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GMHC Treatment Issues
Now There are Eleven,
by Dave Gilden
With the April 7 FDA approval of Pharmacia & Upjohn's delavirdine (brand name: Rescriptor), there are now 11 drugs marketed in the U.S. for suppressing HIV. Delavirdine, like nevirapine (Viramune®) before it, is a nonnucleoside reverse transcriptase inhibitor, or NNRTI. NNRTIs chemically combine with HIV's reverse transcriptase enzyme to block the virus' infection of new cells. Their role in HIV therapy has always been uncertain because HIV rapidly develops resistance when exposed to the current members of the class, at least when these drugs go up against HIV alone: The best bet seems to be as first-line therapy in combination with fresh nucleoside analogs. Then, the protease inhibitors could be saved for occasions when HIV levels are very high or stubbornly resist treatment with other drugs. But then again, maybe it is best to go to maximum suppressive therapy with the less resistance-prone protease inhibitors in the first place.
Reading delavirdine's package insert is a scary experience that will put off most people from trying the compound. In the first place, resistant HIV emerges within a few weeks of taking the drug, due to a single mutation. That mutation most often occurs at reverse transcriptase's amino acid 103. This same mutation also reduces HIV's sensitivity to Du Pont Merck's experimental and much more active NNRTI DMP 266. It would be a shame to lose some of the advantages of DMP 266 through previous use of delavirdine. Largely because of its resistance problem, delavirdine provided no statistically significant benefit in two of the three clinical trials that led to its approval. One of these, ACTG 261, involved participants who had no prior therapy or less than six months of AZT. Preliminary analyses of the viral load and CD4 count data in ACTG 261 indicate that AZT/ddI is virtually equal to AZT/ddI/delavirdine or ddI/delavirdine and decidedly better than AZT/delavirdine. In another study, the AZT/delavirdine combination did do better than AZT alone in a cohort with six months or less of prior AZT therapy. This improvement was not apparent when evaluating CD4 count changes, only in terms of viral load. (A further reduction in HIV levels of only about 0.1 log -- 20% -- after week eight could be attributed to delavirdine. At week four, this difference briefly reached 0.5 logs or 67%.)
Then there is the problem that delavirdine therapy requires taking four 100 mg pills three times a day. This comparatively large burden, of course, comes in addition to the other antiviral drugs with which delavirdine must be taken (delavirdine monotherapy is strongly advised against). With the recommended regimen, delavirdine blood levels vary considerably from person to person, and on average women achieve 31% higher levels than men. Delavirdine is metabolized by the liver and inhibits the same CYP3A hepatic enzyme that the protease inhibitor ritonavir does (though not to the same extent). Like ritonavir, delavirdine comes with a long list of warnings concerning drugs whose blood levels it raises due to this suppression of liver metabolism. Delavirdine also causes skin rashes, usually (but not always) temporary, in about 20% of patients. Finally, it causes birth defects in rats.
This is not a very attractive drug. Except, except... One of the pieces of information that led the FDA to OK delavirdine was some data from Paul Bellman, M.D., a New York City AIDS specialist in private practice. Taking advantage of the preapproval delavirdine expanded access program, Dr. Bellman added the compound to the regimens of 60 of his patients who were experiencing rising viral loads despite being on AZT/3TC/indinavir. (In some patients, the AZT was switched to d4T at the same time). Lo and behold, 15 of the 27 patients whose records have been made available experienced a rapid viral load decline amounting to more than one log (90%) by the second or third month. Dr. Bellman has no way of checking, but he thinks that the people failing the indinavir regimens were not achieving high enough blood levels of this protease inhibitor, possibly due to poor absorption in the digestive tract. Delavirdine conceivably could have raised the patients' average indinavir levels by two-fold or more, due to its effect on the liver, where 80% of indinavir is broken down.
Dr. Bellman observes, "Delavirdine added to nucleoside analogs does not have these benefits. But adding delavirdine, a potent drug, to indinavir makes it potent, too. So now there are two potent new drugs in the patient's antiviral combination."
Dr. Bellman combines delavirdine with the standard indinavir dose of 800 milligrams three times a day. Upjohn, though, recommends that indinavir should be reduced to 600 mg three times a day when co-administered with delavirdine. The worry with high indinavir levels in the body is that some of the compound will end up in the kidneys as an extremely painful precipitate or sediment. Dr. Bellman says he has noticed no increase in this kidney stone problem, which strengthens his feeling that his failing patients had abnormally low indinavir levels to begin with.
The doctor's whole strategy rests on his personal intuition. He has not actually monitored the indinavir levels in any of his patients since such a test is not commercially available. His experience points out a gap in current research -- why people fail treatment regimens is not examined systematically. In particular, the drug levels achieved in patients are rarely looked at.
