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Indiana man's death send feed commodities lower
Corn, Soybeans Fall on Mad Cow Fear
Bogus claim of "worldwide" incidence of CJD
Variations in CJD rates: Neilson
More US surveillance needed
Is bovine spongiform encephalopathy solely food-borne?
Intimidation of researchers who threaten vested interests
Disaggregation of Alzheimer - amyloid by antibodies; prion epitopes

Indiana man's death send feed commodities lower

April 16, 1997 AP

CHICAGO -- Beef, corn and soybean futures fell Wednesday on the Board of Trade with a newspaper report that an Indiana man died of an ailment linked to mad cow disease. The report prompted worries that people will eat less meat, leaving less need for livestock feed.

The Centers for Disease Control and Prevention said there is no direct evidence that mad cow disease -- bovine spongiform encephalopathy -- can spread to humans. But a story in Saturday's The Times of Hammond, Ind., said Joseph Gabor, 62, died of Creutzfeldt-Jakob disease, a rare and fatal brain-wasting disease in humans. Mad cow disease has been linked by the British government to the practice of mixing ground-up sheep into feed for cattle. Mad cow, in turn, is suspected as the cause of a new strain of Creutzfeldt-Jakob disease.

The newspaper didn't specify the strain that killed Gabor. At least 10 people from Great Britain have died of the new strain, which might have been caused by eating infected beef. However, that hasn't been proved. Gabor, a retired electrician from Schererville, Ind., died March 30. His wife, Marcia Gabor, said she does not know how he contracted the disease, speculating that it may have been transmitted through garden fertilizer containing bone meal that he spread on his roses.

"We ate the same things and were always together, so I should have it, too," Mrs. Gabor said. "The only thing he did alone was garden a lot and grow roses. He should have worn a mask and gloves to put the bone meal on them."

The U.S. Department of Agriculture banned imports of bone meal years ago from countries with mad cow disease. "I think it's safe to say that the source for this gentleman's disease was something else," USDA spokesman Patrick Collins said.

After hearing of the newspaper report, investors thought people won't eat red meat anymore, analysts said. And pork prices gained on speculation that people may switch from beef to pork. [But see mad pigs story from last week. -- webmaster]

The USDA and the Denver-based National Cattlemen's Beef Association insisted Wednesday that there is no mad cow disease in the United States. The beef association was unhappy with investor response to the report. "Floor traders at the Chicago Mercantile Exchange should not use issues like this to add volatility to the market," the group said in a statement.

The family may have gotten the rose garden/bone meal idea from the Dateline show instead of the book. And the source of this is not Richard Rhodes but a Nobel Prize winner in medicine, Carleton Gajdusek. The quote:

"I was sitting with Dr. Gajdusek when he finally leaned forward and said, "Did you use bone meal on your roses?" And I said, "Well, yes I do." And he said, "I wouldn't if I were you."
Dateline preceded that with:
"...the governments's chief researcher on these brain diseases, the cautious Dr. Gibbs, told Dateline that the few people he's knonw personally who've died of CJD had one unusual thing in common: Gibbs: "They all used bone meal, but I can't say that there's a relationship between bone meal and the disease in the humans.

Stone Phillips: "But it's kind of spooky to hear that."

Gibbs. "Kind of spooky, yeah."

The issue in the US is primarily indigenous amplified US strains of BSE and PSE, not the British strain of BSE or British strain of CJD. British BSE and British nvCJD in the US are, on the whole, red herrings [US slang for decoys used to divert attention from real issues]. US strains would likely be very different in presentation, histology, infectivity and manifestation in human from UK strains. Based on CJD, by far the best studied of any mammalian TSE, no one can reasonably expect the bovine spongiform encepatholpathies to fall into a single strain. Indeed, that is why the USDA focuses on the British BSE strain -- it's irrelevent.

Conventional wisdom in molecular biology would have 100 cases of familial-BSE a year in the US just from the Gibbs Principle, never mind any amplification through feed. I would find the USDA press releases more credible if they said we looked for all BSEs using modern immunological methods but cannot find any more cases on top of the irreducible basal level of 100 cases per year. The public accepts and adsorbs far far worse risks than this every day of their lives, so let's get on with it. There were 6,514 pedestrians killed by vehicles in 1996 with over 100,000 injuries, for example.

