Genomics, a San Diego-based biotech firm, announced they’d sell over-the-counter spit kits for around $25 through an arrangement with the retailer. A curious consumer could follow the simple package instructions and send their stuff in a plastic tube, provided in a handy box with pre-paid postage, for DNA analysis.

DNA helix structure (Wikimedia Commons)

Once the sample’s in the lab, the cost of genomics testing depends on what, and how much, you want to know. Pathway offers a variety of options. A pre-pregnancy planning report would check to see if you carry mutations for each of 37 inherited diseases – conditions as varied as beta thalassemia, cystic fibrosis and familial Mediterranean fever – for $179. A profile of tests for genes involved in metabolizing specific drugs, such as Plavix and Coumadin, goes for $79. A vaguer, health conditions panel suggests a propensity to develop particular diseases including Type II diabetes and melanoma. This series runs $179 if purchased separately, but might be had for less through a discounted package rate. A genetics ancestry evaluation lists for $249.

Within two days, after some controversy and a receipt of a letter from the FDA Office of In Vitro Diagnostic Device Evaluation and Safety addressed to James Plante, Founder and CEO of Pathway (dated May 10), Walgreens nixed the plan. Now, Congress wants to know more about direct-to-consumer personal genomics testing. On May 19, the House Committee on Energy and Commerce sent letters to Plante and the CEOs of two major competitors – Navigenics and 23andMe. House Committee Chairman Henry Waxman and colleagues have some questions about how samples are processed and the accuracy of the results:

“The Committee is requesting information from the companies on several aspects of the tests:  How the companies analyze test results to determine consumers’ risk for any conditions, diseases, drug responses, and adverse reactions; the ability of the companies’ genetic testing products to accurately identify any genetic risks; and the companies’ policies for the collection, storage, and processing of individual genetic samples collected from consumers.

The Federal Trade Commission has cautioned consumers about genetic testing kits since 2006.  Still, personal genomics tests are readily through available on-line sales. You can get the 23andMe “DNA Test for Health and Ancestry Information” from the manufacturer or at Amazon.com for $499. Navigenics takes a distinct approach by marketing its genetic tests strictly as a laboratory service for medical practitioners and so, thus far, avoids some rules regarding in vitro diagnostic tools.

New York State, my home, is one region where Walgreens wouldn’t have sold the kits in stores. That’s because of stricter state laws regarding genetic testing.

Dan Vorhaus, writing for the Genomics Law Blog, provides a considered analysis:

At present, whether a genetic test is subject to FDA regulation largely depends on how it is developed and marketed. The literature, as well as current FDA regulatory policy, divides genetic tests into two primary categories:

(i) in vitro diagnostic test kits (also sometimes referred to as IVD kits or, simply, as genetic test kits), which may be sold by their manufacturers directly to consumers, testing laboratories, clinicians or other approved recipients, depending on the device; and

(ii) laboratory developed tests (or LDTs, also sometimes referred to as “home brew” assays), which are not sold directly to the general public or to physicians; rather, a testing service (as opposed to the actual test itself) is marketed, and samples (e.g., of saliva) are collected and submitted to the laboratory for evaluation.

The FDA regulates IVD kits as medical devices…

Up until now personal genomics testing companies have had few constraints, and little profit. What’s clear from the recent news is that we’ll be hearing more about these kits – their manufacture, distribution, accuracy and interpreting results. And that doctors, for our part, have some serious studying to do. Whether the test results go directly to patients, or not, they’re sure to raise many legitimate questions. We’ll need some solid answers about the testing process in itself, besides meaningful responses about what’s found in our DNA.

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A New Nurse Jackie in Preview

Nurse Jackie’s back on TV tonight. I know this because when I logged on to the New York Times this morning her ad flashed right at me, front page and right center. She’s displayed prominently on Huff Po, vanishingly on Dictionary.com. With just a quick search I can’t find her anywhere in the Wall Street Journal. At the LA Times she takes over the screen.

Poster for Nurse Jackie, Season 2

(As an aside, on the shifting nature of medical information, most future readers of this post will not know for sure if what I’ve described about the present on-line positioning of these commercials for TV is true. The same happens in practicing medicine, when clear signs of disease – like abnormal crackles on a lung exam – can be fleeting, leaving no digital or even a film imprint, yet very real. So you’ll have to trust me, or take no value from this depiction.)