Merck, which developed indinavir, is now collecting blood samples from people who have not responded well to the compound. The reasons why people fail seem varied, according to Merck researcher John Condra. He says, "We don't have any evidence that failures have low blood levels. This is one possibility. Among the other explanations are drug resistance and inadequate compliance." If the problem is failure to take indinavir on schedule or to take it with food rather than on an empty stomach, this should be corrected first before adding delavirdine. If the problem is indinavir-resistant HIV and not low indinavir levels, the benefits and dangers of adding delavirdine are uncertain.
Adding to the mystery, Dr. Bellman notes that he has seen patients continue to fail when delavirdine was added to their indinavir regimen and then succeed on indinavir plus nevirapine. But nevirapine reduces indinavir levels rather than raising them.
Like the reasons for protease inhibitor failure, protease inhibitor/NNRTI combinations have suffered from lack of attention. Manufacturers in the past have tried to position their NNRTIs as substitutes for the more expensive protease inhibitors in combination regimens with nucleoside analogs. It nonetheless makes more sense to combine NNRTIs with protease inhibitors rather than nucleoside analogs since then two different HIV enzymes and points on the virus lifecycle are attacked rather than just one. In one small Vancouver trial, for people with AIDS who had failed all nucleoside analogs, the combination of 3TC, indinavir and nevirapine was surprisingly successful (see Treatment Issues, February 1997). Also, the two-drug combination of DMP 266 and indinavir in trials has suppressed HIV as effectively as most three drug combinations.
Dr. Bellman's results in his first patients are drawing increasing attention in New York City and elsewhere. The complete results are not in, though. For most of these initial patients, adding delavirdine to indinavir did not drive HIV down to undetectable levels (below 400 HIV RNA copies/ml of plasma). This leads to fears that long-term stability will not be maintained, given HIV's propensity to develop resistance to either of these two compounds when residual viral replication is possible during treatment. The clock may be set back, but usually it is still ticking; successful ways to recover from treatment failure need further elaboration.
Part of that solution appeared to be Upjohn's "spawn of delavirdine," a series of altered delavirdine compounds that the company tested in the lab and found to be active against delavirdine-resistant HIV. These compounds were described in a series of four papers over the past year, but Upjohn now says it has no attention of developing them further because they exhibited poor stability in animal studies. More recently, Upjohn has come up with a new set of NNRTIs, the "pryrimidine thioethers," which also are potent against delavirdine-resistant HIV as well as nonresistant virus. Their absorption and stability reportedly are excellent in rats, but Upjohn is still evaluating their future development. There is considerable speculation in the AIDS community that Upjohn is pulling back from HIV research. It will be interesting to see what the company does.
Ganciclovir Implants:
by Jill Cadman
Chiron Vision's Vitrasert eye implant for treating CMV was approved by the FDA in March of 1996 (see Treatment Issues, March 1996). The implant is an important breakthrough because it is able to deliver steady amounts of ganciclovir directly to the retina for months. Besides making massive daily infusions of ganciclovir unnecessary, it increases the drug's effectiveness by bypassing the blood-retina barrier and delivering high levels of ganciclovir to the localized site of CMV retinitis. A year's experience with Vitrasert has better defined its potential for treating CMV.
There were initial concerns about safety, especially regarding the risk of retinal detachments. Daniel F. Martin, M.D., in Atlanta, a major figure in the pre-approval implant trials, was among the first to voice these concerns. But CMV disease itself leads to retinal detachments in a large proportion of patients. Cumulative one-year risk ranges from 24% to 50%, according to various reports. Hence, it is not easy to pinpoint the cause of a detachment in an implanted eye.
CMV ABCs
CMV (cytomegalovirus) is a prevalent virus from the herpes family which can cause opportunistic infections in immune-compromised persons. It is estimated by the Centers for Disease Control (CDC) that one-third of all Americans are infected with CMV. The virus is transmitted through body fluids or transfusions. It is common for infected people to show no symptoms while CMV is inactive. There is a CMV antibody test commercially available for those wishing to know if they are infected. The risk of developing active CMV disease increases in persons with AIDS as CD4 counts decrease. Those with CD4 counts below 100 are at greatest risk and should begin ophthalmologic screenings for CMV retinitis. As CD4 cells drop below 50, screening should become more frequent. Screenings should continue even if CD4 cell counts increase due to antiviral therapy.
CMV is a systemic infection that can cause disease in many parts of the body in addition to the eye, including the brain, colon, esophagus and other organs. The most common manifestation is CMV retinitis, which causes lesions on the retina. Severity depends on the location of the lesion. Zone 1 disease causes damage in the highly sensitive central retina (the macula) and is most sight-threatening. Zone 2 includes the periphery of the retina. Infection there is less dangerous to vision, although it may spread to the central retina. CMV retinitis is frequently associated with CMV encephalitis, a severe brain disorder with multiple neurological complications (see Treatment Issues November 1996).
