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by David Tuller
Note: This account draws from interviews, a close reading of a fraction of the 4608 studies that pop up (as of today; yesterday it was 4606) on a PubMed search for "chronic fatigue syndrome," and a review of many pages of government documents–in particular the minutes and testimony from meetings of the Chronic Fatigue Syndrome Advisory Committee to the U.S. Department of Health and Human Services, one of many such panels established to provide guidance to federal health officials. Not much here will be a surprise to anyone who has read the better ME/CFS blogs, or Hillary Johnson's authoritative and prodigiously researched 1996 account, Osler's Web: Inside the Labyrinth of the Chronic Fatigue Syndrome Epidemic. I want to thank Professor Racaniello for letting me invade his space to post this very long story.
David Tuller is coordinator of a new concurrent masters degree in public health and journalism at UC Berkeley. He was a guest on TWiV 119.
In the early 1990s, Mary Schweitzer, a history professor at Villanova University near Philadelphia, suffered through successive bouts of sickness—mononucleosis associated with Epstein-Barr virus, a stomach parasite, repeated episodes of bronchitis. One day, while reviewing student exams in her office, she slumped over and blacked out. Not long after, she received a diagnosis of chronic fatigue syndrome.
In written testimony to a federal advisory committee a few years ago, Dr. Schweitzer described how disabled she eventually became: "On a bad day, I would never get up at all, or would lie in bed curled up under the covers…I experienced pain behind my eyes and in the back of my neck. It felt as if somebody had hit me in the back of the head with a baseball bat, and someone else was trying to unscrew my eyeballs with a pair of pliers."
Over the years, Dr. Schweitzer has tested positive for multiple viruses. She experiences severe lapses in memory, concentration and other cognitive skills. She suffers from "neurally mediated hypotension," a form of low blood pressure arising from nerve dysfunction, which causes nausea, loss of balance, and fainting. Her muscle and joint pain can be intense, and she frequently requires a wheelchair. Her white blood cell counts have been way off; her immune system is often out of whack. She left her position at Villanova because of disability and has been unable to work most of the years since.
Like others with chronic fatigue syndrome, Dr. Schweitzer is used to having her illness ignored, mocked or treated as a manifestation of trauma, depression or hypochondria—not only by doctors, colleagues and strangers but by friends, family members and federal researchers, too. So when the U.S. Centers for Disease Control and Prevention reported last year that people with chronic fatigue syndrome are more likely to suffer from "maladaptive personality features"—in particular from "higher scores on neuroticism" and higher rates of "paranoid, schizoid, avoidant, obsessive-compulsive and depressive personality disorders"—Dr. Schweitzer dismissed the research as "incredibly stupid" but "not surprising." In another recent study, the CDC had reported—also incredibly stupidly, from Dr. Schweitzer's perspective–that childhood trauma, such as sexual or emotional abuse, was a "an important risk factor" for the illness.
For Dr. Schweitzer, other patients and advocates, and much if not all of the non-CDC research community involved with the illness, those two studies symbolize much of what has gone wrong with the agency's research program on chronic fatigue syndrome. As the country's leading public health organization, the CDC has enjoyed remarkable success in the fight against many diseases. But its history with chronic fatigue syndrome, commonly called CFS, is a matter of bitter–and ongoing—dispute.
"We're talking about a million people who are really, really sick with something," said Dr. Schweitzer, 61, in one of a series of recent conversations. "And we have been mistreated for years by people who are convinced that it's just personality disorders or stress or some behavior that we can change and miraculously be well. None of us want to be sick or are doing this to ourselves."
The CDC's mandate is to investigate threats to the health and safety of the population; develop ways to prevent, disable or mitigate those threats; and disseminate key information to the public, policy-makers, health care providers and other audiences. Given those varied responsibilities, the CDC's pronouncements about any topic—in this case, chronic fatigue syndrome–exert an enormous impact on policy, clinical care, insurance reimbursement and public attitudes. Advocates say that when the agency reports that people with CFS suffer from paranoid personality disorder, the public remembers the association, as do other scientists, government officials, health care providers, and insurance adjusters.
In fact, since the CDC first investigated an outbreak of a non-resolving, flu-like illness in the Lake Tahoe area in the mid-1980s, the agency's CFS program has been marked by financial scandal, an epidemiologic strategy rejected as fatally flawed by the top researchers in the field, and the kind of toxic relationship with much of the patient community that can undermine the trust and cooperation needed for effective policy-making and public health strategies. On a more substantive level, over the past quarter-century, the CDC's research program has yielded little or no actionable information about causes, biomarkers, diagnostic tests, or pharmaceutical treatments. Nor has the agency done much to track long-term outcomes–such as cancer rates, heart attacks and suicides–among people with the illness.
The reason for those failures, critics charge, is that the CDC has spent years looking in the wrong places. Starting with its 1988 report on the illness, they say, the agency has downplayed or dismissed abundant evidence that CFS is an organic disease, or cluster of diseases, characterized by severe immune-system and neurological dysfunctions as well as the frequent presence of multiple viral infections. Instead, say the critics, the agency has focused major resources on investigating proposed psychiatric and trauma-related factors and associations–the personality disorder and trauma studies were published, respectively, in the journals Psychotherapy and Psychosomatics and Archives of General Psychiatry–even though stress and trauma make people more vulnerable to any number of health conditions.
Moreover, they charge, the CDC's website on the illness has long been a font of misinformation and has been routinely used by insurance companies to deny legitimate claims for tests ordered by doctors. (After years of complaints from patients and doctors, a paragraph that dismissed the usefulness of many tests, including those for various infectious agents, was finally changed this month.) Critics also note that the CDC website does not incorporate much clinical expertise from doctors who have treated patients for years, but it does highlight a behavioral form of treatment—a gradual increase in exercise, known as "graded exercise therapy"–that is widely discredited in the CFS community. Patient surveys and anecdotal testimony, as well as an increasingly robust body of research, suggest that the therapy might cause severe relapses in CFS patients by encouraging over-exertion.
"The CDC has never taken chronic fatigue syndrome seriously," said San Francisco writer and former psychotherapist Michael Allen, who suffered a severe flu in the early 1990s and has never recovered his health. "They pay lip service to it being a serious physical illness, but in their hearts they think it's just a form of mental illness."
Much of the anger for the CDC's perceived failings over the years has targeted Dr. William Reeves, an epidemiologist and architect of the CFS research program from 1989 until his abrupt move last year to another division of the agency. With his gruff and sometimes dismissive manner, Dr. Reeves was never popular with the patient community, which came to view him as hostile to the search for viral or other organic causes of the illness; many non-CDC researchers echoed that complaint. When it emerged in the late 1990s that the agency had been diverting funds designated for CFS to other programs and then lying to Congress about it, Dr. Reeves—who was in charge of the program while the financial irregularities were taking place–sought and received whistle-blower protection.
Dr. Reeves also enraged the patient community by his refusal to consider changing the much-hated name of the disease—a name endorsed by the CDC in its 1988 paper and aggressively promoted in a public awareness campaign the agency launched in the mid-2000s. Patients say the name, like the term 'yuppie flu,' reinforces stereotypes that they are a bunch of self-entitled whiners and malingerers and that the illness itself is a form of hysteria, the latter-day version of the Victorian malady known as "neurasthenia." That's why many doctors, researchers and patients have long promoted a less-stigmatizing clinical name for the illness that predated the selection of chronic fatigue syndrome: "myalgic encephalomyelitis," or ME, which means "muscle pain with inflammation of the central nervous system."
It is not possible to exaggerate how much patients despise the name and believe it has hindered public understanding—and how much they fault the CDC and Dr. Reeves for championing it. "If they'd hired a focus group to come up with a name that screams 'silly' and 'meaningless,' they couldn't have done a better job than 'chronic fatigue syndrome,'" said Dr. Schweitzer.
In an interview with The New York Times earlier this year, bestselling author Laura Hillenbrand (Seabiscuit, Unbroken), who has lived with CFS for decades, called the name of the illness "condescending" and "so grossly misleading." She added: "The average person who has this disease, before they got it, we were not lazy people; it's very typical that people were Type A and hard, hard workers… Fatigue is what we experience, but it is what a match is to an atomic bomb. This disease leaves people bedridden. I've gone through phases where I couldn't roll over in bed. I couldn't speak. To have it called 'fatigue' is a gross misnomer."
After Dr. Reeves unveiled a revised epidemiologic method for identifying people with CFS, the CDC estimated in 2007 that there were 4 million people in the U.S. with the illness—a remarkable ten-fold increase over the previous CDC estimate in 2003. Other experts dismissed this dramatic rise as an artifact of the agency's poor epidemiology. Subsequent research reported that the new CDC approach misclassified people with primary depression as having chronic fatigue syndrome, when they did not; that kind of misclassification could easily lead to increased prevalence rates as well as false and possibly harmful research results.
In the late 2000s, leading patient, advocacy and scientific organizations engaged in an increasingly public revolt against Dr. Reeves' leadership. In January of 2010, the CDC abruptly appointed him as senior advisor for mental health surveillance in another part of the agency. Dr. Elizabeth Unger, an expert on human papillomavirus who had worked with Dr. Reeves for years, was named to replace him—first temporarily, then permanently–as chief of the Chronic Viral Diseases Branch, which currently houses the chronic fatigue syndrome program.
Now, almost two years after Dr. Reeves' departure, advocates and researchers say they have seen a shift in tone—some believe it is genuine, others not–but so far little change in substance. (Requests to interview both Dr. Reeves and Dr. Unger, conveyed through the CDC media office, were declined; however, with a press officer acting as intermediary, Dr. Unger responded to questions via e-mail.)
