Badpuppy Gay Today |
Monday, 12 January 1998 |
CONTENTS: 1998 Outlook: Treatment; Research; Access Efavirenz (Sustiva) Expanded Access Now to 400 CD4 San Francisco: Blood Needed for HIV Immunology Studies Treatment Conferences and Meetings, 1998 1998 Outlook: Treatment; Research; Access At this time there is more good news on treatments than bad. And in research, at least as much progress is happening today as at any time. Treatment development today does not have a high profile, however, since there is no single big picture, as there was when the protease inhibitors and modern "cocktails" were introduced. Here are some of the issues and developments we believe will be important this year. Part I: Current Antiretroviral Treatment Death Rate Remains Lower Some have feared that the reduction in death rate seen in the last two years could prove temporary, as patients' viruses develop more resistance to the drugs now used, before new ones become available. This could still happen, but it does not seem to be happening now. There are continuing reports of major declines in AIDS deaths and infections; for example, Frankfurt University Hospital recently had a 70% drop in the incidence of AIDS-defining infections (H.R. Brodt and others, "Changing Incidence of AIDS-Defining Illnesses in the Era of Antiretroviral Combination Therapy," AIDS, 1997, pages 1731-1738), and the Massachusetts prison system, a leader in making modern treatments available, had AIDS deaths decline from 29 in 1990, to 14 in 1995, to 5 in 1996, to 1 in 1997 (BOSTON GLOBE, December 26, 1997, page A1). Most official figures are months or years old by the time they are summarized andreleased. So for the earliest indicator we also check the number of obituaries in the weekly BAY AREA REPORTER, a San Francisco gay newspaper which for years has published these death notices as they are received. The average number per week fell by half during 1996, to about four; even at the beginning of that year, the number was much lower than it had been. Today the average is still about four; there is no sign of the possible increase in deaths which some had feared. (These figures may underestimate the improvement, since some of the deaths are not AIDS related, some who died did not get modern medical care, and many patients move into or out of the San Francisco area; all of these factors are likely to mask the reduced risk here. On the other hand, the number of HIV infections per year in San Francisco fell greatly from 1984 to 1987; this would likely have caused a gradual decrease in deaths today even without treatment.) Still, there are many deaths despite the best treatment. And the anti-HIV drugs now available are expensive and difficult, they do not suppress the virus in everyone, and some patients cannot tolerate them due to side effects. Also, there is little hope today that merely suppressing the virus for a few months or years will be enough to completely eradicate it from the body. Clearly today's treatments are not enough. New options must be developed. Virological Treatment Failure, Clinical Consequences Uncertain At the ICAAC conference in October 1997, San Francisco General Hospital researchers reported that only about half of a cohort of patients receiving modern combination treatment including protease inhibitors were consistently maintaining an undetectable viral load. This contrasted to reports of about 85% maintaining suppression in some clinical trials. Recently a similar finding was reported from two German tertiary care treatment centers (Gerd Fatkenheuer and others, "Virological Treatment Failure of Protease Inhibitor Therapy in an Unselected Cohort of HIV-Infected Patients," AIDS, 1997, pages F113-F116 (fast track). It is not surprising that "real world" results are different from those of clinical trials. The trials are run under idealized conditions, including carefully selected volunteers (usually with little previous treatment with the drugs), and plenty of staff to make sure that the volunteers understand how to use the drugs correctly, and appreciate the importance of doing so. Some treatments may still be beneficial even after they have failed to control HIV viral load. A number of physicians have noticed that patients have remained healthier than expected, when they stayed on combination treatment including a protease inhibitor despite partial return of the virus. It is not known why this has happened, or how long the benefit may last. One possibility is that HIV which has become resistant to certain drugs has been weakened in some way, and is less harmful. But also it is possible that in time the virus will develop more resistance, or in some other way this apparent clinical benefit of some treatments even after virological failure may prove temporary. The possible value of continuing certain treatments even after viral return will be a closely watched question in 1988. No Time Clock for Viral Escape It now appears that there is no significant development of viral resistance while a patient's viral load is suppressed to below the level of detection of the best viral load tests. This suggests that, under ideal