Treatment for CMV retinitis is given in two phases. An initial induction therapy consists of twice a day intravenous ganciclovir or foscarnet (or once weekly cidofovir) administered for two to three weeks. The purpose of induction therapy is to halt disease progression and prevent blindness. Induction is followed by maintenance therapy which consists of daily ganciclovir or foscarnet infusions, biweekly cidofovor infusions, or other treatments (see article) to prevent or delay reactivation of viral replication. It is difficult to completely suppress CMV, and if there is a reactivation, the patient will need "reinduction" via intravenous infusions.
Systemic medication can also be used as prophylaxis for persons with low CD4 counts who have never developed active CMV disease. There are indications that the choice of such therapy depends on a patient's CMV viral load. Those with very high plasma CMV burdens (over 50,000) may require preemptive intravenous (high dose) therapy, even when there is no evidence of active disease, while those with low CMV viral loads (below 50,000) may receive satisfactory results from a course of daily oral ganciclovir. (See Treatment Issues , September 1996).
Retinal detachment is a frequent complication of CMV infection. It occurs when a hole in the retina allows ocular fluid to seep behind, causing the retina to separate from the back of the eye (the choroid). The first symptom is often the appearance of small moving spots known as floaters. Surgery may be necessary to repair the hole and reattach the retina. The injection of silicone oil may also be used in the treatment of retinal detachments. Whatever the treatment, some loss of visual acuity can result. -- JC
With the advent of highly active antiretroviral therapy (HAART), some doctors hoped that improvements in CD4 counts would translate into lower risk for reactivation of CMV disease, calling into question the need for pre-planned implant replacement. However, increasing a patient's CD4 count through HAART does not always prevent CMV reactivation. Dr. Martin stated, "I stopped doing scheduled exchanges for awhile and was disappointed. I had some patients with very high CD4 counts and their CMV reactivated at about the same time I would have expected."
Dr. Martin advises those who have Zone 1 (central) disease to have scheduled replacements because they cannot afford to take a chance on loss of vision. For those with Zone 2 (peripheral) disease, Dr. Eviatar stated, "If the patient is doing better systemically and the lesion is not site-threatening, I think it's reasonable to wait and see how they respond. It may be that with the protease inhibitors, they are better able to control the CMV on their own or with oral ganciclovir."
Caution should be used when interpreting this small number of case reports. The first author of the letter and clinical director of the National Eye Institute, Scott Whitcup, M.D., stated, "We will need more information before recommending that all people with CMV retinitis and elevated CD4 counts stop their anti-CMV medications." Dr. Whitcup would not recommend coming off anti-CMV medication outside of a carefully picked patient population with extremely close supervision.
Mark Jacobson, M.D., and colleagues at the University of California San Francisco presented a study at the Fourth Conference on Retroviruses and Opportunistic Infections (abstract 353) representing the other end of the spectrum. The Jacobson study looked at five patients who had CMV retinitis diagnosed despite a CD4 count of 200 or more. Four to 24 weeks before the diagnosis, all patients had CD4 counts below 85, and four to eight weeks before the CMV diagnosis, all patients had initiated HAART. The researchers then examined data from 76 consecutive patients enrolled in a treatment trial for CMV retinitis. During the period from July, 1995 through February, 1996, only one patient out of 27 had CD4 counts above 50 and zero out of 27 patients had CD4 counts above 100. From March, 1996 (when HAART became widely available) through August, 1996, 14 out of 49 patients had CD4 counts above 50 and seven out of 49 had CD4 counts above 100. The investigators concluded that the immunological benefits of HAART may not fully protect against CMV retinitis, which may occur more commonly now in patients with CD4 counts above 50.
The authors of the JAMA letter suggest that such cases of CMV may be due to subclinical (asymptomatic) CMV retinitis existing prior to the onset of HAART. Dr. Whitcup notes that retinitis developed in patients in the Jacobson study shortly after initiation of HAART and feels that CMV would have eventually emerged in these patients in any case. Dr. Whitcup has seen his own patients develop such symptoms of CMV retinitis as vitreous floaters shortly after starting on HAART. It is possible that HAART cannot immediately protect a patient who already has a subclinical case of retinitis, but it may be protective against CMV progression over the longer run no matter what the initial status of the disease.
Dr. Whitcup said, "I have yet to see someone develop CMV retinitis who has been on HAART for over three months and whose CD4 counts are over 50 -- although I think there may be cases out there where that occurs." Of course those who have been on combination therapy for extended periods may experience "HAART failure" and subsequent CD4 count declines. Once CD4 counts fall below 50, there will be renewed risk for CMV progression.
The National Eye Institute is seeking to recruit AIDS patients with non sight-theatening CMV retinitis for further study at the NIH. A small 12-person trial will attempt to provide further insight into when it is appropriate to discontinue CMV treatment in patients on HAART. Anyone interested in this trial should contact Cheryl Perry at 301/435-4559.