"I'm committed to continuing an aggressive program to address the needs of CFS patients and families for quality medical care and to move CFS into the mainstream of public health," wrote Dr. Unger. She added that the agency is developing new materials about CFS for medical and health care professionals, and has contracted for studies that will help clarify questions about how to identify the illness.
Dr. Unger has made a point of meeting with patient, advocacy and scientific organizations. In contrast to her predecessor, she has impressed some advocates and researchers with her willingness to listen to their concerns and seek out joint initiatives. But reflecting a widespread view, one activist (who preferred to remain anonymous) said that "overall, I do not feel much has changed under Dr. Unger…I do look forward to changing my mind, though, if appropriate actions are taken."
Another person with a long history of involvement in the CFS issue offered a similar assessment, noting that Dr. Unger needs to do much more, and do it more quickly, to demonstrate that she's pursuing a different approach. "I think she has got a window of opportunity, but the patient community is only going to give her so long," said this advocate. "She can throw off the Reeves mantle and make a break with the past, or she can maintain the past. But there's not a middle ground here, and she's got to make a decision."
Kim McCleary, president and CEO of the CFIDS Association of America, the oldest organization on the illness, said she believes Dr. Unger "is trying to restore some credibility to the CDC's program." But, added McCleary, whose organization worked closely with Dr. Reeves for years but ultimately opposed his leadership, "she's not going to move quickly, she's not going to do anything bold, she's going to move pretty methodically along a linear path."
Although Dr. Reeves' departure received little public notice, it was a watershed event for patients and advocates, many of whom blame the agency for the prolonged lack of significant progress in CFS research. (They also blame years of inadequate funding from the National Institutes of Health, but that's another long story; it is worth noting, however, that the NIH online database of spending by disease category indicates only $4 to $6 million allocated annually for CFS in recent years, a small amount compared to other illnesses associated with similar levels of morbidity. While the roles of the CDC and NIH can overlap significantly, the NIH generally focuses more on basic research into disease processes than on epidemiology and the development of public health strategies and interventions.)
The personnel shift at the CDC also occurred during a volatile period in the scientific domain. In October 2009, the journal Science published a headline-grabbing study that linked CFS to XMRV, a poorly understood mouse leukemia retrovirus. The finding thrilled the patient community because it appeared to offer a plausible explanation for the disease and to suggest treatment possibilities. Although a second study found links between CFS and a group of mouse leukemia retroviruses related to XMRV, other research has failed to support the proposed association. The Science report was partially retracted earlier this year, and most researchers now believe the initial findings were an artifact of laboratory contamination. Results expected early next year from a large NIH-sponsored study should settle the XMRV issue, although not the issue of whether another retrovirus might eventually be linked to cases of CFS.
(In the meantime, in a bizarre and unsettling turn of events, the senior author of the original XMRV paper, Dr. Judy Mikovits, is engaged in a fierce legal battle with her former employer, the Whittemore Peterson Institute for Neuro-Immune Disease, at the University of Nevada in Reno. The institute sponsored the XMRV research but has accused Dr. Mikovits, its erstwhile star scientist, of stealing laboratory notebooks and other materials—a charge she has denied. Public feuding between the institute and Dr. Mikovits ratcheted up as the hypothesis they jointly championed appeared to be falling apart. The institute filed a lawsuit against her earlier this month; she has also apparently been charged with "possession of stolen property," according to a news update in Science. Last Friday, Dr. Mikovits was arrested in California as a "fugitive from justice" and spent the weekend in jail; she was released on bail after a hearing on Tuesday.)
Nevertheless, the heightened focus on CFS during the past couple of years has brought the illness greater attention from a larger group of scientists, including many infectious disease experts who had not previously given it much thought (e.g. the host of this blog, Columbia University virologist Vincent Racaniello). Experts now believe that one or a combination of viral or other infections, or perhaps other physiologic insults such as environmental toxins, can trigger an immune response that never shuts itself off; the immune response itself is likely the cause of many of the symptoms.
Dr. Racaniello said that when he used to question colleagues about chronic fatigue syndrome, they would argue that it was an imaginary illness. "Every time I asked someone about it, they would say it doesn't exist, it isn't a real disease, even as recently as the past year," he said. "But once you start paying attention and reading papers, this looks like a chronic or hyper-immune activation. These patients have a lot of signs that their immune systems are firing almost constantly." (Note: Dr. Racaniello is on the scientific advisory board of the CFIDS Association of America.)
According to this view, the revved up immune system is actually much less effective at controlling other infections, and studies have found associations between CFS and a grab-bag of pathogens, including members of the herpesvirus, parvovirus, and enterovirus families. Recent research from Norway has also lent support to the hypothesis that at least some people with CFS are suffering from a form of autoimmune disorder, perhaps triggered by one or multiple infections. Neurological impairments are also virtually always part of the complex; a study last year in the journal PLoS One found that people with CFS and a form of Lyme disease have patterns of proteins in their cerebrospinal fluid that clearly distinguish them from each other as well as from healthy controls.
In many cases, additional research has failed to confirm associations from prior studies. Yet there is a reasonable epidemiologic explanation for such divergent results: Most experts believe that there are likely many sub-groups or clusters of CFS patients, with a variety of infectious and possibly environmental exposures; studies that don't account for such distinctions—and most haven't–are much less likely to reach consistent results about causation or treatment. Moreover, different research groups have used different methods of identifying people with chronic fatigue syndrome, making it even harder to compare findings across studies—a situation that can encourage speculation that the roots of the illness lie in patients' psyches.
"This ambiguity over definitions has made it difficult for researchers to pinpoint a biological cause," wrote Leonard Jason, a professor of community psychology at DePaul University in Chicago and an expert in CFS, in an essay published this year in The Wall Street Journal. "When investigators compare very different samples, it is difficult, if not impossible, to replicate findings from one lab to another. And when consistent biological findings do not emerge, investigators might inappropriately conclude that CFS is only a psychiatric problem."
In any event, the most promising research into the disease has been taking place not at the CDC or NIH but at academic medical centers; much of the new work is being funded by private donors who have family members with CFS. Researchers from Stanford, Harvard, University of Miami, Columbia, and other leading institutions are all engaged in innovative efforts focused on pathogenesis, diagnosis and treatment, and in particular on such issues as infectious triggers, biological markers, and medical therapies.
Dr. Derek Enlander, a longtime CFS clinician in New York, recently helped to launch an ME/CFS research and treatment center at Mt. Sinai Hospital; his highly regarded team hopes to explore genetic as well as other factors involved in the illness. The center was founded with the aid of a $1 million private donation, said Dr. Enlander, adding that such outside funding allows the group the freedom to pursue promising avenues of investigation. "I believe that an independent organization such as ours, which is not funded by the government or answerable to the government, can be the leader in new research," said Dr. Enlander.
The Role of Case Definitions
Chronic fatigue syndrome is estimated to afflict about one million people in the U.S., although most remain undiagnosed. Some patients improve over time or have periods of better and worse health, but many remain disabled or even homebound for years. The symptoms include profound exhaustion, especially following minimal exertion, as well as disordered sleep, cognitive impairment, sore throat, and swollen lymph nodes, among others. It is one of a number of so-called "contested illnesses" that have emerged in recent decades to present thorny dilemmas for public policy and medical care; others include chronic Lyme disease, Gulf War syndrome, fibromyalgia, and multiple chemical sensitivity.
These conditions are characterized by shifting patterns of symptoms, a lack of agreed-upon biological markers and diagnostic tests, arguments over the interpretation of evidence, and competing claims of scientific authority. Patients presenting with these illnesses can bedevil doctors, who want to help but have few proven tools at their disposal. They might or might not be willing to try unorthodox strategies; some doctors clearly take advantage of patients who are desperate for relief. Such contested illnesses impact millions of people and their families, cost the U.S. billions in lost productivity, and consume a significant chunk of health care resources—and yet remain poorly understood. With so much at stake, they often emerge as societal and legal battlegrounds, with patients, clinicians, researchers, insurers, health officials and government bureaucrats all seeking to influence and control dialogue, debate and policy.
This conflict often plays out in struggles over a critical epidemiologic tool known as the "case definition"—a set of criteria for research or clinical use that ideally identifies all those who have a condition and screens out all those who don't. Creating a case definition is easiest when a definitive laboratory test exists, as with HIV or hepatitis C. With an illness like CFS that is identified through symptoms, devising a completely accurate case definition is almost impossible; some people with the illness will always fall outside the parameters of the case definition, and some who have some other condition, or nothing at all, will be misdiagnosed—or will self-diagnose–as having CFS. Yet without a case definition that is as accurate as possible, researchers cannot achieve valid or reliable results.
"If you recognize something is happening, you need a case definition so you can count it," Andrew Moss, an emeritus professor of epidemiology at the University of California, San Francisco, and an early AIDS investigator, told me for an article I wrote about case definitions earlier this year. "You need to know whether the numbers are going up or down, or whether treatment and prevention work. And if you have a bad case definition, then it's very difficult to figure out what's going on."
Non-CDC researchers say the problem with the agency's 2005 method for identifying CFS cases is that it mistakenly classifies people with primary depression as having chronic fatigue syndrome instead. Depression and CFS can resemble, overlap and interact with each other in multiple ways; patients with CFS may get very depressed about their situation, and depression often causes fatigue, as can many other ailments. So distinguishing chronic fatigue syndrome from primary depression—in other words, depression that preceded and perhaps caused the fatigue—is important but tricky, and requires nuanced instruments. In epidemiologic studies that conflate the two, treatments that are known to be effective for depression could appear to be effective for chronic fatigue syndrome, even if they might not be.