If the USDA/APHIS can rebut the Gibbs Principle, it is high time for them to step forward and put their reasoning on the table. Frankly, I am quite confident that they can't and that's why they don't. -- webmaster

More US surveillance needed

Thu, 17 Apr 1997 Mary Fishler-Fisk

Whether or not nvCJD and the link to BSE is relevant regarding TSE in US cattle, proving or disproving the presence of CJD AT ALL can be achieved only by increased surveillance. If, as some contend, there is a native BSE in US cattle, an odd, uniquely US strain may show up through this surveillance. It was the UK CJD Surveillance unit that identified the nvCJD over there and the Public Health people made the tentative link to BSE. If you're not looking, it's unlikely you'll find--until it hits you over the head, that is.

On the the bone meal and roses (sounds like a rock group) attribution issue, it is not so much from which source the quote comes (I have, by the way, read Deadly Feasts and seen the Dateline piece--even have it on tape), but the fact that of all possible modes of infection the bone meal and roses was the only one specifically mentioned. This is typical of the sensationalism of today's journalism. Not too many people have had dura transplants or first degree family members die of CJD; gardening is the number one hobby in America. Journalists know where to go for an audience.

Red herring or not, journalistic hype or not, the bottom line is that there IS VIRTUALLY NO surveillance for CJD in the US and without surveillance we are unlikely to prove or disprove the presence of any form of US cattle to human TSE transmission. If officials want to protect the public health and if the beef industry wants to be taken as honest, forthright and interested in more than their own bottom line, and if they truly believe what they say about lack of any TSE in US cattle, then they should all be encouraging heightened surveillance.

Corn, Soybeans Fall on Mad Cow Fear

17 Apr 1997 Associated Press

CHICAGO - Corn and soybean futures fell Wednesday on Chicago's Board of Trade as reports that an Indiana farmer died of an ailment similar to mad cow disease prompted worries that people will eat less meat, leaving less need for animal feed.

The U.S. Centers for Disease control says there is no direct evidence that mad cow disease - bovine spongiform encephalopathy - can spread to humans. But news that 62-year-old Joseph Gabor died of Creutzfeldt-Jakob disease, which has been linked by British researchers to mad cow disease, prompted a selloff in animal feed grains and beef futures.

``There's a lot of selling in beans and also other feed grains because (investors) think people will not eat red meat anymore. It's pretty suspicious rational, but that's what it was,'' said analyst Mike Young of Pacific Futures Trading in Seattle. Corn is used primarily to feed cows, so expectations of less demand pressured prices. Soybeans, another popular feed, dropped in sympathy.

Corn futures also retreated on speculation farmers will be able to increase spring fieldwork because of clear skies over much of the Midwest. Despite calls for cool weather, farmers will head to their fields, said analyst David Armstrong at Chicago Corp. ``Farmers in the spring, start planting as soon as they can. They decide to plant one field, and once they start, they never stop,'' he said.

Corn also fell on expectations that acreage will increase as farmers plow under once-frozen wheat plants and plant corn, said analyst Daniel Markey at AgriAnalysis consultants in Evanston. Wheat futures retreated in continued follow-through selling from suspicions the winter wheat crop suffered only slight damage from a weekend frost.

Corn for May delivery fell 5 1/2 cents to $2.97 1/4 a bushel; May soybeans fell 3 3/4 cents to $8.32 1/4 a bushel; July wheat fell 6 1/4 cents to $4.15 1/2 a bushel, and May oats fell 3 cents to $1.71 1/4 a bushel. Creutzfeldt-Jakob reports also sent beef futures plunging on the Chicago Mercantile Exchange.

Pork prices, which have been independently strong, gained on speculation that people may switch from beef to pork, analysts said. Live June cattle fell the 1.5-cent limit to 63.90 cents a pound; May feeder cattle fell 1.42 cents to 70.22 cents a pound. June lean hogs rose .37 cent to 83.45 cents a pound, and May frozen pork bellies rose 1.95 cents to 84.55 cents a pound. AP-NY-04-16-97 1609EDT

Protection Urged for Researchers Who Threaten Vested Interests

By GINA KOLATA ... NY Times 17 April 1997

A group of researchers has called for stronger protection for scientists who make discoveries that threaten vested interests, saying that some have paid a high price. The scientists, from the University of Washington at Seattle, say that they themselves had been attacked by doctors, patient advocacy groups and drug companies, that their careers were threatened and that even a federal agency was undermined.