There also is room for improvement in oral ganciclovir for maintenance therapy to prevent CMV reactivation. The current standard three-gram dose is not as effective as IV ganciclovir. Raising the daily dose of oral ganciclovir to 4.5 grams works better (see Treatment Issues, September 1996), but requires even more pills and expense. Roche's ganciclovir prodrug (RS-79070) is much more absorbable in the gut than the present version of ganciclovir and breaks down into the active form once in the body. The prodrug's oral bioavailability is about 61%, compared to about 8% for the current oral formulation. Data presented by Roche this past winter at the Fourth Conference on Retroviruses and Opportunistic Infections (abstract LB19) demonstrated that the same levels of serum ganciclovir can be achieved with the prodrug as with IV ganciclovir.
Providing that the pharmaceutical companies move forward, the future standard of care might employ Vitrasert II to treat the local manifestation of CMV retinitis for two years and one pill of ganciclovir prodrug per day to control extra-ocular disease. This treatment strategy would avoid what Dr. Martin calls "the emotional roller coaster of going back and forth from induction to maintenance therapy," which is the current experience of most people with CMV retinitis.
As this article was being readied for press, Hoffmann-La Roche announced that it was deferring development of the ganciclovir prodrug -- see box.
Roche Puts Ganciclovir Prodrug Program On Hold
Roche had planned three clinical trials for the prodrug: one for treatment, one for prevention and one for induction therapy. Two of those three trials are now on hold. According to a company letter sent to investigators, "A decision has been taken within Roche to reassess the development of the ganciclovir prodrug. This action has been precipitated by an apparent decrease in the incidence of new CMV disease which may be attributed to the wide availability of highly active antiretroviral therapies (HAART)."
The induction trial (Protocol WV 15376B) is currently the only one to go forward. About 20 sites across the country are now seeking to enroll a total of 70 participants. The trial will compare three weeks of intravenous ganciclovir induction therapy (two two-hour infusions a day) and one week of IV ganciclovir maintenance therapy (one two-hour infusion a day) with three weeks of prodrug induction therapy (two pills a day) and one week of prodrug maintenance therapy (one pill a day). After four weeks all participants will receive the prodrug.
Slow enrollment in this trial was another factor in Roche's decision to hold off on the other two studies. The induction trial is due to be fully enrolled by the end of July, but not all sites were ready to enroll participants until April. Quick enrollment now may cause Roche to reconsider its position. Anyone interested in participating should call 800/TRIALS-A for more information.
The induction trial is too small to be decisive in the FDA approval process. Unless Roche makes a stronger commitment to the development of the prodrug, approval will be delayed indefinitely, and the drug will not reach the market any time soon.
Aside from being unconscionable, the decision to delay the prodrug's development is based on little hard information and runs counter to prevailing medical opinion. Although HAART may delay CMV emergence by slowing AIDS progression, most experts fear that this is only a temporary reprieve. Some clinicians feel that CMV incidence is already rebounding. As people with AIDS are living longer, the occasion to administer CMV medications for prophylaxis, induction or maintenance and the length of time on such medications may well increase.
Therapies that are easy to administer are vital to successful management of AIDS and HIV infection The dosing requirements of the current oral and intravenous formulations of ganciclovir make them unsuitable for extended use. The prodrug would improve the quality of life of many people. Roche needs to look beyond its own short-term profit margins to the larger picture. --JC
Happiness Reigns in the Drug Marketplaceby Karen Kuller
A new trend is changing the face of AIDS. Increasingly, information on HIV treatment options is gaining exposure through drug companies' marketing tactics -- specifically, mass-advertising. A two-page ad in this month's issue of GQ depicts a mountain-climber who struggles to make his way up a rocky cliff, and ends up on top. The ad, which also appears in Esquire and Details magazines, is for Merck's protease inhibitor, Crixivan. Initially distributed exclusively through the Pittsburgh-based Stadtlanders Pharmacy, Crixivan will be sold at more than 25,000 pharmacies nationwide starting in May.
Once lured to court AIDS and gay community groups because of their wide consumer reach, drug companies are resorting to more traditional methods of direct-consumer marketing as competition among the protease inhibitors heats up. The market's dominant player, Merck, has felt this pressure the most.
Its newest and fiercest rival, Agouron, launched an aggressive campaign to publicize Viracept's low toxicity and ease of use upon its approval in March. Only one month later Viracept represented 23% of new protease inhibitor prescriptions, according to one analyst report.
With an estimated 10,000 new prescriptions being filled each month, drug companies are becoming more and more anxious to get the message out that theirs is the superior product by whatever argument they can advance. The irony is that the messages conveyed about HIV through the media continue to reduce the disease to mere imagery, even as treating it grows more medically complex. Such imagery includes the notion of a war being waged in the blood where billions of T-cells are destroyed every day, says Joseph Sonnabend, M.D., and that "now we have drugs that can stop it all." In Merck's ad, phrases like "battle against HIV" and the tagline "focus on the rest of your life" are typical of ideas feeding the popular perception that AIDS is a manageable, even curable disease. Roche's tagline "consider a protease inhibitor you can live with," which accompanies pictures of happy, smiling people, strikes a particularly ironic chord: though perhaps tolerable, the product in its present formulation and dose does little to reduce viral load.