A case in point is a treatment called "graded exercise therapy," a slow increase in exercise that has been promoted for CFS patients by the British psychiatric, medical, and insurance establishments; it is also highlighted as a treatment option on the CDC's website and educational materials.
There is no dispute that exercise can be a very effective treatment for depression. But people with chronic fatigue syndrome generally suffer from a distinctive symptom known as "post-exertional malaise"—a disproportionate depletion of energy following minimal activity that is not a typical feature of depression. (However, the word 'malaise,' like the word 'fatigue,' is a complete misnomer; post-exertional malaise is much closer to a serious crash or relapse than a Victorian fainting spell.) An emerging field of research—much of it taking place at the University of Utah and University of the Pacific in Stockton, California–indicates that people with CFS suffer from problems with oxygen consumption, energy production and muscle recovery. So it's not surprising that increasing activity levels could lead in some or many cases to a prolonged resurgence of their symptoms rather than the improvement predicted by proponents of graded exercise therapy.
Patients with CFS are very familiar with post-exertional malaise. Many report having recovered for a period of time, then pushing themselves too hard and suffering a devastating set-back, repeating the cycle multiple times before learning to adjust their pace. When Mary Schweitzer experiences post-exertional malaise, she said, she loses her formidable communications skills.
"I get close to incoherent," she wrote in a recent e-mail. "I can't make sense, and nobody can make much sense out of what I say. I am used to it now and try to make a joke out of it, but it's sad." As a result, she wrote, she has learned what people with CFS call 'envelope theory,' based on published work from Dr. Jason's research group at DePaul University: how to harness their energy by recognizing their limits, and not pushing beyond them. That approach is essentially the antithesis of graded exercise therapy.
"You learn what will bring on a crash–sitting upright at a restaurant, for example–and you just don't do it," wrote Dr. Schweitzer. "You live in what we call your 'envelope.' Then if something special comes along like a birthday, you push the envelope, and if you get a push-back, you know you still have the same boundaries."
Like Laura Hillenbrand, Mary Schweitzer is an author (although the book she wrote from her doctoral research at Johns Hopkins, Custom and Contract: Household, Government, and the Economy in Colonial Pennsylvania, has undoubtedly never reached Seabiscuit-y heights in Amazon's rankings). She grew up in Richmond, Virginia; boogied in the mud at Woodstock; wooed her future husband, Bob, with home-cooked lasagna (he was the teaching assistant in an economics course she as an undergraduate at Duke); and was teaching, conducting research, and raising two kids when CFS whacked her life upside down.
Dr. Schweitzer said she could never have managed through the years without the support and devotion of her husband, a professor of finance and economics at the University of Delaware. But she has also improved significantly on intermittent treatment with Ampligen, a drug that appears to be effective for some people with CFS. The drug hasn't been approved by the U.S. Food and Drug Administration, but Dr. Schweitzer currently receives it as part of an ongoing clinical trial. She travels twice a week from her home in Delaware to her doctor's office in Manhattan for infusions of Ampligen; unlike in most clinical trials, she has to pay for the drug, which costs her $16,000 a year.
When off Ampligen, she has suffered major crashes; at one point several years ago, she tested positive for four herpesviruses—Epstein-Barr, cytomegalovirus, HHV-6A, and HHV-7—and Coxsackie B, an enterovirus. Whenever she can, she addresses public forums, in particular the twice-yearly meetings of the Chronic Fatigue Syndrome Advisory Committee, one of many committees created to offer guidance to the U.S. Department of Health and Human Services; she estimates that she has testified to date at thirty hearings, conferences or meetings. When she speaks, in a public forum or one-to-one, she is articulate, passionate, loud, tender, demanding, funny and fierce. In one of her many statements to the federal advisory committee, Dr. Schweitzer described one of her severe relapses.
"I lost the ability to walk normally and we had to bring the wheelchair back up from the basement," she wrote. "I dropped things, and when I tried to load the dishwasher I crashed one glass against another…It made no difference that now I knew the names of the various symptoms–ataxia, expressive aphasia, short-term memory loss, central auditory processing dysfunction, etc. My brain had disappeared."
A Bit of History
The conflict over the nature and definition of CFS–between the CDC and the patient community, as well as between the agency and other researchers–dates back to the initial investigations of an outbreak in Incline Village, Nevada, near Lake Tahoe, of a mysterious illness, possibly associated with Epstein-Barr virus. The outbreak was one of many reports in the mid-80s of what was already being called "chronic Epstein-Barr syndrome" or "chronic mononucleosis." (Epstein-Barr virus causes most cases of mononucleosis).
In its 1988 paper on the illness, a CDC-led team of researchers cast doubt on the Epstein-Barr hypothesis and rechristened the phenomenon "chronic fatigue syndrome" to discourage unproven assumptions about viral origins. (Ironically, because CFS began as a suspected viral illness, the research program has remained housed in the agency's viral section.) The paper proposed a complicated case definition requiring six months of unexplained fatigue, plus either six of eleven "symptom criteria" (mild fever, sore throat, painful lymph nodes, muscle weakness, muscle pain, prolonged fatigue post-exercise, headaches, joint pain, neuropsychological complaints, sleep disturbances, and sudden onset of the illness) and two of three "physical criteria" (fever, sore throat, and palpable or tender lymph nodes, documented by a physician twice, at least one month apart); or eight of the eleven symptom criteria, without the physical criteria.
In retrospect, for many patients the CDC's first big blunder was in not calling the Tahoe illness myalgic encephalomyelitis in the first place. Benign myalgic encephalomyelitis has long been recognized by the World Health Organization as a synonym for "postviral fatigue syndrome," which is listed as a neurological illness. The term was coined to refer to a similar flu-like outbreak at a major London hospital in the 1950s (although "benign" has since dropped out of common usage.) In practice, many patient and advocacy groups now combine the two terms as CFS/ME or ME/CFS, or use ME alone.
Dr. Reeves was not on hand for the original investigation, but joined the CDC in 1989 as chief of what was then called the Viral Exanthems and Herpesvirus Branch. Dr. Reeves received his B.A. in 1965 from the University of California, Berkeley, where his father was a renowned expert in mosquito-borne illnesses and served as dean of Berkeley's School of Public Health; he studied medicine at University of California, San Francisco, earned a masters in epidemiology at the University of Washington, and worked at a major medical research center in Panama for a dozen years before joining the CDC in 1989.
A Harvard-led research team described the Tahoe outbreak in far more serious terms than the 1988 CDC report: the patients, they reported in 1992 in the Annals of Internal Medicine, had abnormal MRI brain scans, significant alterations in white blood cells counts and functioning, and signs of active infection with a recently discovered pathogen, HHV-6. The illness, they wrote, was likely a "chronic, immunologically mediated inflammatory process of the central nervous system."
In a letter to the journal listing more than a dozen purported methodological flaws, the CDC—with Dr. Reeves as the lead author—dismissed the Harvard study and its findings in unusually blunt terms. "We conclude that the disease…described is not the chronic fatigue syndrome or any other clinical entity and that they showed no association with active HHV-6 replication," wrote Dr. Reeves and his colleagues.
A pattern appeared to have been established. In a subsequent episode in the early 1990s, chronicled in detail in Osler's Web, the CDC failed to confirm other researchers' reports of a retroviral link to chronic fatigue syndrome. These and other contradictory results gave rise on both sides to claims and counter-claims and counter-counter-claims (etc.) of methodological flaws, unjustified assumptions, and other scientific sins of omission or commission.
In the early 1990s, a CDC-led team reviewed the complex 1988 case definition and published a revised and somewhat simplified version. According to these 1994 guidelines, a diagnosis of CFS required the presence of six months of disabling, medically unexplained fatigue, along with at least four of eight other symptoms: impaired memory or concentration, disordered or unrestful sleep, muscle pain, joint pain, headache, tender lymph nodes, sore throat, and post-exertional malaise. Although the definition relied on self-reported symptoms rather than biological tests or standardized instruments to measure levels of fatigue and disability, it soon became the most widely used set of criteria in both research and clinical settings.
The Financial Scandal
Two years after the CDC issued its 1994 case definition, Osler's Web was published to strong reviews. The book documented how the CDC routinely diverted money slated for CFS research to other projects because of lack of concern about the illness. (The CDC did not officially comment on the book at the time, according to a CDC spokeswoman.) Two years later, Dr. Reeves leveled similar charges against his superiors, noting that the CDC lied to Congress about how it spent CFS funding; he received whistleblower protection.
In his statement, he reported that, for example, in 1996 the agency spent $1.2 million for laboratory equipment and supplies for measles and polio and charged it to the CFS account. In 1995, he reported, the agency charged the CFS program $2.6 million for funding spent on unrelated studies. He had, he stated "attempted to rectify this within CDC" before going public.
"I believe that CDC has intentionally misrepresented monies allocated to CFS research and I cannot ethically support this," wrote Dr. Reeves in his public statement. "The misrepresentations involve systematically charging between $400,000 and $2 million incurred by unrelated activities to CFS between 1995-97 and reporting to DHHS [Department of Health and Human Services], Congress and patients that the monies were used for CFS research."