For the “facts” on Nurse Jackie you can find her on Showtime’s original website. There, the program promises to continue “its look deep inside the complicated heart and soul of a functioning addict, a loving wife, mother, and a first-class nurse.” I’m curious but must admit that last year I watched only part of one episode and didn’t return.

Back then I was turned off preemptively by the image of Edie Falco looking harsh, white-coated and unsmiling. The syringe and needle in her raised, gloved hand suggested a third finger, or at least that’s how it seemed as we drove past her image, repeatedly, on a giant billboard. That poster was enough for me. I’d spent too much time in hospitals in trust of innumerable nurses to want to see that side of health care delivery.

Also, I liked Edie as Carmela Soprano so much, then fresh in my memory. Why ruin it?

But today she beckons, half-smiling, an aura of pills and syringes above her head. Maybe she’s happy about the health care reform bill’s passage last night, but I don’t think she could have known about that when the photo was taken, or in her TV unreality world, that legislation matters. What’s clear is that Nurse Jackie looks warmer, tired maybe from her work. She’s appears ready to help someone, a stethoscope slung over her neck. Her right arm is raised, like in last year’s pose, but gentler, calmer. It’s no accident the poster heralds a “Holy Shift.”

Back to reality –

This morning I was listening to WNYC while reading the newspaper and eating my healthy breakfast. As I recall, according to a reporter assigned to assess the public’s and health care workers’ response to the health care reform bill among people on the street near Lenox Hill Hospital, in my neighborhood, one individual said she doesn’t really know what to expect from the changes because she gets most of her news from TV. I didn’t catch any more details – if she meant CNN, for example, or Fox or The View – and exactly how and why she found the source limiting.

One thing I did note in the Times, and also on the Kaiser Health News website, both of which provide excellent summaries of the hopefully-real health care changes to come, is that reform won’t even start to happen for the most part until 2014. Meanwhile grows an authentic addiction to the Internet, TV, radio and even some blurry advertisements for information on medicine that people can’t or don’t get elsewhere.

So I’m thinking I should watch Nurse Jackie tonight. Give it another try. Maybe I’ll learn something. And whatever did happen to the House of God?

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The High Cost of Food-Borne Illness, and Some Steps To Avoid These in Your Home

A new report from the “Make our Food Safe” project, based at Georgetown University, makes clear that food-borne illnesses – from bacteria, parasites and a few viruses – are ever-present and costly.

The study, authored by Robert Scharff and funded by the Pew Charitable Trusts, finds that food-borne illnesses tally nearly $152 billion per year. This measure includes some subjectively-measured expenses like pain, suffering and missed work. Even without those, the toll registers above $100 billion – a huge sum, either way.

The main culprits are familiar: salmonella, that commonly reside in uncooked poultry and eggs, sometimes lace vegetables and lately tinge peanut butter, causes some 1.5 million illnesses per year. E coli 0157:H7, a dangerous bacterial strain that turns up disproportionately in ground beef and recently on fresh spinach leaves, is less prevalent but more often damaging; it takes kidneys and sometimes lives.

The Centers for Disease Control (CDC) provides a lot of useful information on its website regarding food safety.

As a doctor, and as a mom, I see this report as a nudge to be mindful in our kitchens, to follow what should be obvious advice from a collectively-conjured grandmother.

1. Before starting to prepare food, wash your hands with soap. Do this again after handling any raw meat, eggs or fish.

2. Keep raw meat, especially poultry, apart from any surfaces where cooked food is placed, stored or served. Cook chicken thoroughly, always.

3. The same goes for eggs.

4. Salad is one of the most dangerous foods we eat. It’s loaded with dirt from the ground. To wash lettuce for salad, let water pass over each leaf and rinse, fully, at least three times. Tomatoes should be handled similarly. Carefully peel carrots, cucumbers and most other vegetables if they’re to be eaten raw.

5. Unpeeled fruits like grapes and berries are handled like vegetables for salad; they’re washed at least three times.

(N.B.: this method of aggressively washing produce 3x is hardly full-proof; it reduces the amount of dirt on the surface of fruits and vegetables but does not completely eliminate germs.)