In a paper published Wednesday in The New England Journal of Medicine, the University of Washington researchers described nightmarish experiences that they said resulted from three findings in particular: that a popular form of spine surgery might not be effective, that tests of immune system dysfunction, used to support disability and liability claims of patients who say they have "multiple chemical sensitivity," might be meaningless, and that a popular drug used to lower blood pressure was associated with an increase in heart attacks.

The scientists, led by Dr. Gilbert S. Omenn, the dean of the School of Public Health and Community Medicine at the University of Washington, report that the attacks included an effort by the North American Spine Society [a group representing spine surgeons, started a letter-writing campaign to Congress saying that Deyo and his colleagues were biased and inept. ] and a patient advocacy group founded by a surgeon to eliminate the federal agency that paid for the research on the spine surgery. Now, they say, that agency no longer offers clinical guidelines.

The attacks also included a series of misconduct charges lodged by a patient advocacy group against two researchers who studied multiple chemical sensitivity. The investigation of the charges was so prolonged and so unrelenting that even though the researchers were cleared, they say in interviews that they will never study that subject again.

And, Omenn and his colleagues say, their findings on the drugs for lowering blood pressure were met by harassment from drug companies and their academic consultants.

The paper, by coincidence, comes just a day after The Journal of the American Medical Association published a long-suppressed paper by a scientist who found that Boots Pharmaceuticals' brand name thyroid drug was no better than generic versions. Pfizer had paid for the research and prevented its publication for seven years.

Dr. Gregory Simon who, with his colleague Dr. Edward H. Wagner, conducted the study of multiple chemical sensitivity, said he was so disheartened by attacks on his work that he abandoned it. Patients with multiple-chemical sensitivity claim to be made ill by a variety of common chemicals. But some doctors question whether the disorder exists. Dr. John Sergent, a former president of the American College of Rheumatology, said, "The disease is a haven for quacks and hucksters."

Describing his experience after his research was reported, Simon said, "I would go to meetings and be roundly denounced." Although his study was paid for by a research fund from the Boeing Co. that was run by the union and management, Simon said, "We were being attacked as being somehow in the thrall of or beholden to chemical companies."

Donnay of the patient advocacy group asked that Simon's medical license be revoked, spurring action by the state medical board. He complained about the researchers to the University of Washington and to the Group Health Cooperative of Seattle, where they also had appointments. The complaints were dismissed, appealed, dismissed again and appealed again, Simon said.

"We were accused of all kinds of things: withholding data, fraud, conspiracy," Simon said. When investigatory bodies concluded that the accusations were without merit, Simon said, "they would be attacked themselves as part of conspiracy."

The Messenger under Attack
Intimidation of Researchers by Special-Interest Groups

NEJM April 17, 1997 -- Volume 336, Number 16

Attacks on health researchers are not new. Pierre Louis, for example, was vilified nearly two centuries ago for suggesting that bloodletting was an ineffectual therapy. (1) In an open society such as ours, controversy is common and often socially useful. The fact that scientists are sometimes challenged by special-interest groups should be no surprise. However, with widening media coverage of health research, growing public interest in health hazards, and expanding research on the outcomes of clinical care, such attacks may become more frequent and acrimonious. The huge financial implications of many research studies invite vigorous attack.

In Marcia Angell's recent Shattuck Lecture, she argued that litigation, fear, bias, and greed interfere with scientific efforts to answer questions of importance to public health and that an antiscientific social attitude encourages premature or ill-informed political and legal solutions to medical questions. (2) She noted that intimidation may cause investigators and institutions with access to critical sources of data to shy away from conducting research on controversial topics.