A 1999 report from the inspector general of HHS found that of the $22.7 million the CDC charged to its CFS program between 1995 and 1998, less than half was clearly spent on the illness. The report noted: "CDC spent significant portions of CFS funds on the costs of other programs and activities unrelated to CFS and failed to adequately document the relevance of other costs charged to the CFS program…As a result of these inappropriate charges, CDC officials provided inaccurate information to Congress regarding the use of CFS funds."
The inspector general's report found that $8.8 million was spent on non-CFS projects and that the documentation on an additional $4.1 million was so poor that it was impossible to determine whether they were used to support CFS research or not. Even as the CDC shortchanged the CFS program, the report noted, it disregarded Congressional requests to support important research initiatives. As an example, the report noted that Congress had urged the CDC to expand its surveillance of CFS among adolescents and to hire a neuroendocrinologist "to enable expansion of its research efforts and pursue promising findings from other Federal agencies and the private sector."
At the time of the inspector general's report, however, the CDC had halted an ongoing adolescent study and had not hired an endocrinologist—even as allocated money wasn't being spent. The report noted: "Internal correspondence… indicated that delays were forced due to a 'lack of available funds.' Yet, we found that large portions of budgeted CFS funds had been held in reserve by the Division Director during the year, and were not released until after the deadline for obligations had passed. Thus, while important enhancements were not being implemented, more than $850,000 of FY 1998 budgeted funds were never made available to the program."
In the wake of the scandal, Dr. Reeves' boss left his position; the agency agreed to reform its accounting practices and restore more than $12 million to the CFS program over the next several years. Although Dr. Reeves' whistleblower status effectively solidified his position at the CDC, his statement didn't answer all outstanding questions. Given the revelations from Osler's Web in 1996, it seemed unlikely to many patients and advocates that key officials at the agency could have been unaware of accounting irregularities–especially since they apparently continued through 1998, according to the federal investigators.
A subsequent investigation in 2000 from the U.S. General Accounting Office (now called the Government Accountability Office) found that communication between the CDC and the NIH about CFS research programs and priorities was poor. The limited coordination, as well as the CDC misspending, had hampered progress in the search for answers to the illness, the investigators reported.
The financial scandal left many CFS advocates, patients and researchers with a lingering distrust toward the CDC. In the following years, however, some of the CDC's work in chronic fatigue syndrome—funded by the millions restored to the budget–received praise.
In 2003, Dr. Reeves' study of CFS in Wichita, Kansas, yielded a disease prevalence of 235 per 100,000 percent of the adult population, or about 400,000 overall in the U.S. That figure was below the generally accepted estimate of one million sufferers, derived from a community-based study in the Chicago area by Dr. Jason's research group at DePaul University. Yet the new figure was accepted as far more accurate than the agency's earlier estimates, from research in the 1990s, that less than 20,000 people had the illness; that research had been criticized for relying on doctors' reports of patients with CFS, a far less effective epidemiologic method of assessing prevalence than community-based surveys. The Wichita research also provided a sense of the societal burden of CFS; the CDC team reported that the illness cost the economy $9.1 billion a year in lost productivity, and people with CFS lost an average $20,000 annually in earnings.
Also praised was the CDC's partnership with Australian researchers on a study reporting that more than 10 percent of a cohort suffering from acute viral illnesses went on to develop CFS–one of the agency's few successful efforts to document viral links. And in 2006, the CDC published—with great fanfare–a set of 14 studies in the journal Pharmacogenomics, which found significant variations in CFS patients of gene expression and activity related to how the body handles and adapts to physical and emotional challenges and stress.
Much of the research focused on genes associated with the hypothalamic-pituitary-adrenal axis, which regulates the body's stress responses, among other functions. At a press conference introducing the studies, Dr. Reeves outlined his understanding of the illness: "The working hypothesis is that the HPA axis and the brain is a plastic organ which changes its actual physical architecture depending on stresses accumulated over the lifetime," he explained. "So as people experience stress, and that can be childhood abuse, it can be childhood infections, it can be multiple injuries…to some extent the genetics determine how you are going to react to them, they determine how your allostatic load [a stress-related indicator] may accumulate, and more importantly, they actually determine your subsequent reaction to stress applied at a later time during the lifespan."
Dr. Reeves himself declared the illness to be a matter of great public health concern and expressed empathy for patients. "People with CFS are as sick and as functionally impaired as someone with AIDS, with breast cancer, with chronic obstructive pulmonary disease," he told me in 2007, when I wrote my first story about the disease for The New York Times.
Some advocates welcomed the genetics studies for providing evidence that the illness had a biological basis and was not a figment of patients' imaginations. But a news article in Science about the Pharmacogenomics papers reported that other scientists had raised serious methodological questions about the CDC's approach, with one prominent researcher calling the new findings "meaningless." Others in the CFS community feared that the focus on stress and trauma as major factors left the door open for the CDC to focus on a wide range of psychologically and behaviorally oriented approaches in the search for both causes and treatments—and they note the recent personality disorder and childhood abuse studies as proof of their concerns.
The Rejected Empiric Criteria
Other CDC efforts, such as the multi-million-dollar public awareness campaign to brand the name "chronic fatigue syndrome," dismayed much of the patient and advocacy community, given ongoing and fervent attempts to have the illness officially renamed ME. And in a highly controversial move, Dr. Reeves spearheaded in 2005 the creation of the new, purportedly more precise method of identifying patients; critics feared the approach would wreak havoc with epidemiologic studies by mixing a lot of people with depression but not CFS into samples of people all presumed to have chronic fatigue syndrome.
During the 2000s, researchers—including many clinicians who actually treated patients and understood how seriously ill they could be—had continued to be dissatisfied with the 1994 case definition, which they felt imprecisely described the condition. For one thing, the definition allowed for but did not require the presence of post-exertional malaise (reminder: read "relapse" or "crash," rather than "malaise"). Yet it was increasingly apparent that post-exertional malaise, and not fatigue alone, was a cardinal symptom for many if not most patients, and one that clearly helped distinguish CFS from primary depression, as well as other chronic illnesses. The CDC definition also allowed for but did not require the presence of cognitive and neurological problems, although these appeared to afflict almost everyone with the condition.
Other research groups were using their own case definitions, making it hard to compare results. The "Oxford criteria" developed in Great Britain required only the presence of six months of disabling fatigue; that single-symptom criterion was criticized as so broad that it was likely to identify many people with primary depression rather than CFS. A more detailed 2003 case definition developed in Canada focused on post-exertional malaise as a cardinal symptom of what it called ME/CFS. Required symptoms also included disordered sleep, pain, and neurologic symptoms, as well as signs of dysfunction in the immune, endocrine and autonomic nervous systems.
Earlier this year, a team of top researchers—not surprisingly, without any participation from the CDC–published a new "international consensus" case definition, which adopted the name myalgic encephalomyelitis and abandoned chronic fatigue syndrome altogether. Using the Canadian definition as a jumping-off point, the new international definition also dropped the construct of "fatigue" in favor of requiring post-exertional malaise, which they renamed "post-exertional neuroimmune exhaustion." Other required symptoms include neurological and energy production impairments.
In contrast, the 2005 effort by the CDC to "operationalize" the earlier 1994 case definition–by introducing standardized questionnaires and measurement scales to assess levels of fatigue and functional impairment—has found no support outside the CDC itself. In suggesting specific instruments and scales, Dr. Reeves and his research team proposed cut-off points to represent sufficient grounds for identifying CFS.
Yet when the CDC researchers applied these new "empiric" criteria, as they called them, to a population in Atlanta in 2007, they found a prevalence of 2.54 percent of the adult population. Extrapolated nationwide, that meant that four million people—in other words, ten times the CDC estimate from its Wichita research just four years earlier, and four times the widely accepted figure of about one million—had the illness. Dr. Reeves and his co-authors defended the new numbers, attributing the increased prevalence estimates to a broad sampling strategy and "application of more sensitive and specific measures of the CFS diagnostic parameters."
Others outside the CDC dismissed the new numbers as absurdly inflated and argued that the empiric criteria, like the Oxford criteria but unlike the 2003 Canadian case definition, blurred and expanded rather than clarified the disease boundaries. While some advocates believed the increased estimates would focus more attention on the illness and should therefore be embraced, many others—including leading epidemiologists–believed that the expanded category could make it harder to isolate physiological correlates; that failure, in turn, would make it more likely that others would continue to perceive it to be largely a psychiatric illness.
One study from Dr. Jason's research group at DePaul University, frequently cited by advocates, found that 38 percent of a group suffering from major depression but not chronic fatigue syndrome were misdiagnosed as having CFS using the new empiric case definition. The researchers reported that the scales, measurements and cut-off points indicated by the CDC group did not sufficiently distinguish between emotional and physiological sources of fatigue and disability; in other words, someone could be identified as having CFS under the new method solely because of fatigue or disability arising largely from psychological causes, such as depression.
"Given the CDC's stature and respect in the scientific world, this new definition might be widely used by investigators and clinicians," wrote Dr. Jason and his co-authors. "This might result in the erroneous inclusion of people with primary psychiatric conditions in CFS samples, with detrimental consequences for the interpretation of epidemiologic, etiologic, and treatment efficacy findings for people with CFS." The authors also noted pointedly that the population prevalence for CFS calculated using the empiric definition was close to that for major depressive disorders.
Although the empiric case definition was published six years ago, it has not found any favor outside the CDC, raising questions about the comparability of CDC data derived from its use to results from other studies. Dr. Unger wrote in her e-mail response that she knew of no other researchers who had adopted the empiric criteria, although she noted that "others have started applying case definitions using instruments as tools, recognizing the improved ability to get consistent results." Three major ongoing CDC studies have samples selected through use of the empiric criteria.