6. It’s hard, if not impossible, to adequately wash leeks, scallions, potatoes, mushrooms and most other vegetables. These are best washed and then cooked by sautéing, roasting, steaming or another method. The point is to cook with heat – of sufficient duration and intensity – to kill most bacteria, parasites and other germs.

7. Hygiene matters, especially around the kitchen and eating area. It’s a good idea to wipe down the table and kitchen counter surface after each meal.

These are just some suggestions for ways we can reduce the likelihood of being affected by food-borne illness at home. For people whose immune systems are compromised, such as those undergoing chemotherapy, with HIV and some other conditions, there’s reason to take extra care with salad and raw produce.

Knowing what we do about food-borne illnesses can influence choices we make when we eat outside of our homes. For example, in a restaurant, I’ll eat cooked but not raw spinach, because I know how difficult it is to properly wash that vegetable. If I order a burger, I’ll ask that it be very well-done, to minimize the risk from e. coli.

When traveling, I sometimes avoid uncooked fruits and vegetables entirely – but that’s another story.

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Today’s Press on Targeted Therapy for Cancer

Today the NY Times printed the third part of Amy Harmon’s excellent feature on the ups and downs and promise of some clinical trials for cancer. The focus is on a new drug, PLX4032, some people with melanoma who chose to try this experimental agent, and the oncologists who prescribed it to them.

What I like about this story is that, besides offering some insight on the drug itself, it balances the patients’ and doctors’ perspectives; it explains why some people might elect to take a new medication in an early-stage clinical trial and why some physicians push for these protocols because they think it’s best for their patients.

And it provides a window into the world of academic medicine, where doctors’ collaborate among themselves and sometimes with corporations.

Here’s some of what I learned:

PLX4032 is a targeted therapy, a drug that’s designed to interfere with a specific, disease-causing molecular abnormality. It’s a small compound, taken by mouth, manufactured by Plexxikon that alters BRAF activity.

BRAF is a cellular enzyme, or kinase, that normally regulates how cells grow and divide. It’s encoded by an oncogene, a segment of DNA that can cause cancer when overly-expressed.

In most but not nearly all cases of melanoma, and in some other cancer clones, the malignant cells bear a mutated BRAF gene. This change can lead to a perpetually “turned on” state in the cells’ signaling machinery by which they proliferate without control. It’s thought that when PLX4032 works, it does so by blocking BRAF-mediated signaling and growth activity.

Harmon’s piece is long but easy to get through. She covers the human side of the story realistically. Some of the patients she describes with advanced tumors are desperate. The oncologists are, for the most part, hard-working idealists who work tirelessly for their patients.

There are real issues here, as in the setting of most clinical trials. I recommend this series to anyone who contemplates enrolling in a new drug study.

A remarkable point, as reported, is that the patients who ultimately succumbed to melanoma after a long period weren’t angry. As described, they didn’t feel “used” by their doctors or otherwise. Rather, they expressed appreciation. If these reported feelings are representative, that’s a testament to the quality of the care they received on study and, perhaps even more so, to effective communication between the patients and their physicians.

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News on Aspirin After Breast Cancer

There’s some astonishing news on the breast cancer front.

A study published on-line this week in The Journal of Clinical Oncology (JCO) suggests that regular, low-dose aspirin use reduces the risk of recurrence and death from breast cancer among women who’ve had stage I, II or III (non-metastatic) disease.

This is a phenomenal report in three respects:

1. The dramatic results: among women who’ve had breast cancer, regular aspirin use is associated with a reduced risk of recurrence and death from cancer by more than half;

2. The relevance; these findings might affect millions of women living after breast cancer, today;

3. The cost: aspirin is widely available, without patent restriction. Aspirin costs around $5 for 100 tablets, several months’ supply.

About aspirin:

First, a concern that’s cited in the report:

Aspirin is an old and generally safe drug, available over the counter, that can be very dangerous in people with have bleeding problems or low platelets (blood clotting cells). Among women with breast cancer who are actively undergoing chemotherapy, radiation and some other treatments, aspirin use can exacerbate bleeding problems and may be inadvisable.

Anyone who considers taking aspirin should discuss, first, with their doctor if it’s OK.