Studies of health hazards are illustrative of this problem. Media and courtroom approaches rapidly overshadowed clinical and epidemiologic studies of the potential adverse effects of breast implants. (2,3) The lead industry hobbled the work of Needleman and colleagues on the health risks of low-level lead exposure and intimidated others through coordinated attacks at scientific meetings and skillful manipulation of the procedures for investigating scientific misconduct. (4,5,6) The National Rifle Association and its allies, angered by studies funded by the National Center for Injury Prevention and Control, part of the Centers for Disease Control and Prevention, that demonstrated the risks to family members posed by guns in the home, tried to eliminate the agency that provided the funding. (7)

Such attacks often focus on "hot-button" policy issues (chemical exposure, firearm injuries) or on data relevant to large disability or liability claims (breast implants). Three recent experiences involving our institutions illustrate how vituperative such attacks may be and the range of tactics employed. Such episodes warrant close scrutiny, because intimidation of investigators and funding agencies by powerful constituencies may inhibit important research on health risks and rational approaches to cost-effective health care.

Disaggregation of Alzheimer -amyloid by site-directed mAb

Proc. Natl. Acad. Sci. USA Vol. 94, pp. 4109-4112, April 1997 Beka Solomon, Rela Koppel, Dan Frankel, and Eilat Hanan-Aharon In Alzheimer disease, -amyloid peptide accumulates in the brain as insoluble amyloid plaques. Amyloid filaments, similar to those found in amyloid plaques, can be assembled in vitro from chemically synthesized -peptides. In this study, we report that antibodies raised against the N-terminal region (1-28) of the -amyloid peptide bind to the in vitro-formed -amyloid assemblies, leading to disaggregation of the fibrils and partial restoration of the peptide's solubility. The concomitant addition of fibrillar -amyloid with these antibodies to PC 12 cells leads to the inhibition of the neurotoxic effects of -amyloid. Some of the mAbs raised against soluble -peptide (1-28) have been found to prevent in vitro fibrillar aggregation of -amyloid peptide. These experimental data suggest that site-directed mAbs interfere with the aggregation of -amyloid and trigger reversal to its nontoxic, normal components. The above findings give hints on how to convert in vivo senile plaques into nontoxic, diffuse components and may have therapeutic interest for those studying Alzheimer disease and other human diseases related to amyloidogenic properties of physiological peptides and proteins.

New immunoassays for PrPSc

new Prusiner paper: fulltext online. "N-terminally tagged prion protein supports prion propagation in transgenic mice"

If an epitope tag can be engineered into a region of PrPC where it is hidden from detection by Abs but still allows conversion of the molecule into PrPSc, then such recombinant PrP molecules might be ideally suited for a PrPSc immunoassay. Because the conformational transition is so large during the conversion of PrPC into PrPSc, it is likely that an epitope buried in PrPC might become exposed in PrPSc. If such an epitope tag can be designed that is detected in PrPSc but not PrPC, then transgenes carrying such epitope-tagged PrP molecules might form the basis for a rapid assay for prions in humans, cattle, and sheep. The report of possible prion transmission from cattle to humans makes the need for rapid prion assays all the more pressing (Will et al., 1996).

"Worldwide" incidence of CJD

Webmaster 18 April 1997

I have tracked down the source of an oft-quoted factoid that on its face has to be rubbish. And that would be that somehow the "worldwide" cross-cultural incidence of CJD has been determined and furthermore is a constant.

For starters, this could not apply to Africa (data from Zaire?), India (1 person in 6; see below), China (1 person in 5, earlier posting), Russia (one 1991 clinical paper), Iran (first case described in 1996), Indonesia / Malaysia (nothing), and so on. It seems to boil down to a 1979 paper on various Europeans plus maybe Japan and some N. African immigrants.

Perhaps what was originally meant was that the nominal rate, ignoring the Alzheimer's effect, in _Europeans_ was the same wherever in the world they went, meaning mostly Australia/NZ and the US. Later this got taken by third parties to mean vegetarians in India had the same rate, which has been asserted many times on this listserve. However, India would need 18,000 cases whereas they are reporting 30, some of which are reported sheep-brain rabies vaccine iatrogenic:

CJD in India (1971-1990).

Neuroepidemiology 10 (1): 27-32 (1991) 
Satishchandra P, Shankar SK
Thirty cases including 20 definite and 10 probable cases of Creutzfeldt-Jakob disease (CJD) seen in India between 1971 and 1990 are reported. Demographic analysis has shown similarities to the previously published reports from other parts of the world. Though 21 (70%) of cases were from two centers--Bombay and Bangalore-, suggesting clustering, this seems to be more apparent than real. One subject worked in the medical field, where possibility of iatrogenic transmission could not be ruled out. None of the cases had positive family history of CJD. There is no epidemiological data of CJD from India so far and hence this report is one such pilot study. [Note date: this is 12 years _after_ the 1979 paper's conclusions]

Acquisition of spongiform encephalopathies in India through sheep-brain rabies vaccination.