Dr. Unger appeared reluctant to whole-heartedly endorse the estimate, based on the empiric criteria, that 4 million people in the U.S. have CFS, but she did not back away from it either. "No single study or approach can be considered sufficient to determine the true population prevalence of an illness as complex as CFS," she wrote. "Like all studies, the 2007 prevalence estimates of CFS based on the Georgia surveillance study are subject to the limitations of the study design. However, the Georgia study, along with those from other investigators, does demonstrate the public health importance of CFS and it is the CDC's most recent study on the prevalence."
Dr. Unger indicated that the agency "is in dialogue with other investigators about instruments and methods to best characterize and stratify CFS patients." The agency is also launching studies with several investigators to enroll and characterize patients from seven clinical practices headed by leading CFS physicians to help clarify issues involving the case definition as well as the name.
"We are planning to collect standardized data on all the domains of illness included in the Canadian Consensus Criteria of CFS/ME, the 1994 CFS definition and the newly proposed International ME definition," she wrote. "We anticipate that this data will assist researchers and clinicians in considering further refinements of the case definition." With regards to the name of the illness, she wrote: "Opinions of advocates, clinicians and researchers remain divided about whether CFS and ME are the same or different entities. However, we are following the discussions with interest and would consider any consensus that is reached by patient groups and the scientific community going forward."
The Website Conflict
Another conflict that has dogged the agency involves its CFS website. Advocates and patients have long complained that it conveys serious misinformation, in particular on aspects of diagnosis, treatment and management of the illness. For example, until this month the website included the following language: "No diagnostic tests for infectious agents, such as Epstein-Barr virus, enteroviruses, retroviruses, human herpesvirus 6, Candida albicans, and Mycoplasma incognita, are diagnostic for CFS and as such should not be used (except to identify an illness that would exclude a CFS diagnosis, such as mononucleosis). In addition, no immunologic tests, including cell profiling tests such as measurements of natural killer cell (NK) number or function, cytokine tests (e.g., interleukin-1, interleukin-6, or interferon), or cell marker tests (e.g., CD25 or CD16), have ever been shown to have value for diagnosing CFS. Other tests that must be regarded as experimental for making the diagnosis of CFS include the tilt table test for NMH, and imaging techniques such as MRI, PET-scan, or SPECT-scan."
Advocates and patients appealed to the CDC many times over the years to remove the language. They acknowledged that these and other tests were not diagnostic for CFS but insisted that wasn't the point; even though the tests couldn't be used to confirm that a patient had CFS, they were important weapons for disease management. Experienced clinicians, like Dr. Enlander at Mt. Sinai and Dr. Nancy Klimas, a top researcher at the University of Miami, have long used tests such as these to identify CFS sub-groups and individualize treatment strategies, given their patients' histories of immune dysregulation and viral infections. Yet clinicians report that they have received letters from insurance companies citing that paragraph in rejecting claims for tests they have ordered, in some cases as recently as last summer.
The agency finally removed that language this month, after an advisory group reviewed the website and requested a host of changes. "They [the reviewers] provided useful feedback in early October and CDC is incorporating this feedback into our ongoing efforts to improve the CFS website," wrote Dr. Unger. Replacing the old language is a new passage that suggests that some of the same tests once disallowed for diagnosis of CFS can be useful for disease management—as advocates have been saying all along. Patient groups welcomed the change, but some advocates said it was minimal and long overdue, given that many insurance claims had been rejected unfairly in years past.
Another major complaint about the website has been the agency's longstanding promotion of two treatments developed and championed in the United Kingdom: graded exercise therapy and cognitive behavior therapy. In the U.K, mental health professionals have dominated research into and treatment of chronic fatigue syndrome; they use the Oxford criteria, requiring only six months of unexplained fatigue. A major British study using this case definition and published earlier this year indicated some improvement with graded exercise therapy and cognitive behavior therapy. But U.S. experts on the illness, at least those outside the CDC's immediate orbit, generally believe that the U.K. case definition—like the CDC's empiric definition–is likely to define a cohort that includes a lot of people with depression, and not actual CFS, as their primary complaint.
To those convinced that CFS is a condition of psychogenic and not organic origin, it probably doesn't matter if people with depression are mixed up in a study sample. In the framework of chronic fatigue syndrome endorsed by the British medical establishment, the prolonged fatigue and associated illness are largely considered to be caused by the patient's inability or unwillingness to maintain an active lifestyle—an avoidance triggered by some form of stress, psychological issues or perhaps even an infectious illness. That avoidance of activity then leads to a physiological deconditioning that impacts multiple body systems and organs.
"It's a psychological model," said Dr. Jason of DePaul University, of the British view of CFS. "It's an illness that might be caused by some kind of virus or trauma, but what's maintaining it is that you have some sort of phobic avoidance of activity. The idea is your bone and muscle mass decrease, you become weak. So if you can get a person to slowly increase the amount of activity that they do, they will break this phobic avoidance."
In the U.K. framework, graded exercise therapy is often paired with cognitive behavior therapy in the treatment protocol for CFS. Cognitive behavior therapy is a treatment modality with widespread application, and is likely to be useful to many people undergoing major stresses–whether from cancer, a back injury, an existential crisis, fear of sex, migraines, a bad divorce, or cognitive fatigue syndrome. However, the kind of cognitive behavior therapy prescribed in Great Britain to treat people with CFS—as Dr. Jason and other researchers have repeatedly noted–is largely geared toward convincing patients to overcome their avoidance phobia and increase activity levels; in other words, to encourage them to participate in something very much like graded exercise therapy.
But for people who experience post-exertional relapses of their symptoms, graded exercise therapy could be harmful, not helpful; in addition to the emerging research about post-exertional malaise, patient surveys in the U.K. have indicated a high degree of unhappiness and increased morbidity among those who have been through a course of graded exercise therapy. And, say critics, cognitive behavior therapy could also be harmful, if the goal is to convince patients to engage in graded exercise therapy or otherwise ramp up activity levels.
Dr. Unger wrote in her response that she was aware of patient concerns about including information on graded exercise therapy and cognitive behavior therapy on the website, and that the agency was reviewing those sections. The goal of the information, she wrote, was to let patients know about treatment options they could discuss with their health care providers. "Though these approaches may not work for everyone, the scientific literature shows that they provide some benefit to some patients," she wrote.
However, Dr. Unger declined to comment specifically on the contested scientific literature from the U.K. that actually reported the modest benefits from these therapies, noting that "as a rule, CDC doesn't comment on research not conducted by CDC."
The View from the Chronic Fatigue Syndrome Advisory Committee
The growing dismay about Dr. Reeves' leadership and the agency's problematic CFS research program are evident in the minutes and testimony from the twice-yearly meetings in the late 2000s of the Chronic Fatigue Syndrome Advisory Committee of the Department of Health and Human Services. The mandate of the committee, with a rotating membership of clinicians, researchers, patients and advocates, is to offer guidance and recommendations to the department. In 2007, the committee requested financial records from the CDC's CFS program. Dr. Jason, a member of the CFSAC, and Dr. Reeves, an ex officio member as the CDC's representative, sparred publicly over access to the records.
By the time of the next CFSAC meeting, in October of 2008, Dr. Reeves had been replaced as the CDC's ex officio member (although he retained his CDC position). Another CDC official at the meeting said he hoped the change would help "to leave behind past tensions to make a fresh start."
At that meeting, however, Kim McCleary, the head of the CFIDS Association of America, testified that the CFS program, based on a review of the CDC financial documents that the committee had sought, suffered from "shameful scientific leadership, zero accountability, invisible outcomes and millions and millions of dollars stuck in suspended animation, if not wasted…Only the government contractors seem to be benefiting from millions spent for which there are no worthwhile outcomes for American taxpayers, or CFS patients."
The largest chunk of the program's funding, reported McCleary, went to a single private research organization, Abt Associates in Cambridge, Massachusetts, in sole-source or no-bid contracts for the epidemiologic research that was being widely criticized by other scientists. At least $2.7 million committed to Abt was "in limbo"–obligated to specific projects but remaining unspent—and work on other projects was proceeding slowly and at great cost, she testified. The financial mismanagement, testified McCleary, "has resulted in program management coming often to this committee and telling other investigators that no funds are available for new projects or collaborations."
(The CFIDS Association of America had been criticized by some other advocates over the years for its previous close association with Dr. Reeves. The organization had provided essential public support for Dr. Reeves during the accounting scandal in the late 1990s; in the mid-to-late 2000s it implemented the agency's controversial multi-million-dollar CFS public awareness campaign at a time when others were seeking to change the disease name. McCleary's public rebuke of Dr. Reeves' leadership, therefore, was viewed as a significant blow to the CFS program and found a welcome audience.)
McCleary's report further shredded support for Dr. Reeves among committee members; some were researchers struggling with their own funding issues. The financial accounting appeared to confirm a frequently heard complaint about the CDC and Dr. Reeves—that they were not taking full advantage of opportunities to collaborate with outside scientists at academic research centers.
Christopher Snell, a professor of sports sciences at the University of the Pacific in Stockton, CA, and a committee member, stated, according to the minutes: "As somebody who works on a shoe string budget, when I start to look at some of these numbers, I was somewhat appalled… It just does not seem to be the best use of the funds. The thing that we asked for at a couple of previous meetings was for the CDC to consider more collaboration with outside entities. We meant people who work a lot cheaper. It would seem that there are people out there with great ideas who would love to work with the CDC for much less money."