All ads include the highly technical patient package insert as required by the FDA. The duality of advertisements, where self-promotional imagery juxtaposes objective information, is reflective of the larger issue that is at stake with this approach to disseminating information on the treatment options available to people with AIDS. "Maybe these companies are reaching people who aren't getting this information elsewhere, and maybe they're giving them very useful treatment information," says Spencer Cox of the Treatment Action Group, "On the other hand, these people may be getting information that is not accurate or which they can't evaluate within the appropriate informational context."
Indeed, if raising awareness about HIV and combination therapy among the public-at-large can be construed as one advantage of mass-advertising, then the consequences of increased brand-name recognition should be construed as a disadvantage. Given the highly complicated regimens that characterize triple-combination therapy, using potent imagery and slogans to describe a protease inhibitor can seem oddly inappropriate. "This is not Rogaine or an antihistamine," says Jeanne Bergman, a policy analyst at Housing Works, "I find it peculiar to see ads for such heavy, heavy drugs."
With this comes the fact that combination therapy is still a matter of choice best addressed through active dialogue between a patient and his or her physician. Brand-name recognition should carry no clout in a decision-making process that involves individual considerations for physician and patient alike, including patient history and ease of use. As Spencer Cox put it, "I'm not sure that engendering consumer confidence is the most effective way to ensure the best healthcare." Rather, says Mark Snyder, M.D., an infectious disease specialist with the Mid-Atlantic Permanente Medical Group in Washington, D.C., the advertising can do more harm than good by "creating the belief that one drug is superior to the others when, in fact, it is not."
But creating that impression seems to be what the pharmaceutical industry is focusing more of its efforts on doing. With analysts predicting that the protease inhibitor market will exceed $2 billion by 1999, protease inhibitors are becoming a promising commercial enterprise indeed (Alex Brown Report, April 29, 1997). Concerns about cross-resistance are further supporting the ambitions of companies like Merck, Abbott, Roche, and Agouron to make their protease inhibitor first in line for inclusion in triple combination therapy. Drug resistance is a completely unsettled field that lends itself to widely different spins by the various protease inhibitor manufacturers.
The AIDS community has been insisting that drug companies proactively communicate information about their products since the beginning of the epidemic. "PWAs revolutionized the way medicine is practiced in our country," says Joy Schmitt of Agouron, "They are our most educated consumers, and the industry has responded to that." Yet information about just how these new drugs will affect the future of people with AIDS or HIV remains scarce. HIV therapy has come a long way since the introduction of AZT and ddI. Today, the only thing that is definite about HIV treatment is the dissenting medical opinion on when to initiate therapy, and the plethora of possible combination protocols. Observes Harold Grossman, M.D., "The truth is always somewhere between what all the companies tell you."
As Abbott, Agouron, Merck and Roche ponder their response to each other's latest ads, the bottom line is that clinical data remain the sole basis for judging the value of their products. Generating solid, clear information on potency and durability of effect is the best marketing technique there could be, whether that information is communicated through patient education material, community groups -- or ads.
Roche Brings New Formulation
by Jill Cadman
On May 12, Hoffmann-La Roche announced that it was applying to the FDA for approval of the long awaited "soft gelatin capsule" formulation of saquinavir. The soft gel capsule contains the protease inhibitor saquinavir blended with a proprietary lipid mixture that raises intestinal absorption of the compound to 12% of the total drug available, three times the abysmally low 4% observed with the hard capsule.
The recommended dose of the new version is 1,200 mg three times a day (TID), compared to 600 mg TID for the hard capsules. Taking this much will require 18 saquinavir soft gel capsules per day and provide eight to ten times the drug exposure of the current formulation. The eight-week dose-ranging study (NV15107) that identified 1,200 mg TID as the preferred dose recorded a respectable, though hardly record-breaking, 1.43 log (96.3%) drop in viral load among 22 volunteers on saquinavir monotherapy.
The safety study (NV15182) showed few adverse side effects with the new formulation, but caution should be advised for those with a history of liver disease. In addition to the safety data, the FDA has recently requested a head-to-head activity study comparing the two formulations to prove that the soft gel is an enhancement over the hard capsule. Sixteen-week activity data from this study (NV15355) should be available by mid-summer and will be submitted to the FDA during the review process. Roche expects to receive the FDA's go-ahead to market the improved saquinavir by the end of this year.
Community activists have raised concerns about the continuation of Roche's aggressive marketing campaign which is advertising saquinavir as "a protease inhibitor you can live with." The hard capsules are administered at 600 mg TID, a suboptimal dose that may breed resistance to both the new formulation and other protease inhibitors by failing to have much impact on HIV replication. At a community meeting in May, activists asked Roche to pull the campaign until the soft gel capsules are available. Tammy Lewis, Product Director for saquinavir, conceded that the best way to use the current formulation is in combination with the protease inhibitor ritonavir, which raises blood levels of saquinavir ten-fold by blocking the drug's metabolism in the liver. But the saquinavir/ritonavir combination has not been reviewed, much less approved, by the FDA, and Roche is prohibited from promoting it.