The study participants reported taking aspirin (acetylsalicylic acid, or ASA in medical parlance) at varying doses and for a variety of reasons. More than a third of the breast cancer survivors used aspirin for heart disease. In that scenario, the typical dose is a baby aspirin (81 milligrams) on most days. Other women reported they took the drug for muscle and joint pains, backaches, headaches and other reasons.

About the study:

The work derives from the Nurses’ Health Study, a three-decades-and-going-strong observational analysis of health among over 238,000 registered nurses.

This particular analysis hones in on 4,164 of those nurses who had non-metastatic breast cancer (BC) found between 1976 and 2002. The investigators monitored these post-breast cancer patients with periodic questionnaires until the time of their death or 2006. It’s a large study, involving some 45,139 person-years.*

About the findings:

Figure 1. Aspirin Use and Relative Risk of Death from Breast Cancer

Aspirin Use, Relative Risk for Death from Breast Cancer

These graphs represent data from “Aspirin Intake and Survival After Breast Cancer,” JCO, Holmes, et al,  published on-line 2/16/10. The data are listed in Tables 2 and 3 of the paper, multivariate analysis, with 1.0 as the relative risk for women who had breast cancer and do not take aspirin (ASA).

Figure 2. Aspirin Use and Relative Risk of Breast Cancer Recurrence

Aspirin Use, Relative Risk of BC Recurrence.

Among BC survivors who reported taking aspirin between 2 and 5 days per week, the chances of dying from breast cancer were 29 percent relative to the baseline (no ASA) group and the odds of BC recurring, 40 percent. In other words,  aspirin use was associated with a 71 percent decline in deaths from breast cancer and a 60 percent drop in the recurrence rate for these women.

For those who ingested aspirin 6 or 7 days per week, the effects were similar: the death rate from cancer was 36 percent and the recurrence rate 57 percent, both significantly reduced in comparison to women who didn’t use aspirin. Among survivors who used 0-1 aspirin tablets per week, there was no measurable effect on either breast cancer recurrence or survival.

The results applied pretty much across the board – to premenopausal and post-menopausal women, to those with Stage I, II, and to a lesser extent, Stage III disease and to survivors with estrogen receptor positive (ER+) and negative (ER-) tumors.

The findings were not anticipated, according to the investigators, because earlier studies failed to show that aspirin prevents breast cancer from developing in the first place. What’s different here, they speculate, is that aspirin inhibits some inflammatory molecules, like prostaglandins or cyclooxygenases. The authors suggest these enzymes promote growth and metastatic spread of tumors that are already present.

Some details:

The study statistics are sound, with good (low) p-values for the aspirin-use trends, meaning that the likelihood of the observations being due to chance is extremely low. There are some limitations: first that the trial was not randomized, and second, that the reported use of aspirin was based on survey data provided by the nurses. But the size of the study, involving more than 4000 women who had breast cancer, the duration of analysis (over decades) and the not-slight differences in results between the treatment groups speak to the significance and potential implications.

—–

*In this analysis, person-years would be defined as the sum, for all women registered in the study, of the years for which they’ve been monitored. For example if 3 women were evaluated, each for 10 years, the study would include 30 person-years of data.

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A Bit More on False Positives, Dec 2009, Part 1

The question of false positives in breast cancer screening – why and how these happen, how often these occur, and how much these cost, in physical, psychological and financial terms – remains a puzzle.

A few weeks ago the New York Times Magazine featured a piece on “Mammogram Math” under the heading “The Way We Live Now.” The author, a mathematics professor, argues that the risks and costs of mammography, though incalculable, outweigh the benefits. The paper printed the article along with a subtitle, “Why evidence-based medicine is actually right and scary” and later published three letters including one truncated response by me.

After a hiatus, I’ve rescanned the literature – just to be sure the question hasn’t been resolved in the past few weeks by a much-needed interdisciplinary team of health care policy experts, economists,  statisticians, surgeons, radiologists, oncologists, nurses and for good measure, perhaps a few breast cancer patients and survivors.

There’s little published progress to report, aside from more hype and theoretical numbers such as I offered in a November essay. So I’ve decided to take the analysis a step further by outlining a tentative framework for thinking about false positives in breast cancer screening.

In a separate post, I will outline a proposed outline for categorizing false positives as they relate to mammography. Why bother, you might ask – wouldn’t it be easier to drop the subject?