Dr. Klimas, also a committee member, noted that she had been collaborating with the CDC on a study comparing people with CFS and Gulf War illness, and that the agency had failed to finish its testing on samples, citing funding problems. She also unleashed another common charge: that the CDC was simply not interested in the role of pathogens. According to the minutes, "Dr. Klimas said that CDC has made it known that the agency has no intention of looking for infectious agents. She added that other research organizations are pursuing identification of pathogens and that CDC should be embarrassed not to be looking for them as well…despite the evidence, the CDC is still saying that viruses don't matter in the illness even though people are already being treated for them. She said that the science is there to provide options way beyond the CDC's recommended behavioral treatment and exercise."
At its meeting in May 2009, the committee unanimously voted to recommend "progressive leadership" for the CFS program; although the recommendation, in an apparent nod to decorum, did not cite Dr. Reeves by name, the intent was clear. The request for a top personnel change—essentially a vote of no-confidence in the current leadership–was considered an aggressive move for this kind of federal advisory committee. At the same meeting, the International Association for CFS/ME, a leading scientific and research organization, endorsed the call for new leadership.
In October of 2009, Dr. Reeves committed what many in the CFS world regarded as a major public gaffe: an off-hand remark to a New York Times reporter (not this one) about the mouse retrovirus research that had just sparked a wave of excitement. In the interview, which occurred shortly after the publication of the Science paper reporting the link between XMRV and CFS, Dr. Reeves said his research team would look for the retrovirus but that they were unlikely to find anything. He told the Times: "If we validate it, great. My expectation is that we will not."
For a scientist to predict his team's outcomes in a contested field of research during a highly public and volatile debate is not the best way to demonstrate impartiality and open-mindedness (notwithstanding that the XMRV hypothesis appears not to have panned out). Even more so for someone like Dr. Reeves, who was already facing coordinated calls for his ouster from almost every corner.
At the CFSAC meeting later that month, the committee again approved a recommendation for new leadership and emphasized the urgency of the issue. According to the minutes: "CFSAC considers that recommendation important and would like to get some feedback, including whether or not the recommendation is being considered. This has become more important because of certain quotes that have been made in The New York Times concerning the retrovirus by the person in charge of the CDC program."
The committee also formally rejected the CDC's empiric case definition—the centerpiece of Dr. Reeves' epidemiologic approach—and recommended support for "a national effort to arrive at a consensus definition of CFS that is accurate, standardized, and reflective of the true disease."
Within months, Dr. Reeves was gone from his position, although no public explanation for the move was offered. For the most part, the elements of the CFS program that Dr. Reeves championed—the empiric criteria, the name of the illness, (most of) the disputed website information, etc.—remain in place under Dr. Unger.
Reaction to Dr. Unger's efforts appears decidedly mixed so far. Yet some members of the research community express optimism about being able to develop, with Dr. Unger, the kind of cooperative framework that many felt was absent when Dr. Reeves ran the program. Dr. Fred Friedberg, president of the International Association for CFS/ME, said that Dr. Unger was "way more responsive" than Dr. Reeves, noting that she had attended the association's annual conference this fall in Ottawa.
"We reached out to her and she has been very accommodating and engaged in conversation to talk about some joint efforts," said Dr. Friedberg, a professor of psychology at Stony Brook University Medical Center. "It remains to be seen what goals she's going to set up and what kind of studies she's going to do exactly. So this is kind of a work in progress, but the level of cooperation is pretty good. For the first time in years, there's an opening."


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subset: commoncrawl


text:
'Fearless Girl' to leave Wall Street's 'Charging Bull'
(Photo: AP)
The "Fearless Girl" statue near Wall Street that has become a global symbol of female can-do business spirit will be moved from her spot facing the "Charging Bull" to a location by the New York Stock Exchange.
The ponytailed girl in a windblown dress became a tourist magnet last spring when the artwork popped up confronting the famous bull that was a symbol of the American financial resilience in the wake of the 1987 stock market crash.
State Street Global Advisors, the firm that installed the "Fearless Girl" statue in March 2017, said Thursday that it will be moved by the end of the year.
"Fearless Girl" was designed to call attention to a State Street initiative to increase the number of women on corporate boards.


text:
Confirmation dialog box.
The Seven Top Tips to Feel Full Faster ...so You Consume Less Calories © 2019 Health Realizations, Inc. Update
Have you ever had a day when your stomach felt like a bottomless pit and that no matter how much you ate, you just didn't feel full or satisfied? What if there were ways to fill your stomach so that you would feel full faster, yet end up consuming fewer calories overall? Would you try them?
Grapefruits are 90 percent water with very few calories. These and other water-rich fruits and vegetables make you feel full faster.
Well, there's good news. There are a number of healthy "tricks" you can use to feel full faster, meaning you're less likely to overeat, take in too many calories and ultimately gain weight.
1. Eat More Fiber Fiber is not only good for your health (it helps to lower your risk of heart disease, type 2 diabetes and more) but eating more of it is a simple way to satisfy your hunger.
High-fiber foods give you volume (making you feel full), plus they take longer to digest, so you feel satisfied for a longer time period. Tasty high-fiber foods include vegetables, berries, pears, avocados, whole grains, seeds and nuts, brown rice, beans, apples, grapes and oranges.
2. Eat Foods That Contain Lots of Water
Certain foods, particularly fruits and vegetables, contain a lot of water. Similar to high-fiber foods, water-rich foods provide volume, making you feel full, but without a lot of calories. For instance, grapefruits are about 90 percent water, but contain only 39 calories per serving (half a grapefruit). This is why loading up on veggies and some fresh fruit (or eating a big veggie salad or bowl of broth-based veggie soup before dinner) is an excellent way to satisfy your stomach but not take in a lot of calories.
3. Take Your Time When You Eat
It's a proven fact that if you wolf your food down your body won't have a chance to feel that it's full (and in the meantime you may have reached for an unnecessary second portion).
"We don't have immediate feedback from our bodies telling us we've eaten enough," says Janet Polivy, Ph.D., professor of psychology at the University of Toronto, Canada. "It takes about 20 minutes for food to be digested enough that glucose gets into the bloodstream and the hormones start working."
In other words, eat slowly (this includes taking the time to thoroughly chew each bite before swallowing it) and if you think you're still hungry, wait about 20 minutes before deciding if you really want more.
Always take the time to savor your food when you eat. Chew thoroughly, put your fork down between bites and only go for a second helping after you've waited about 20 minutes.
4. Eat Protein with Every Meal
"Protein is the most satiating nutrient," says former Harvard University researcher Thomas Halton, Ph.D. You should strive to eat some protein with every meal (breakfast, lunch, dinner and even with your snacks).
Remember that there are a wide variety of ways to get protein. Some excellent choices include a hard-boiled egg, nuts, a small piece of cheese, meats (preferably grass-fed and organic), beans, chickpeas, or a high quality protein whey shake.
5. Take Smaller Portions
Studies have found that the larger a portion a person is served, the more they will eat. However, their feelings of satiety are no higher than people who ate smaller portions.
So take a small portion and eat it slowly. Chances are high that you'll feel just as full as you would have with a larger portion.
6. Limit Your Choices
People tend to eat more at buffets or in situations where there are a lot of different foods offered. You naturally feel compelled to try a little of everything, and end up eating significantly more overall (i.e. Thanksgiving dinner). When you make meals at home, limit the number of foods you're serving and you'll have an easier time feeling satisfied on less food.
7. Think About Your Food
We often eat while we're completely distracted (while driving, watching TV, standing at the kitchen counter, etc.), which allows us to easily consume more than we need, often without ever realizing it. As you eat, think about the food, give thanks for it, and really taste each bite. When you savor your food in this way, you will feel full and satisfied on much less food.


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text:
Traditional IPv4 Routing
- UNIX Configuration Commands
- Cisco IOS Configuration Commands
- IPv4 Dynamic Routing
- UNIX routed and Cisco RIP Configurations
- Sample Linux Router Setup
UNIX Configuration Commands
You should now understand the fundamental thought behind traditional IPv4 routing. However, at this point, you need to step back and look into the methods of implementation. First consider UNIX commands. These commands are traditional both in function and in age. Once you have learned how to use them under one UNIX, including Linux, you will know essentially how to use them in any UNIX. This section details how to use these commands under Linux to configure a basic two-network router with a single default route. You will also add additional specific routes to illustrate the meaning behind the fundamental thought of traditional routing.
The two primary utilities used in configuring IPv4 routing under UNIX are ifconfig and route. You will step through the use of both of these utilities to configure a simple dual connected router under Linux.
ifconfig Utility
The ifconfig utility has been used with UNIX systems for quite some time and is the original utility for configuring network interfaces under UNIX. The utility is appropriately named InterFace CONFIGuration, or ifconfig. On many UNIXes as well as Linux, ifconfig supports multiple protocol suites, or address families. The complete syntax and supported address families can be found in the man pages. This book is only concerned with the inet family, which is the address family for IPv4. There is also an inet6 family for IPv6 but we will not cover that usage in this book. In Chapter 9, "IPv6," you will learn how the ip utility is used for Policy Routing in IPv6.
The basic ifconfig syntax for an IPv4 interface under Linux is as follows:
ifconfig interface IP-address netmask netmask broadcast broadcast
The italicized words will be replaced with the relevant information to configure the interface.