Roche is now pursuing approval of an expanded indication of saquinavir for use in combination with other protease inhibitors. Approval is not likely within the next 12 months and would probably be limited to specific drug combinations initially (in particular, 400 mg saquinavir plus 400 mg ritonavir), rather than a broad saquinavir/other protease inhibitor indication. Discussions have already taken place between Roche, Abbott and the FDA regarding registration trials in Europe for saquinavir/ritonavir.
Another long-standing community complaint is the current price of saquinavir. At $5800 per year wholesale, the hard capsule saquinavir is at least as expensive as the other protease inhibitors even if it is the weakest. Ms. Lewis says it is "premature" to comment on the pricing of the soft gel capsule. Especially at the preferred 1,200 mg TID dose, the soft gel could prove much more costly than the present version.
No Attrition in Research
by Dave Gilden
One of the most prevalent and dangerous conditions in AIDS and HIV disease has been chronic wasting, in which people progressively become so depleted of lean tissue and protein stores that their bodies can no longer perform basic functions. In this new era of highly active antiretroviral therapy (HAART), is it still a major concern? Kathleen Mulligan, M.D., who has studied AIDS wasting extensively at San Francisco General Hospital answers in the affirmative: "There're lots of anecdotes -- people proclaiming the end of wasting syndrome," she says, "but I'm not knocked out by what I see here. I don't think we're out of business."
It may be that once the conditions for wasting exist, the syndrome persists even when HIV levels decline. Several small surveys presented at April's Nutrition and HIV Infection conference in Cannes, France found that about a fifth to a quarter of those on aggressive antiviral therapies continue to lose weight or lean body mass. One of the studies observed that there was little correlation between viral load response to therapy and changes in weight. Serono Laboratories has made similar findings in an ongoing survey it is conducting. And the initial results from a study at Tufts University indicate that over the first seven to nine months on HAART, patients gain significant amounts of weight as they eat more, but it is all fat. (presented by Sherwood Gorbach, M.D., at the NIH Conference on AIDS Wasting Syndrome, May 20-21, 1997).
An inability to restore lean body mass (muscle in particular) after acute or chronic weight loss has been the hallmark of wasting syndrome. That inability remains even when a person recovers from an opportunistic infection that triggered the weight loss episode. Another on-going study at Tufts University is observing that, at least in people with high HIV levels, even strenuous exercise programs do not improve body composition. Trial participants did increase their weight by an average 3.8% after eight weeks, but the percent increase in fat and lean tended to be the same (presented by Ronenn Roubenoff, M.D., at the NIH Conference on AIDS Wasting Syndrome, May 20-21, 1997).
(A more definitive word on recovery after successfully suppressing viral load may come from the weight gain substudy that is part of the recently concluded ACTG 320, a trial of AZT (or d4T) plus 3TC with or without indinavir. The substudy will try to determine whether adding the protease inhibitor and obtaining greater reductions in viral load result in greater increases in lean body mass, and whether increased lean body mass is associated with changes in appetite and the body's pro-inflammatory agents (such as TNFa, see below). Until now, drug companies have either not collected or refused to release much information on weight changes in their protease inhibitor trials.)
It seems that in addition to potent antiviral therapy, an anabolic (muscle-enhancing) or anti-inflammatory agent may be necessary to reset the body's chemistry after chronic HIV plays havoc with it. Developments in this area continue to make news. December 2 marked the introduction of Serono's brand of human growth hormone (Serostim), which was granted accelerated approved for treating AIDS wasting system in August after a rough ride through the FDA. (For the details of the FDA's critique of Serostim, see Treatment Issues, March, 1996 and August, 1996.)
Glaxo's Parsimonious Compassion1592U89 is a new nucleoside analog from Glaxo Wellcome that promises to be a marked improvement over present analogs such as d4T or 3TC. In early trials, it was shown to reduce HIV viral loads on its own by up to 1.8 logs (98.4%), and in lab tests, it has strong residual potency against mutant, drug-resistant HIV. Because of this exceptional activity, 1592 is very appealing as salvage treatment for people who are not responding to the antiviral drugs currently on the market.
Discussions between Glaxo and community activists have taken place sporadically for over a year concerning some sort of expanded access program to supply such people while 1592 is under development. On April 28, the company announced the impending commencement of a limited compassionate use program. But this program is so restricted that it has touched off a tidal wave of community criticism.
Glaxo's proposal consists of three programs: a pediatric compassionate use for children who have failed one nucleoside analog, a program for people with "severe" AIDS dementia, and a general adult program. Entry to the general adult program would be restricted to people with viral loads over 50,000 and CD4 counts under 100 after having failed at least two nucleoside analogs and one protease inhibitor. The total worldwide availability will have a ceiling of 2,500 people, which by itself has been cause for a considerable outcry: "We will lose another five to six thousand people in the next year who could be saved by 1592," commented Jeff Getty of ACT UP/Golden Gate.