conditions, the combination treatments we have today may continue to work indefinitely for some patients; if complete viral suppression can be maintained, there is no slowly developing resistance which will eventually cause viral escape from the drugs. The drawback, of course, is that ideal conditions are hard to come by. For many patients--especially those who have already used antiretrovirals in ways now recognized as not optimal--the drugs will not fully suppress the virus, allowing resistance to develop. Others will lose their chance to maintain complete suppression by being careless about using the drugs, again allowing HIV to develop resistance--or they will be prescribed the drugs but not effectively told what they are and how to use them. Some may adhere to treatment exactly as directed, but still get inadequate blood levels to fully suppress the virus, because of individual differences in their absorption or metabolism of one or more of the drugs. Others may not be able to afford to continue treatment--or they may be entitled to receive the drugs, but lose access from time to time because of rigid rules of insurance companies, pharmacies, medical practices, or other institutions. And many others will be unable to tolerate long-term use of these treatments. New Antiretrovirals Now in Expanded Access Three new antiretrovirals have recently become available on expanded access. They are: * Abacavir (1592); * Efavirenz (brand name Sustiva(TM), DMP-266); * Adefovir dipivoxil (brand name PREVEON(TM), bis-POM PMEA) A major importance of their availability is that, when antiretrovirals are changed due to treatment failure, it is important to have at least two new drugs which do not have cross resistance with the ones that have failed, to increase the chance of suppressing the virus enough to prevent ongoing replication and therefore development of virus resistant to the new treatment regimen. Because many patients are already resistant to the approved drugs, new treatment options are needed. (However, there are unfortunately no data yet on combining these three drugs.) And these are still experimental treatments, on expanded access because there is not enough data yet for marketing approval by the FDA. Less is known about potential side effects than with approved drugs, and much less is known about how to use them effectively. Importance of Adherence (Compliance) A major problem in medicine is that many patients do not use drugs or other treatments as directed. Studies have found that a large fraction of prescriptions are not taken properly--and that even as they leave the doctor's office, many patients cannot identify the medications they are being given, or tell the interviewer what they should do with them. With HIV treatment this problem is especially severe, because of the difficulty of the regimens, the fact that they will need to be used for years, and the serious consequences of using them badly (which can result in the permanent loss of an important drug or class of drugs, because the patient's virus has become resistant). What is being done is to bring together HIV specialists with experts who have studied adherence in other fields. Many strategies can be used to reduce problems--from devices like timers, pagers, or other reminders, to organizing healthcare so that patients get the right counseling before starting modern antiretroviral regimens (including advice about what to do if a dose is forgotten or other problems occur). Meanwhile, companies in their own interest are developing drugs which will be easier to use--taken no more than twice a day, taken without regard to food, and more forgiving than the current antiretrovirals if mistakes are made. Part II: New Treatment Approaches A number of new approaches to treating HIV disease were discussed in our recent interview with Dr. Robert Gallo, (AIDS TREATMENT NEWS #285, December 19, 1997), and will not be repeated here. They include MDC (macrophage derived chemokine), HAF (HCG-associated factor), treating human herpes virus 6 to see if this virus is harmful in late-stage AIDS, and using vaccination technology to reduce excess levels of certain cytokines in the body. Here a few additional approaches that we will be watching in 1998: Restoring the Immune System's Ability to Control HIV Early in HIV infection, the human immune system does an excellent job of controlling HIV, reducing viral load more than any known combination of drugs. But usually this ability is lost early in HIV disease--although it may be retained in some long-term nonprogressors. If researchers could learn how this immune response is lost, and restore it by therapy, then the need for difficult, expensive, and often toxic antiretroviral drugs might be greatly reduced. A number of possibilities are now being studied. One, the recently published finding from Bruce Walker's group at Harvard that CD4 cells which specifically recognize HIV correlate very well with who will be a long-term nonprogressor, and who will have a high or low "set point" of HIV viral load, has generated much enthusiasm, even though this particular study involved only a handful of patients. These