Make it go away,” sang Sheryl Crow on her radiation sessions.

Instead, I’ll answer as might a physician and board-certified oncologist who happens to be a BC survivor in her 40s:

To determine the damage done to women by screening mammography (as some claim and refer as evidence) we need establish how often false positives lead, in current practice, to additional procedures such as sonograms (fairly often, but the costs are relatively small), MRIs (less standard and more expensive), breast biopsies (scarier, slightly risky and more valued – how else can a pathologist determine if a woman with a breast lesion has cancer and, in the future, what type of therapy is best) or frankly inappropriate treatments such as chemotherapy for a non-cancerous condition (very damaging and the most costly of all putative false positive outcomes).

These numbers matter. They’re essential to the claim that the risks of breast cancer screening outweigh the benefits.

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Legitimate Concerns and Unfortunate Timing on Radiation from C.T. Scanning

This week’s cancer news features a study in the current issue of the Archives of Internal Medicine, first reported by Reuters:

CHICAGO (Reuters) – Radiation from CT scans done in 2007 will cause 29,000 cancers and kill nearly 15,000 Americans, researchers said on Monday:

…The findings, published in the Archives of Internal Medicine, add to mounting evidence that Americans are overexposed to radiation from diagnostic tests, especially from a specialized kind of X-ray called a computed tomography, or CT, scan.

The risks of radiation from CT scanning will almost certainly add to the current confusion and concerns about the risks of breast cancer screening.

Mammography differs from CT scanning in several important ways:

1. Mammograms involve much less radiation exposure than CT scans.

According to the American Cancer Society, a typical mammogram uses between 0.1 to 0.2 mSV per image. So even if multiple images are taken of each breast, the total dose remains under 1 mSV.

Another source, the Health Physics Society, estimates a dose of 0.7 mSV per mammogram. So if a woman were to have a screening mammogram every other year between the ages of 40 and 49, she’d receive approximately 3.5 mSV in total from those procedures.

By contrast, a single CT scan involves over a 10-fold greater amount of radiation (such as 8 mSV for a CT of the chest, 10 mSV for a CT of the abdomen) according to the Health Physics Society fact sheet.

2. Mammography is well-regulated by the Food and Drug Administration (FDA) and other agencies.

The Mammography Quality Standards Act (MQSA) requires mammography facilities across the nation to meet uniform quality standards. The law, first passed in October, 1992, requires all mammography facilities to 1) be accredited by an FDA-approved accreditation body, 2) be certified by FDA, or its State, as meeting the standards, 3) undergo an annual MQSA inspection, and 4) prominently display the certificate issued by the agency.

3. Women who undergo screening mammograms can control when and where they get this procedure.

Screening mammograms are elective by nature; a woman can choose an accredited screening facility and, in advance, learn something about its reputation and screening methods. Most women between the ages of 40 and 50 are capable of tracking their mammograms, whether they choose to have those annually, biennially, or less often.

Many CT scans are ordered for patients who are in the hospital – a very different sort of circumstance. Many hospitalized patients don’t feel well, don’t understand what’s happening to them and/or lack the needed assertiveness or language skills to ask about a scan before it’s done.

Summary:

Mammography is a relatively safe and highly-regulated procedure in the U.S.  The recent news on risks from radiation in CT scanning should not confound the discussion of breast cancer screening.

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Stats in the News!

False positives have hit the headlines.

Check the New York Times, Wall Street Journal, CNN – they’re everywhere. Even the Ladies’ Home Journal skirts the subject.

The discussion on mammography runs something like this: studies show that cancer screening save few lives. Among women younger than 50 years, there’s a high rate of false positive results. Those misleading tests lead to more imaging procedures such as sonograms and MRIs, additional biopsies and, necessarily, higher screening costs.

Women are ignoring the numbers, choosing reassurance over hard facts. Some say members of the pro-mammogram camp are irrational, even addicted.

The best response is to look carefully at the research findings.

Two recent publications sparked the current controversy: one, a single paper in the Journal of the American Medical Association and the other, a cluster of articles in the most recent Annals of Internal Medicine. Using a variety of research tools, the authors in both journals examine the effectiveness of cancer screening. Here, the investigators consider the risks and benefits of mammography from a medical perspective; they don’t focus on monetary aspects of the issue.