Indian J Pediatr 58 (5): 563-565 (1991) 
Arya SC  Centre for Logistical Research and Innovation, Greater Kailash, New Delhi. 

Prion disease

Will, R. G. [Correspondence]
Lancet (British Edition) 1990 336 8711 369-370 
A letter followed by five others on the same subject by H. Diringer, L.R. Bridges, H. Fraser, J. Hardy and A. Goate, and S.C. Arya. The correspondence by S.C. Arya suggests the cases of Creutzfeldt-Jakob disease in India may have resulted from scrapie in rabies vaccine made from sheep's brain.
Arya, S. C. [Correspondence]. National Medical Journal of India 1991 4 6 311-312 
Because of the widespread use of Semple-type rabies vaccines produced from sheep brains there is a possibility of the number of spongiform encephalopathy cases in man increasing due to transmission of the scrapie agent. The author suggests a number of measures that should be adopted to monitor prevalence of Creutzfeldt-Jakob disease in those vaccinated with the Semple-type vaccine.
To the Editor: NEJM
Geldmacher DS, Whitehouse PJ. Evaluation of dementia. N Engl J Med 1996;335:330-6. 
December 26, 1996 -- Volume 335, Number 26
Geldmacher and Whitehouse state that the annual incidence of Creutzfeldt-Jakob disease in the United States is 1 per 167,000 population. This is the incidence for a subgroup of the population that is 70 to 74 years of age. The study to which the authors refer, an epidemiologic analysis of national mortality data by Holman et al., (1) reports an "average annual age-adjusted mortality rate of 0.9 deaths per million persons, a rate consistent with published estimates of the crude incidence worldwide of 1 case per million persons." The study by Masters et al. (2) to which Holman et al. refer states, "In the United States, the average annual mortality rate is used by epidemiologists to estimate annual disease incidence due to the rapidly fatal course of the disease for most patients with CJD [Creutzfeldt-Jakob disease]." Elizabeth W. Lazzara, M.D. College of Physicians and Surgeons of Columbia University New York, NY 10032
References 

            1. Holman RC, Khan AS, Kent J, Strine TW, Schonberger LB. Epidemiology of
            Creutzfeldt-Jakob disease in the United States, 1979-1990: analysis of
            national mortality data. Neuroepidemiology 1995;14:174-81. 
            Return to: Text 

            2. Masters CL, Harris JO, Gajdusek DC, Gibbs CJ Jr, Bernoulli C, Asher DM.
            Creutzfeldt-Jakob disease: patterns of worldwide occurrence and the
            significance of familial and sporadic clustering. Ann Neurol 1979;5:177-88.

Variations in CJD rates

Dr Stuart Neilson 18 Apr 1997
CSHSD, Brunel University
Not only is there obvious worldwide variation in the rates of CJD (Jeff Almond had some nice slides of this, showing no geographical association with sheep density or scrapie prevalence), but there is an association with life expectancy - a greater proportion of the population of countries with a high life expectancy die from CJD. There is also a continuous increase in CJD in all countries for which reliable data is available - the CJDSU has some European summaries on its web pages. Mortality rates from CJD have approximately doubled in the last two decades, although you might choose to attribute this to greater awareness.

The same pattern of change (including shifts in age distribution of death) is apparent for almost any disease in which genetic susceptiblity is a factor, including many cancers, Alzheimer's disease, MS and ALS. If death due to competing causes (principally infectious and circulatory disease) declines, then a greater proportion of susceptible individuals die from genetic causes, leading to an apparent increase in rates. No change in risk factors is required.

In Down's syndrome, the prevalence has increased by a factor of eight (ie: 700%) and death rates by several thousand percent at ages older than 5 over the last three decades. This is not because Down's syndrome is becoming more frequent but because infectious disease (eg: bronchitis and pneumonia) has declined as a competing cause of death for individuals with trisomy-21. Life expectancy for people with Down's syndrome has increased from 4 to 43 years over this time scale. If one did not know the genetic basis of Down's syndrome and simply studied death rates (just as CJD rates are currently being discussed), one might well assume that a potent new factor had led to an epidemic of the condition.