cells are not found in uninfected people, but are found early in infection, and then usually disappear quite early in HIV disease, long before the large drop in total CD4 cells. These HIV-specific cells do not automatically come back when HIV is suppressed by successful antiretroviral treatment. A major reason for the enthusiasm is that these cells suggest a biologically plausible target for intervention. Could they be restored by certain vaccination techniques while the HIV is suppressed by antiretrovirals? Could their loss be prevented in the first place if antiretroviral treatment is begun very early in HIV infection? Could they be a potential target for testing a potential preventive vaccine (so that rapid trials in a few people could help predict which vaccine candidates are most likely to work)? No one knows yet if these cells can serve as a useful marker of effective immune-based treatment. But the new finding certainly suggests that this possibility should be tested--offering some very plausible directions for research on immune-based treatments, and for combining immune approaches with the effective antiretroviral treatments already in use. Hopefully this finding will give more momentum to the strategy of laboratory-intensive clinical trials with a few patients. Such studies specialize in sophisticated laboratory testing to answer major, focused questions--instead of the more common strategy of treating enough volunteers to find out whether one inadequate treatment is marginally better than another. There are other approaches to restoring an immune response against HIV. One example is the universal T-cell receptor, being developed by Cell Genesis and now in early human trials, which uses a genetically engineered cell to overcome some of the limitations of naturally occurring CD8 cytotoxic T lymphocytes. (A recent description is Otto O. Yang and others, "Lysis of HIV-1-Infected Cells and Inhibition of Viral Replication by Universal Receptor T Cells," PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES USA October 1997, pages 11478-11483.) Preventive Vaccines. Recently IAVI (the International AIDS Vaccine Initiative) announced three research grants: to study a live-attenuated SIV vaccine, a DNA-based live-attenuated vaccine, and hybrid viruses (SIV with HIV type E and C envelopes). Besides the immense importance of a preventive vaccine, the research to develop it is also important for persons already infected, since some of the key problems for developing preventive vaccines or immune-based therapies are the same--especially the identification of correlates or markers of effective immune response against the virus. New Generation Protease Inhibitors and RT Inhibitors A number of companies have new protease inhibitors in the research pipeline. Usually these are active in lower doses against HIV, and/or are active against a wider variety of viruses, including those which are resistant to protease inhibitors now approved. This research will probably lead to antiretrovirals which offer new and better treatment options. However, HIV resistance is likely to remain a problem with these new drugs as well. There are also new reverse transcriptase inhibitors--which could also lead to important treatment advances--now in clinical trials. Integrase Inhibitors So far all of the drugs approved specifically for use against HIV have targeted either the reverse transcriptase, or the protease, of the virus. Integrase, which the virus needs to integrate its genetic material into that of the host cell, is a third viral enzyme target for drug development. Unfortunately the major pharmaceutical companies have been slow to develop integrase inhibitors; but one drug, Zintevir(TM) (being developed by Aronex Pharmaceuticals) is now in human trials. It is not yet known how well this new drug class will work. But one advantage will be that there is not likely to be any cross resistance between integrase inhibitors and the existing classes of antiretroviral drugs (just as there is no cross resistance between RT inhibitors and protease inhibitors). Zinc Finger Inhibitors The "zinc finger," a structure in HIV which cannot readily change by mutation, provides yet another target for drug development. This approach, researched for years in laboratories, is now in early human testing. Other Experimental Treatments Many other experimental drugs are worth following in 1998, for example: T-20 This genetically engineered peptide, designed to target a certain step in the process by which HIV attaches to cells, has already shown that it can substantially reduce viral load in humans. Due to its unique mechanism of action, there is unlikely to be cross resistance with the treatments currently in use; therefore T-20 may work as well on those who have been heavily pretreated as on those who are treatment naive. No adverse events have been found in the phase I/II trials. The main disadvantage of T-20 is that it will probably have to be given by continuous infusion. A small computerized pump with a flexible catheter--worn like a pager and used successfully in diabetes treatment--is used to deliver T-20 in clinical