The problem of false positives in mammography is most-fully addressed in the AnnalsScreening for Breast Cancer: An Update for the U.S. Preventive Services Task Force. The authors assess, among other newsworthy subjects (such as the value of breast self-examination) the potential risks and benefits of mammography. In the Results section, they delineate five sorts of mammography-associated harms (see “key question 2a”):

1. Radiation exposure – not a big deal, the exposure level’s low;

2. Pain during procedures – women don’t mind this, at least not too much;

3. Anxiety, distress and other psychological responses – the patronizing terms tell all;

4. False-positive and false-negative mammography results, additional imaging, and biopsies – the subject of this and tomorrow’s posts;

5. Over-diagnosis – this interesting and, in my view, exaggerated issue warrants further discussion.

For now, let’s approach the problem of false positives in mammography (as in #4, above).

What is a false positive?

False positives happen in mammography when the images suggest the presence of a malignancy in a woman who doesn’t have cancer in her breast.

How often do these occur?

To their credit, the Annals authors state clearly: “published data on false-positive and false-negative mammography results, additional imaging, and biopsies that reflect current practices in the United States are limited…”

Before we can establish or even estimate the costs of false positives in screening mammography, medical or economic, we need to better define those and, then, establish the frequency with which they occur.

Turns out, the calculation’s not so simple as you might think.

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A Note on False Positives

A colleague sent me an email about my math. You’re more or less right, he said, but you need to account for the false positives.

I agree with him. (It’s true.)

The problem is, among others, how to present those numbers in the press.

Statistics don’t sell; still, an explanation is due.

In my next full post I’ll consider the meaning of false positives  – their significance and costs –  in the cancer screening debate.

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Another Take on Mammography

In my latest piece, Mammography: a Not-So-Fatalistic View, I outline reasons why the recent task force findings on mammography don’t hold.

Three key issues have escaped the headlines:

1. The expert panel carried out a careful analysis using data that are, necessarily, old;

2. The recommendations don’t apply to digital mammography;

3. Mammograms are not all the same – the quality varies by the methods used and skills of the radiologists who read them.

We need to set the bar higher for mammography. If everyone could have a state-of-the-art mammogram, as I did some years ago, followed by a sonogram to better analyze the tiny abnormalities the radiologist noted (before rushing to biopsy), the stats on cancer screening would be incontrovertible; there would be no debate.

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Getting the Math on Mammograms

The latest news’ focus on the breast cancer screening madness is about money.

So let’s do the math:

First, for argument’s sake, let’s say the U.S. Preventive Services Task Force is right – that to save the life of one woman between the ages of 40 and 49, on average, you’d have to screen some 1903 additional women every year or so for a period of 10 years.

This is, admittedly, a huge assumption; the panel analyzed two decades’ worth of data, some unpublished, involving complex models applied to millions of data points (humans) amassed in imperfectly-collected data sets that vary in size, scope and accuracy.

Next, let’s say the cost of a mammogram is $150, around what Medicare pays (yet another assumption, but we need to keep this simple or we’ll never get a sense of what’s really at stake here).

So if 2000 women (I’m rounding up) undergo annual screening for 10 years, the bill would come to $300 thousand per year, for a total cost of $3 million over a decade.  If those same middle-aged women were to get their mammograms biannually (every other year), the cost would be roughly $1.5 million per life saved.

This, the so-called cost of screening mammography for women between the ages of 40 and 49 (let’s call it “X”), is all over the news in various calculations, some that get closer to the right answer than others.

But what’s the cost of caring for one 45 year old woman with metastatic breast cancer?

Let’s call that amount “Y.”

Even the heartless among us would admit that we need to subtract, X-Y, to determine the financial cost of breast cancer screening to save one middle-aged woman’s life.

An insurance executive might say it’s in the range of $400 thousand, or a million dollars, or maybe even two million, if the woman lives long enough to go in and out of the hospital over the course of five years, undergo multiple surgical procedures, have semi-permanent intravenous catheters inserted and removed, suffer infections from those requiring at-home multi-week courses of intravenous antibiotics, all of this besides, of course, receiving chemotherapy, radiation, hormone treatments, incalculably expensive antibody infusions and newer, targeted therapies, followed by hospice (hopefully) or ICU care in the end.