In the case of CJD, I would contend that there is no basis for assuming that any CJD is sporadic; furthermore I would contend that all cases have a genetic predisposition modified by exposure to unknown trigger factors. Incidentally, this may mean that there can be no large-scale epidemic of nvCJD and that numbers of cases of CJD in the UK will actually begin to FALL if exposure to the BSE agent was/is a risk factor.

Is bovine spongiform encephalopathy solely food-borne?

Dr Stuart Neilson 18 Apr 1997
CSHSD, Brunel University
Here's a letter I wrote in August last year at the end of the Weybridge trial. It was not published, but may interest some. In general terms, for both BSE and CJD, I assume the arguments Nora Hunter makes for scrapie: genetics determines susceptibility, but there is another factor preceding disease. In the case of BSE in the vertical transmission trial, feed is one additional factor. The point I wish to make is that even in the absence of any genetic data, the proportion of susceptible individuals in the population is estimable. The incorporation of these susceptibility factors (absent from all the published models of the BSE epidemic) is essential to interpreting any results. The recently reported excess of bovine spongiform encephalopathy amongst the calves of cattle with the disease is just as easily explained by inherited susceptibility combined with post-natal exposure as it is by any putative maternal transmission. The highly significant risk ratio (2.9:1, X2 = 17, p < 0.001) is compatible with autosomal recessive inheritance of a trait with an allelic frequency of 0.2 in the cattle population. Thus 20% of the offspring of selected cattle with bovine spongiform encephalopathy mated with unselected bulls could be expected to inherit the recessive trait, as compared with only 4% of the offspring of unselected cattle mated with the same bulls.

A second estimate of allelic frequency is possible from rates of bovine spongiform encephalopathy in well-documented, affected herds of British cattle [1]. The lifetime risk of the disease (the proportion of animals which ultimately develop the disease) is limited to between 12 and 18% of the herd. This might initially suggest an allelic frequency of between 0.34 and 0.42, although there is considerable upward bias resulting from the exclusion of unaffected herds. It is notable in this respect that 50% of British herds number less than 50 animals [2].

The odds ratio of about 1.3:1 in the original case-control study (not significant) [2] and an odds ratio of about 1.9:1 suggested by data graphed in 1995 Progress Report [1] (no significance reported), combined with the latest results, are compelling evidence that maternal status is important. However, the unexpectedly low numbers of (reported) cases of bovine spongiform encephalopathy in exported British cattle suggest that maternal status alone is not sufficient to cause disease in offspring and that continued or subsequent exposure is a necessary condition for disease.

Significant genetic differences between cattle with bovine spongiform encephalopathy, related cattle and unaffected cattle [3] have been reported in only one study, although an abundance of familial relatedness amongst diseased animals does suggest autosomal recessive inheritance [4]. Maternal transmission of bovine spongiform encephalopathy, as for maternal transmission of scrapie [5], is best explained by inherited susceptibilty.

References

1. MAFF (1995) Bovine spongiform encephalopathy in the United Kingdom: A progress report.

2. Hoinville et al (1995) A case-control study of calf feeding practices. Veterinary Record 136(13):312-318

3. Neibergs HL, Ryan et al (1994) Polymerase analysis of the prion gene in BSE-affected and unaffected cattle. Animal Genetics 1994;25(5):313-317

4. Wijeratne WVS and Curnow RN (1990) A study of the inheritance of susceptibility to bovine spongiform encephalopathy. Veterinary Record 1990;126(1):5-8

5. RM Ridley and HF Baker (1995) The myth of maternal transmission of spongiform encephalopathy. BMJ 1995; 311 (7024): 1071-1075 1. Hunter, Goldmann, Smith and Hope (1994) Frequencies of PrP gene variants in healthy cattle and cattle with BSE in Scotland. Vet Rec, 135(17):400-403.

6. Brown DR, Zhang et al (1993) Bovine gene allele frequencies determined by AMFLP and RFLP analysis. Animal Biotechnology 1993;4(1):47-51

7. Grobet L, Vandevenne et al (1994) Polymorphism of the prion protein gene in Belgian cattle. Annales de Medecin Veterinaire 1994;138(8):581-586

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