trials. Part III: Access to Care The many problems, economic and other, around access to medically appropriate care are likely to be the major focus of activism in 1998. Here are a few of them: Preventing Red-Tape Treatment Interruptions Many people who clearly are insured or covered under public or private programs have had their treatment interrupted because of red tape at HMOs, pharmacies, etc. Sometimes the problem is a "computer glitch"; sometimes an error in medical records; sometimes a delay in the funding stream for a government or private program; and sometimes just the mechanics of processing the prescription in an age of institutional medicine. Or perhaps a patient's medicine has been lost and a refill will not be provided until all of the lost pills would have been used. Or the patient has to be out of town when the new prescription will become available, and red tape prevents it from being picked up in advance. Some pharmacies, etc., may allow flexibility, but many just go by the book. Most people cannot reach into their pockets at short notice and pull out a few hundred dollars to buy their way out of a temporary insurance problem. Another approach is to delay starting antiretrovirals for a certain time after one's prescription begins, perhaps a couple weeks, creating a reserve which can be used to prevent unscheduled interruptions which could lead to viral resistance. (Delaying treatment must *not* be done in some situations when time can be critical, or if the medication will deteriorate; hopefully physicians will provide realistic advice.) Sometimes patients borrow medicines from others, and repay them when their prescription comes through. This cluster of bureaucracy problems, which is separate fromthe issues of getting access to care for those who do not have it, has somehow escaped the attention it needs. One approach would be to create ombuds offices, which could do the fighting when necessary so that the patients would not have to--and also could use their case-by-case experience to learn how to change the system to prevent dangerous treatment interruptions in the first place. Risk Adjustment in Managed Care "Managed care" usually means that doctors are paid by capitation--that is, they are paid so much per patient per month, whether the patient needs treatment or not. If much care is needed, the doctor (or medical practice) must personally cover the loss. Unless the monthly capitation rate is adjusted for severity of illness, each patient with an expensive condition like AIDS or cancer will mean money out of the doctor's pocket. This can make it impossible for a specialized practice to survive--even though it has been clearly shown that AIDS patients live longer if their doctor is experienced in treating HIV. Getting Treatment for the Uninsured or Inadequately Insured Federal funding for ADAP (the AIDS Drug Assistance Program) may be substantially increased. But there will still be major differences between states, with not enough funding for everyone who qualifies. And ADAP--supported by a coalition between people with HIV and the pharmaceutical industry--only pays for drugs, not primary care. Another approach to providing treatment to many who cannot now get it is to expand Medicaid eligibility so that people with HIV who meet the income requirements do not have to wait until they are disabled before qualifying for the program. The idea is to prevent disability, keeping people at work and avoiding expensive hospitalization, by providing access to antiretroviral treatment before clinical illness develops, when this is medically indicated. This proposal appears to have been initially rejected by the Clinton Administration as too expensive. The problem seems to be that it developed with the expectation of being "revenue neutral"--that is, that it would save at least as much money as it costs. While it may be revenue neutral in the long run, there would be a net expense at first, since when people with early HIV infection are treated, there is no immediate hospitalization savings to offset against the drug costs. (For those with advanced AIDS, treatment clearly does save money even in the short term.) In other diseases and public-health programs, the customary calculation is cost per year of life saved. For early treatment of HIV, this cost is on the order of $10,000 per year (about the price of the drugs), since it now appears that HIV disease may be postponed indefinitely in many cases by effective early treatment. This cost per year of life saved is well within what is paid in other diseases, where $50,000 or even much more is often acceptable. (The "revenue neutral" goal would appear to mean that the cost per year of life saved must be $0. or less.) Treatment for Immigrants and the Undocumented Serious problems have developed because of anti-immigrant legislation from Congress. People who have lived in the U.S. for years or decades (sometimes brought here as children), have been part of U.S. society in every way except for voting, and have become HIV-infected here, are now being denied medical care, and being deported--sometimes to countries where they do not know anyone