Quick answer: maybe it’s cost-effective, or nearly so, to do screening mammograms on asymptomatic women in their forties.

But consider –  if the expert panel’s numbers are off just a bit, by as little as one or two more lives saved per 1904 women screened, the insurers could make a profit!

By my calculation, if one additional woman at a cost of, say, $1 million, is saved among the screening group, the provider might break even.  And if three women in the group are saved by the procedure, the decision gets easier…

Now, imagine the technology has advanced, ever so slightly, that another four or five women are saved among the screening lot.

How could anyone, even with a profit motive, elect not to screen those 2000 women?

The truest answer, of course, is that the value of any one person’s life is inconceivably huge.  And that doesn’t even enter into the equation.

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To Screen is Human

Smack in the midst of October-is-breast-cancer-awareness-month, the Journal of the American Medical Association published a provocative article with a low-key title:  “Rethinking Screening for Breast Cancer and Prostate Cancer.”  The authors examined trends in screening, diagnosis and deaths from cancer over two decades, applied theoretical models to the data and found a seemingly disappointing result.

It turns out that standard cancer screening is imperfect.

The subject matters, especially to me.  I’m a medical oncologist and a breast cancer survivor, spared seven years ago from a small, infiltrating ductal carcinoma by one radiologist, an expert physician who noted an abnormality on my first screening mammogram.

The New York Times featured the new findings in a front-page article that elicited over 200 readers’ comments.  Quite a few cheered the frank, non-party line that mammography‘s not all it’s cracked up to be.  Same goes for measuring the prostate specific antigen in men’s blood, a test that sometimes marks for prostate cancer.

Some readers connected the dots between cancer screening, the pharmaceutical industry and physicians’ income.  Because doctors make money by interpreting scans, doing biopsies and giving chemotherapy, perhaps they can’t be trusted to make unbiased recommendations.  Like an aggressive tumor, the story spread everywhere – cable news, NPR, a host of blogs.

Fear, hassle, insurance forms (if you’re lucky), blood tests, anxiety, CAT scans, possibly a cancer diagnosis with attendant surgery, radiation, chemotherapy, nausea and who knows what else ensues.  Yuck.  The toll is huge, even apart from the finances.

The Food and Drug Administration estimates that radiologists perform some 37 million mammograms each year in the United States.  Women undergo 70 percent of those scans for routine screening purposes.  (Doctors order the other 30 percent to evaluate lumps or other signs of cancer that’s already evident.)  My math:  that’s 26 million screening mammograms at, roughly, $100 per scan, for a total cost of $2.6 billion annually.

Compounding the confusion, a few days later the Times ran a related piece highlighting reports that some tumors shrink or even disappear without treatment.  That’s wonderful news, if it’s true.  Perhaps you can skip the mammogram, not find the cancer, and it’ll just go away.

This represents a form of wishful thinking.  Reality check in three points:

1. Prostate cancer is not the same as breast cancer.  You can’t simply lump these together in a study and draw conclusions about testing or treatment for either condition.

2.  Breast cancer is a common and very real cause of death in North America, where each year there are nearly 200,000 new cases and more than 40,000 associated deaths.

3. Mammograms save lives by uncovering tumors when they’re still small enough for surgical removal.

In 2009, there is no known cure for metastatic breast cancer.  A woman’s chances of surviving for five years after she’s found to have a small, localized tumor lie in the 98 percent range; if she’s noted with metastatic disease, those odds hover around 25 percent.

So what’s a woman to do?

Sure, it’s discomfiting to know that screening doesn’t always work.  And for some, it’s disheartening that doctors, insurance companies and x-ray machine makers generate profits by detecting, evaluating and treating cancer.  In case you haven’t been following the health care reform debate, health care’s an imperfect business.

Many will continue to go for annual mammograms, especially in October, and their doctors will, emphatically, recommend that they get those.  And many men will request of their internists, or urologists, or whoever’s taking care of them, that they get a blood test for prostate cancer, “just to be sure.”  Likely, a few more skeptics will opt out of the screening process.

Screening for breast and prostate cancer could be better.  The same applies to pretty much everything in health care, as in any human enterprise.  But it’s the best that we’ve got, for the time being.

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