On most UNIXes you can find out the names of the available interfaces through ifconfig by asking it to list all of the interfaces it knows about. Type ifconfig -a and you will see a list of all the interfaces on the system, regardless of whether they are configured. You can also call ifconfig with the name of a single interface to obtain information about that interface only. This feature helps when you are on a strange system and need some quick information.
In UNIX there is an IP interface that should be present whenever the system is enabled for TCP/IP communication. This is the loopback interface, usually specified by the name lo or lo0. By conventional standard this interface has the IPv4 address 127.0.0.1/8 assigned to it. This interface is very important to the correct operation of the TCP/IP networking subsystems. In Chapters 28, as the details of the Linux Policy Routing structures are illustrated and then exemplified, you will see that this interface has a myriad of uses.
The other interfaces that may be on the system will have names that vary according to the UNIX flavor. I will use the Linux conventions herein and refer primarily to using Ethernet (ethxx) and Token Ring (trxx) interfaces.
Consider a router that has one Ethernet interface, eth0, and one Token Ring interface, tr0. The appropriate information is as follows:
eth0 - 192.168.1.254/24 tr0 - 10.1.1.254/24 Default Gateway - 10.1.1.1/24
Two networks are represented here, and from the default gateway address you can deduce that the Ethernet network is a stub network off of the main network. The Token Ring could be considered the backbone network if you prefer that terminology because it contains the default gateway.
To set up the interfaces using ifconfig on a typical Linux system, do the following from the command line:
ifconfig eth0 192.168.1.254 netmask 255.255.255.0 broadcast 192.168.1.255 ifconfig tr0 10.1.1.254 netmask 255.255.255.0 broadcast 10.1.1.255
You could then list the interfaces and get information about them using the straight ifconfig command by itself.
route Utility
Now you have a router with three IPv4 configured interfaces. Do not forget about the loopback interface when counting the interfaces! You should now set up your router to actually be able to route between the locally connected networks. In order for the router to do this it needs to have all three of the locally connected networks in the routing table. Here you call upon the route command to populate the routing table.
In general usage the route command is called as follows:
route add -net|host IPv4 Address netmask netmask gw gateway dev interface
Note that there are many other options that can be specified to the route command. Many of the options are UNIX flavor specific. The preceding options are fairly general and should work on most UNIXes. Also the route command, when issued by itself on the command line, will give different outputs depending on the UNIX flavor. In Linux, issuing a route command by itself will dump the main kernel routing table. However, on most UNIXes you will need to use the netstat -r command in order to dump the routing table.
Linux 2.0 Versus Linux 2.2 Routing Changes
In Linux there are some fundamental differences in the IPv4 configuration process between the 2.0 series of kernels and the 2.1 and newer kernels. When configuring an interface for IPv4 using ifconfig under a 2.0 series kernel, only the interface is configured. But the kernel does not know how to get to this address or to the network it defines. You have to add a network route manually in order for the kernel to see where to send the packet.
In kernel 2.1 and newer, the situation is different. When Alexey Kuznetsov rewrote the network routing code for Linux during the 2.1 development kernel series, he added automatic route creation for directly connected networks. Thus, if you run the same ifconfig configuration command on a 2.1 or higher series kernel, you will be able to connect immediately to the network defined by the interface.
Having the route automatically added by the kernel helps users unfamiliar with networking immensely in normal operation of a Linux network. If you want to configure an interface, the kernel will automatically create a connection to the interface address and network. Thus, as soon as you are done configuring the interface, you are ready to use it. However, for advanced usage this can become a nuisance.
For advanced usage you can override this behavior by explicitly configuring the interface with the true host address, which is a netmask of all ones. If you want to have the same behavior in 2.1 and higher that you had in 2.0 for ifconfig, use ifconfig interface IPv4 Address netmask 255.255.255.255 broadcast broadcast, and the automatic route will not be created.
Now that you have seen the syntax for basic routing configuration, it's time to apply it to the router configured in the ifconfig section.
route add -net 127.0.0.0 netmask 255.0.0.0 dev lo route add -net 192.168.1.0 netmask 255.255.255.0 dev eth0 route add -net 10.1.1.0 netmask 255.255.255.0 dev tr0
Note that the loopback interface route is explicitly included here for completeness. You did not see the actual ifconfig statement in the previous section; it is left as an exercise for the reader to determine what command was needed. Note that in all cases where you would want to ensure that your system is correctly configured, you will want to configure all the interfaces, including the loopback interface, manually or through your own set of scripts. Under Linux, and in UNIX in general, any system interface including loopback is not automatically configured.
The router at this point is ready to route all traffic between the 192.168.1.0/24 network and the 10.1.1.0/24 network. But if there is any traffic from either of those networks with a destination address that does not belong to either 192.168.1.0/24 or 10.1.1.0/24, the router will return an error. This is because it has no default route at this point in time.
The subject of default routes contains an explicit security concern. Essentially, a default route enables a router to trust all traffic to another router. In many cases this may not be a necessary or wise decision. For example, in the network structure considered here there may only be one or two other networks of interest. Alternatively, you may not want the systems on 192.168.1.0/24 to see any other networks. The route setup at this point would ensure, in the absence of source-routing capabilities, that the systems on 192.168.1.0/24 would only be able to talk externally to systems on 10.1.1.0/24. When we consider the theory of Policy Routing in Chapters 2 and 3 and the actual implementation usage in Chapters 58, you will see various methods of considering this fundamental security problem.
But to consider standard and traditional usage you should install a default route into your router. This default route provides your router with a router to which all unknown destination addressed traffic should be forwarded. In this case you have a gateway that has been specified for this route. You can then add it in with the following command:
route add -net 0.0.0.0 netmask 0.0.0.0 gw 10.1.1.1
Note that under Linux and under many other UNIXes this command can also be expressed as route add default gw 10.1.1.1, where the default keyword stands for the -net 0.0.0.0 netmask 0.0.0.0 parts of the given example.
You now have a router that will route traffic between the 192.168.1.0/24 and 10.1.1.0/24 networks and will also provide connectivity to any other network destination from the 192.168.1.0/24 network. Of course that does not mean that those networks can get back to the 192.168.1.0/24 network, but that is a different problem.


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Discover Our Difference
We provide students a strong moral focus program and a rigorous college-prep education. Our goal is for students to develop the moral strength, knowledge, and skills they need to succeed in college, work, and life.
NHA Shines: Stanford Study Shows Our Students Surpass Their Peers by 3.5 Months Each Year
Learn More About Stanford's StudyA recent Stanford study shows NHA partner-school students continue to outperform their traditional public school peers. They do so by gaining nearly three-and-a-half months of additional learning. NHA also earned the new "gap busters" designation for outstanding progress in eliminating learning disparities for minority and poverty students.
We Reach Higher
We focus on every child's unique needs, abilities, and interests. We set high standards, make expectations clear, personalize teaching, and as a result, our students thrive.
We Build Character
We make moral focus part of every school day. Virtues such as respect, perseverance, and compassion are essential to what kids need to succeed. Students learn the importance of making good decisions and doing the right thing in life.
We Expect More
Our students are taught how to make wise choices, consider consequences, and take responsibility for their actions. Our "no excuses" approach helps kids learn at a young age that strong character is developed through personal responsibility.
We Work Together
Our teachers make a point of being available to discuss your child's progress. When parents, teachers, and students work together, they form a powerful connection between home and school – a partnership that can change a child's life.
We Focus on Safety
Students require a safe and orderly place to learn and do their best. At Winterville Charter Academy, safety practices are in place which include:
- Keeping our doors locked - all visitors are required to check in at the office before going into the school.
- We provide safety training to all staff and students.
- Bullying is not tolerated and students are expected to be kind to others and demonstrate respect and courtesy at all times.
What Winterville Charter Academy Parents Are Saying
Apply Today!"I like the level of work that my student is getting. It fosters critical thinking and independent learning. In addition, I like the emphasis that is placed on safety and security not only in the drive line but in terms of who picks up my student."
- Winterville Charter Academy Parent
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We know there are a lot of factors in deciding where your child will go to school and we want to help. Use our live chat or leave your contact information and we'll be in touch.
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While a lot of children awoke on Christmas morning to stockings full of toys (or socks and underwear!), my Grandma always stuffed ours with little homemade treats. We of course got the toys and practical items like clothes when we opened the packages, but my favorite thing to find in my stocking was her homemade beef jerky. To be honest, I actually have no idea what she used to marinate it in and really should ask her! Grandma I know you're reading this, so let's swap recipes soon! But, was it healthy beef jerky?
I've loved jerky of any kind ever since, be-it turkey, beef, or even the bear jerky that a friend let us try one time in Colorado when I was growing up. I had never made it though until last year when I actually started scrutinizing the labels of the packages I was buying. There's quite a few brands out there now that use healthy ingredients; but I find it is still easier, cheaper, and more flavorful to just make own at home. There will be a couple of different flavors in my new cookbook next Fall, but for now, here is our go-to Smoky Healthy Beef Jerky. I keep it in the pantry for those days when I need a salty snack or am on the run and don't have time to fix lunch.
Store the beef jerky in an airtight container at room temperature for up to 1 week. *The research I've done shows that this method results in jerky that can last on the shelf in a well sealed container for as long as 2 months. It never lasts long enough in our house to test that out though!


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We have a giveaway for THE WILD GIRL by Kate Forsyth. There's one copy for a US or Canadian address. It's historical fiction with a fairytale theme. And for a sample of Kate Forsyth's wonderful writing you can read an excerpt for THE WILD GIRL by linking on this text.