and do not know the language, and have no way of supporting themselves or continuing medical care. Persons with HIV have not been allowed to become citizens or otherwise legalize their status, because they were singled out by previous Congressional legislation. A recent article in THE NEW YORK TIMES (December 29, page A-14) included an estimate that about 800 persons in New York City are affected (by Congressional revocation of most of the authority of the INS to grant temporary legal status in cases of extreme hardship)--a substantial number of people, but not enough to be a financial burden on the nation. This problem is one of discrimination, not lack of resources. Other Major Issues Treatment, access, and activism issues which will need separate articles include: * Major Federal expansion of medical research; * Managed care reform; * Medical marijuana; * Organ transplantation for persons with HIV; * HIV Care in the Veterans' Administration system; * Treatment issues specific to women; * Alternative treatments and research leads; * Medical care in prison; * International access to AIDS/HIV treatment; * AIDS treatment activism today. Efavirenz (Sustiva(TM)) Expanded Access Now to 400 CD4 On December 17 the DuPont Merck Pharmaceutical Company announced more flexible eligibility criteria for expanded access to efavirenz (Sustiva, also known as DMP-266). Now, U.S. patients who have ever had a CD4 count under 400 can be eligible; before, they had to have a count of less than 50 within the last 90 days. (In Europe, entry criteria will be similarly changed in the first quarter of 1998.) Efavirenz "must be used in combination with and initiated at the same time as at least one other marketed or investigational antiretroviral which the patient has not previously taken. Sustiva is not recommended as monotherapy. Patients are now eligible for this program if at any time they have had a CD4 cell count of less than 400 cells/mm(3), they are failing or intolerant to their current treatment regimen, and their physician is unable to assemble a treatment combination without Sustiva that is likely to produce a sustained reduction of virus in the blood. "DuPont Merck believes that patients who have failed non-nucleoside reverse transcriptase inhibitors are less likely to benefit from Sustiva because of a common mutation (K103N). "Physicians and patients may call 1-800-998-6854 for more information on inclusion criteria and materials for investigator and patient enrollment in the Sustiva Expanded Access Program." San Francisco: Blood Needed for HIV Immunology Studies Persons who are HIV positive--preferable with CD4 count under 300, and no major active opportunistic infections--can contribute to research at the Herzenberg Immunology Laboratory at Stanford University by donating blood for testing. The blood draw (two large and two small tubes of blood) will take place in San Francisco. Some volunteers will be asked to return for a second blood draw. The blood will be used for some or all of the following research: * The impact of glutathione depletion and oxidative stress on T-cell function, surface marker expression, viral load, and other aspects of HIV disease progression. * Measuring the frequency of HIV-infected cells within naive, memory, activated, and other kinds of CD4 cells. * Looking for defects in immune-system cells, by measuring the function of individual cells, classified according to their type. (Most research tests of cell function only measure the activity of mixtures of cells.) * Studying CD8 cells which are specifically targeted to HIV. * Using this information to understand the changes that occur in the immune system during progression of HIV disease. For more information or to schedule an appointment, call Virginia (Virg) Parks, 415-522-2916 (message line). Treatment Conferences and Meetings, 1998 January First Annual Immune Function and Surrogate Markers: Setting the Goal Line, January 9-11, Baltimore. Pain Management and Chemical Dependency, January 15-17, New York. NATAP Treatment Information Forum, January 17, New York. Ninth Annual "Until There Is a Cure" Conference, January 23-24 CPCRA (Community Program for Clinical Research on AIDS), January 25-26, Washington. T Lymphocyte Activation, Differentiation and Death, January 26 - Feb 1 February 5th Conference on Retroviruses and Opportunistic Infections, Improving the Management of HIV Disease, February 13, Atlanta. Molecular Aspects of Viral Immunity, February 16-22, Tamarron, Colorado. Improving the Management of HIV Disease, February 21, Los Angeles. Global Disease Eradication, February 23-25, Atlanta. New Trends in Vaccine R&D: Adjuvants, Delivery Systems and Antigen Formulations, February 26-28, Paris. March Overcoming Resistance: New Strategies for Addressing the Emerging Problem of Antibacterial, Antiviral and Antifungal Resistance, March 4-6, Atlanta. Towards an HIV Vaccine, March 5-8, Palm Springs, California. Improving the Management of HIV Disease, March 11, New York. American Academy of Allergy, Asthma and Immunology 54th Annual Meeting, March 13-18, Washington. HIV Pathogenesis and Treatment, March 13-19, Park City, Utah. Presidential Advisory Council on HIV/AIDS, March 15-18, Washington, D.C. Molecular Mechanisms of Leukocyte Trafficking, March 22-28, Incline Village, Nevada. Micronutrients and HIV+/AIDS, March 22-24, Boston; co-sponsored by Tufts University School of Medicine Department of Family Medicine and Community Health, and Serono Symposia USA. HIV 10th National AIDS Update Conference, March 24-27, San Francisco. April Opportunistic Infections in AIDS, April 2-8, Keystone, Colorado. 