The enrollment criteria generated a whole slew of objections. Requiring adults to fail two nucleoside analogs and one protease inhibitor before receiving 1592 means that there will be little if anything left to combine the new drug with, given the implications of cross-resistance. To ensure adequate viral suppression and durability of treatment effect, people should take 1592 in combination with other drugs still active against the HIV in their bodies. Preferably that combination would include a protease inhibitor, which 1592 cannot replace. At the very least, the requirement to fail a protease inhibitor should be eliminated. (An alternative would be to undertake a joint expanded access program with Glaxo's experimental protease inhibitor 141W94, which lab studies indicate could be active against HIV resistant to the protease inhibitors on the market.)
Glaxo in addition is forcing both adults and children to wait until they have very high viral loads and low CD4 counts before they can receive 1592. Waiting until that point allows irreparable damage to be done as patients' CD4 cells are decimated and HIV replicates to levels that are hard to bring down. It would have been better to define treatment failure as either an upward trend in viral load or stable, but high HIV levels.
A similar concern arises in relation to the dementia program: Why require that dementia be "severe"? Full recovery may no longer be possible at that point.
Glaxo has responded to these objections by saying that the current supply of 1592 is low and that there is a need to collect extra safety and efficacy data before more broadly releasing the drug. To facilitate this data collection, the general adult compassionate use program will take place at "geographically dispersed centers" rather than the usual central mail order operation. This raises the question as to how people in remote areas will obtain the drug. According to a company announcement, instituting a network of separate sites is part of Glaxo's attempt to build within compassionate use an "open label study which allows for collection of safety and efficacy data... in a broad population of people in addition to that which is being collected through our clinical trials."
It is true that testing has been slow, but the supply problems that supposedly held up trials have been resolved. If Glaxo expects to market 1592 in a year, it must now have the capacity to make commercial-size batches of the substance for the traditional 12-month shelf-life test that new drugs go through. It could use that capacity for a true expanded access program, too.
The company does promise to institute a larger expanded access program next winter, but that will be only a few months before Glaxo anticipates receiving FDA approval for 1592. In the meantime, Glaxo's AZT and 3TC have been the best-selling HIV drugs. Although 1592 will steal some of that market , it can be expected to sell exceedingly well, too. The present demand for immediate access can only bolster its future sales. There is little reason for the miserly expedience that would divert compassionate use from an emergency distribution program into a stop-gap trial.
A Welcome and an Apology
Starting with the last issue, you may have noticed a new person on TI's bylines and masthead. Treatment Issues welcomes Jill Cadman as its new associate editor. Jill formerly was assistant coordinator of GMHC's Health Care Advocacy Department. She brings to this publication considerable practical experience resolving GMHC clients' problems with the healthcare system. That experience will be very useful in realistically appraising medical therapies. Jill also is an assiduous investigator who will further Treatment Issues' critical analysis of HIV/AIDS treatment developments.
You also may have noticed that Treatment Issues has been very late this spring. We are very sorry. TI editor David Gilden has been working two jobs lately -- in addition to his regular duties, he has been acting director of GMHC's Treatment Education and Advocacy Department. His temporary tenure in that position is now over, and with him back on the job full-time and Jill Cadman settling in, TI should resume its normal schedule -- or maybe not. All GMHC is moving next month, and who knows what chaos will ensue.