Here's more about the book via the publisher:
One of six sisters, Dortchen Wild lives in the small German kingdom of Hesse-Cassel in the early 19th century. She finds herself irresistibly drawn to the boy next door, the handsome but very poor fairy tale scholar Wilhelm Grimm. It is a time of tyranny and terror. Napoleon Bonaparte wants to conquer all of Europe, and Hesse-Cassel is one of the first kingdoms to fall. Forced to live under oppressive French rule, Wilhelm and his brothers quietly rebel by preserving old half-forgotten tales that had once been told by the firesides of houses grand and small over the land.
As Dortchen tells Wilhelm some of the most powerful and compelling stories in what will one day become his and Jacob's famous fairy tale collection, their love blossoms. But Dortchen's father will not give his consent for them to marry and war, death, and poverty also conspire to keep the lovers apart. Yet Dortchen is determined to find a way.
Evocative and richly-detailed, Kate Forsyth's The Wild Girl masterfully captures one young woman's enduring faith in love and the power of storytelling.
Kate Forsyth is the internationally bestselling and award-winning author of more than 20 novels. Her books have been published in 17 countries. Forsyth holds a doctorate in fairytale retellings from the University of Technology. She lives in Sydney, Australia.
To enter this giveaway fill out the Google form:


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Via Sports Talk Florida
Special to Bucs Report
TAMPA, Fla. (AP) — Antonio Brown's latest messy departure from an NFL team, the Buccaneers, was not about an injury, coach Bruce Arians said Monday.
Yes, the Buccaneers are moving on from Brown, whose NFL career is on hold yet again after another in a series of incidents, including two women accusing him of sexual assault in 2019.
But Arians dispelled the notion that Brown stormed off the field Sunday — tossing some of his gear into the stands and waving to fans at the Jets' MetLife Stadium — after refusing to go back in because of an ankle injury that had sidelined him for several weeks.
Twice, Arians was asked about Brown claiming he was hurt. Both times, the coach answered "No," that Brown didn't tell him he was injured.
"It's Pretty Obvious What Happened"
"It's pretty obvious what happened. He left the field and that was it," Arians said, declining to elaborate on an exchange the coach said he had with the receiver on the sideline.
Pressed for details on what was said and whether Brown claimed he was too injured to play, Arians replied: "We had a conversation and he left the field."
Asked what specifically was said that might move Brown to react the way he did, the coach added: "You have to ask him, brother. I don't have a clue."
"Just Hope the Best for Him"
"I just hope the best for him," Arians said, while shedding little light on what led to Brown taking off his jersey, shoulder pads, undershirt and gloves before walking off during the third quarter of Sunday's 28-24 Buccaneers victory.
Arians added he has no regrets about giving the often-troubled receiver an opportunity to play with Tom Brady and revive a career derailed by on- and off-the-field issues — even though it ended in such a bizarre fashion. Tampa Bay was Brown's third team since his last full season in the NFL with the Pittsburgh Steelers in 2018.
The 33-year-old Brown also had messy departures from Oakland and New England — released before ever playing a game for the Raiders and then suiting up just once during a brief stay with the Brady-led Patriots in 2019.
"I Wish Him Well"
"I wish him well. I hope if he needs help, get some," said Arians, who was Pittsburgh's offensive coordinator when the Steelers drafted Brown in the sixth round in 2010. "It's very hard because I do care about him."
Brown remained in the New York area, sitting courtside Monday night at the Brooklyn Nets' loss to the Memphis Grizzlies.
Brown hadn't played in the NFL in more than 13 months when he signed with the Buccaneers in October 2020 as he neared the end of an eight-game suspension for multiple violations of the NFL's personal conduct policy. At the time, Brown was also facing a civil lawsuit filed in September 2019 by a female personal trainer who accused him of sexually assaulting her on three occasions, including rape.
"I took a lot of time off from the game to re-evaluate myself, to look within, to get a better perspective of myself and work on myself within and without," Brown said in November 2020.
Brady Tried to Help
Brady welcomed the Buccaneers' decision to give Brown a chance and allowed the four-time All Pro to stay with him in a home the quarterback was renting from baseball Hall of Famer Derek Jeter.
"I won't say I'm a different person, but I'm a better person," Brown said then. "Learning a lot about myself, working on myself for a year and a half, I think I'm a better person."
Several members of Arians' staff in Tampa Bay, including offensive coordinator Byron Leftwich, also worked with Brown early in the receiver's career. Brown said he felt those relationships would help him make the most of the opportunity.
For a While, it Worked
Brown had 45 receptions for 483 yards and four TDs over the final eight games of last season. He also contributed during the playoffs and caught a TD pass in the Buccaneers' Super Bowl win over Kansas City.
He signed another one-year deal last May and was off to a strong start when he was sidelined with the ankle injury at Philadelphia in mid-October.
Brown returned to the lineup two weeks ago after serving a three-game suspension for misrepresenting his COVID-19 vaccination status with a fake card, and had 10 catches for 101 yards in a win over Carolina.
He had three reception for 26 yards against the Jets, finishing the season with 42 catches for 545 yards and four TDs.
Brown Before Buccaneers
An impressive streak of six consecutive seasons with at least 100 catches and 1,000 yards receiving ended when Brown's erratic behavior on and off the field led Pittsburgh to trade him to Oakland in March 2019.
A tumultuous short stay with the Raiders ended with Brown demanding and being granted his release during training camp. By that time, the Raiders had voided guaranteed money in Brown's contract after a summer with the team began with Brown, among other things, missing a number of practices because of frost-bitten feet attributed to not wearing proper footwear during a cryotherapy session.
He also tangled with the NFL and threatened to retire if forced to wear a new helmet. He later was fined by the Raiders for what the team said were unexcused absences during camp.
Brown also had an ugly departure from New England after catching four passes for 56 yards and a touchdown in his only game with the Patriots, which released him after the ex-trainer accused him of sexual assault.
Brown's Resume
Over 12 NFL seasons, Brown has 928 receptions for 12,291 yards and 83 touchdowns. He's caught a pass in his last 144 games, the longest active streak in the league.
More AP NFL: https://apnews.com/hub/nfl and https://apnews.com/hub/pro-32 and https://twitter.com/AP_NFL


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Tagged with 'Valorant'
12 Results
Frequently Asked Questions
Frequently Asked Questions
What are Twitch Alerts?
Twitch Alerts are real-time notifications that pop up over a stream when someone donates, subscribes, follows the channel, or makes some other kind of interaction with a streamer. Usually, Twitch alerts consist of an image, GIF or animated video with interactive text and special sound effects on top of it.
Streamers use alerts to interact with the viewers, thank their supporters and celebrate special events that happen during the stream. You can add alerts to your Twitch stream in OBS Studio by using a platform like Streamlabs or StreamElements.
Streamers use alerts to interact with the viewers, thank their supporters and celebrate special events that happen during the stream. You can add alerts to your Twitch stream in OBS Studio by using a platform like Streamlabs or StreamElements.
Why should I use alerts on stream?
These days twitch alerts are required for any successful and uprising streamer. They make your channel look and sound professional by improving the aesthetics of your stream. But most importantly, twitch alerts help to improve the interaction between you and your viewers on a deeper level — from reading a message attached with a donation to personally thanking your new follower — there are loads of possibilities you can use with alerts!
What alerts do I need for streaming?
There are some basic alert types that any streamer needs — follower and subscriber alerts are essential to appreciate your viewers' support. Don't forget about donation and cheer alerts to thank your fans for their contributions and, of course, take care of an alert for raids and hosts.
What is a good size for Twitch alerts?
The perfect resolution for a twitch alert widget is 800x600, and its file size should be not more than 3MB — that way, your alerts won't cover the whole screen and will run smoothly in any case.
How to make twitch alerts?
Want to get creative? Even though creating your own twitch alerts is a tedious task, you can use software such as Adobe Photoshop or Adobe Illustrator for design and Adobe After Effects for animation of your alert. Want to go even deeper? You can utilize CSS, HTML and Javascript to take your alerts to a whole new level.
What are Twitch alert sounds?
Twitch alert sounds are sounds that play on your stream when some event or interaction with your viewers happens. For example, a sound can play when someone follows your channel or sends you a donation.


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INTUITION #7 Mala
Regular price $179.00
Unit price per
This 108-bead traditional mala embodies the energies of the 7th Chakra, CONNECTION, to remind you of your intention to be present in the now.
Our Sterling Silver Septagon bead will serve as your talisman. It carries the strong frequencies of the Number 7 - transformation, growth & protection.
- 8mm Labradorite, Amethyst, Pyrite, Clear Quartz
- 108 beads, 21.5"- 22" long without the pendant
- Crystal Quartz pendant approx. 1.5"
- Sterling Silver ŌM bead & spacers
- Hand-crafted in the U.S.A.
- Comes in our Signature Gift Packaging
- Includes corresponding stones & woods cards
- Labradorite - faith, imagination, new ideas, memory, clarity of thought
- Amethyst - inner wisdom, tranquility, right-brain function
- Pyrite - willpower, focus, motivation, optimism
- Clear Quartz - "Master Healer", amplifies the effect of other crystals, clears, balances and re-energizes all Chakras
- Sterling Silver - creativity, emotional intelligence, calmness, reflection
Our jewelry is made with genuine natural woods & stones that may slightly vary in color. All materials used are responsibly sourced.
Mala Care: Wearing your mala when swimming or bathing will damage the wood. To clean, gently wipe the beads with a damp cloth and place them in the shade to dry.