11th International Conference on Antiviral Research, April 5-10, San Diego The Second National AIDS Malignancy Conference, April 6-8, Bethesda. Improving the Management of HIV Disease, April 7, San Francisco. 11th Annual HIV/AIDS on the Front Line Conference, April 15, Costa Mesa, California. Improving the Management of HIV Disease, April 22, Chicago. Protease Inhibitors, April 23-24, Boston. Contact: Cambridge Healthtech Institute 14th Annual Clinical Virology Symposium, April 26-29, 1998, Clearwater, Florida. 8th Annual Clinical Care Options for HIV Symposium, April 30 - May 3, 1998, Scottsdale, Arizona. May Improving the Management of HIV Disease, May 2, New Orleans. AIDS Watch 1998, May 3-5, Washington. (National lobby day.) Second European Conference of Antimicrobial Chemotherapy, May 10-13, Hamburg, Germany. 8th International Congress on Infectious Diseases, May 15-18, Boston. Enhancing Adherence to HIV Therapies: A Multidisciplinary Approach, May 15, New York. Improving the Management of HIV Disease, May 16, Cleveland. American Society for Microbiology 98th General Meeting, May 17-21, Atlanta. First Annual Conference on Vaccine Research, May 30 - June 1, Washington. June 8th International Meeting on Neuroscience of HIV Infection: Basic Research and Clinical Frontiers, June 3-6, Chicago. AIDS, Medicine, & Miracles, June 4-7, near San Francisco. 12th Annual AIDS Update for Primary Care--The Science of HIV Medicine: The Art of Delivering Care, June 5, Oakland, California. CPCRA (Community Program for Clinical Research on AIDS), June 11-12, Tyson's Corner, Virginia (near Washington). Bio '98 International Biotechnology Meeting & Exhibition, June 14-18, New York City. Presidential Advisory Council on HIV/AIDS, June 15-18, Washington, D.C. 2nd Annual Antisense Therapeutics, June 22-23, San Francisco. (Not AIDS specific.) 12th World AIDS Conference, June 28 - July 3, Geneva. July 17th Annual Meeting of the American Society for Virology, July 11-15, Vancouver. 20th National Lesbian and Gay Health Conference / 16th National AIDS/HIV Forum, July 25-29, San Francisco. August AIDS Clinical Trials Group, August 1-5, Washington. Clinical Care of the AIDS Patient, Summer Symposium, August 6-11, Sun Valley, Idaho. 5th International Congress of the International Society of Neuroimmunology, August 23-27, Montreal. AIDS, Medicine, & Miracles, August 27-30, Phoenicia, New York. September Third National HIV/AIDS Housing Conference, September 16-20, Atlanta. 38th ICAAC (Interscience Conference on Antimicrobial Agents and Chemotherapy), September 24-27, San Diego. October 4th Annual International Congress on Alternative & Complementary Therapies, October 2-4, Arlington, Virginia. (Not AIDS specific.) National Hemophilia Foundation 50th Annual Meeting, October 22-24, Orlando, Florida. CPCRA (Community Program for Clinical Research on AIDS), October 29-30, Alexandria, Virginia (near Washington). 2nd United States Conference on AIDS, October 29 - November 1, Dallas. November 4th International Congress on Drug Therapy in HIV Infection, November 8-12, Glasgow, Scotland. Infectious Diseases Society of America 36th Annual Meeting, November 12-15, Denver. Presidential Advisory Council on HIV/AIDS, November 16-19, Washington, D.C. AIDS, Medicine, & Miracles, November 19-22, Dallas. December National AIDS Treatment Advocates Forum, December (dates not yet set as this issue went to press), Philadelphia. AIDS Clinical Trials Group, December 5-9, Washington. AIDS-Associated Malignancies; Biology and Clinical Management, December 9, San Francisco. Clinical Care of the AIDS Patient, December 10-12, San Francisco. AIDS TREATMENT NEWS P.O. Box 411256 San Francisco, CA 94141 800/TREAT-1-2 toll-free U.S. and Canada 415/255-0588 regular office number fax: 415/255-4659 Internet: aidsnews@aidsnews.org Editor and Publisher: John S. James Statement of Purpose: AIDS TREATMENT NEWS reports on experimental and standard treatments, especially those available now. We interview physicians, scientists, other health professionals, and persons with AIDS or HIV; we also collect information from meetings and conferences, medical journals, and computer databases. Long-term survivors have usually tried many different treatments, and found combinations which work for them. AIDS Treatment News does not recommend particular therapies, but seeks to increase the options available.Subscription Information: Call 800/TREAT-1-2 ISSN # 1052-4207 Copyright 1998 by John S. James. Permission granted for noncommercial reproduction, provided that our address and phone number are included if more than short quotations are used.
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