text: Robert Schedel wrote: > Oliver Endriss wrote: > > Robert Schedel wrote: > >> Oliver Endriss wrote: > >>> Robert Schedel wrote: > >>>> > >>>> Enabling debug traces shows that polling for the PSR in function > >>>> 'saa7146_wait_for_debi_done_sleep' constantly times out after 250x1ms > >>>> sleeps: > >>>> > >>>> > saa7146: saa7146_wait_for_debi_done_sleep(): saa7146 (0): > >>>> saa7146_wait_for_debi_done_sleep timed out while waiting for transfer > >>>> completion > >>>> > >>>> Increasing the 250ms did not avoid the timeout. And as I understood from > >>>> previous list mails, this timeout is normal when no CI/CAM is connected > >>>> to the DEBI. However, for me the high frequency polling does not make > >>>> sense if someone does not plan to plug in a CI/CAM. > >>>> > >>>> When commenting out two lines in 'dvb_ca_en50221_thread_update_delay' to > >>>> increase the polling timer for slotstate NONE from 100ms (!) to 60s, the > >>>> CPU load went down to 0. So this is some kind of workaround for me. > >>> Afaics the polling interval could be increased to something like 5s or > >>> 10s if (and only if) the slot is empty. Could you provide a patch? > >> Attached a patch for 18.104.22.168. Opinions? > > > > Basically it should work but it has to be tested with CI/CAM, too. > > Correct, unfortunately I cannot test it against a CI. @all: Could someone who runs budget-av with a CAM please test Robert's patch? Thanks! > > Furthermore it is not sufficient to test with budget-av because many > > other drivers will be affected. > > > > So I would prefer a patch which does not touch behaviour for other card > > drivers (if possible). > > To my understanding of the DVB code dvb_ca_en50221 is only referenced by > budget_av and budget_ci, at least in the vanilla kernel 2.6.25. You are right (and I am a bit surprised). > The patch only changes the timer for slot state EMPTY if > DVB_CA_EN50221_FLAG_IRQ_CAMCHANGE is not set, which is for > 1) budget_av > 2) budget_ci if the CI firmware version is 0xa2 (because IRQs for CAM > change are not supported in this version) > > And those two cases are probably affected by the load issue and should > be fixed. > > Of course, we could add another DVB_CA_EN50221 flag solely for budget_av > to exclude case 2), but does this make sense? Who is available to test > against a budget_ci with FW=0xa2 whether it is affected by the load issue? After looking closer at your patch I saw that most changes are comments or coding-style related. Afaics the patch should be safe. So I will commit your patch next weekend, unless someone spots a problem. > >> Regarding DEBI_E: Just found a av7110 code comment which also reflects > >> what my recent tests showed: > >> /* Note: Don't try to handle the DEBI error irq (MASK_18), in > >> * intel mode the timeout is asserted all the time... > >> */ > >> > >> So really only DEBI_S would be left, see below. > > > > Did you check whether DEBI_S and/or DEBI_E are ever asserted with your > > setup? If not, an interrupt would never occur anyway... > > DEBI_E was always asserted (as described in the av7110 code comment), so > it was worthless. DEBI_S was never asserted without CI (therefore the > 250ms timeout), so it would probably only be received when a CI is used. > But as described in my other email with measurements, it seems that > there is no need to optimize the debi_done function further. Ok, thanks for checking. > >>>> 4. Are the high timeout periods in debi_done (50ms/250ms) in relation to > >>>> the 100ms poll timer intended? (I found the recent patch to this code in > >>>> the mailing list end of last year) > >>> That patch was applied to reduce the load on the pci bus in busy-wait > >>> mode. Basically it did not change anything for cam polling. (In fact I > >>> was not aware that the CAM was polled every 100ms. Imho this should be > >>> fixed.) > >> Only wondered whether the 250ms might have been smaller in former driver > >> versions. > > > > Iirc it should be even worse with older drivers. > > > > Basically the 250ms timeout is just a last resort to escape from the > > loop, if the debi transfer hangs for some reason. We might try to reduce > > the timeout but I don't know how far we can go. (Touching 'magic' values > > might be dangeous.) > > As above, according to my measurements we would not need to change the > 250ms timeout. Agreed. CU Oliver -- ---------------------------------------------------------------- VDR Remote Plugin 0.4.0: http://www.escape-edv.de/endriss/vdr/ ----------------------------------------------------------------

subset: commoncrawl


text:
Advanced Search
Student Competitions | News
Despite the fact that mainframes are about to celebrate their 50th birthday, they aren't going away any time soon. And that's why IBM has expanded its "Master the Mainframe Contest" to include a world championship designed to entice young people to consider learning more about workings of these general-purpose, very large, very fast servers.
The annual Master the Mainframe contest has drawn 68,000 high school and university students since its launch in 2005. Current participants must attend schools that are part of IBM's Academic Initiative, which provides institutions with curriculum and software for teaching their students computer science, information technology and related subjects. Contestants don't need mainframe experience; students build their knowledge as they move along in the competition. Those who competed in 2013 had the opportunity to win Google Nexus 10 tablets, branded clothes and accessories, and trips to IBM's mainframe lab in Poughkeepsie, NY.
Top students from the previous events have been invited to join in on the world championship. The latest iteration will offer 15 preliminary challenges, such as deploying business applications written with Java and COBOL using DB2 for z/OS APIs. Students will participate in those activities remotely with an online leaderboard tracking their progress. Thirty finalists pulled from these early contests will travel from their home countries to New York City in time for the anniversary of IBM's System/360 mainframe, the first computing machine that could be upgraded and used for multiple purposes within the enterprise.
Students attending the special event will work in teams on a "grand finale challenge." The efforts will be evaluated by a "distinguished panel of judges," according to the company. One student will be named the "Master of the Mainframe World Champion."
Representing the United States will be Mugdha Kadam from the University of Florida, who is currently seeking a position as a mainframe business or systems analyst; Elton Cheng, a third year bioengineering major at the University of California, San Diego; and Rudolfs Dambis a student at the University of Nevada Las Vegas.
"The Master the Mainframe Contest is a great way to get the millennial generation excited about enterprise computing," said Martin Kennedy, managing director, global enterprise systems, Citi. "I've been following the contest for a number of years and have made successful hires from both IBM's Master the Mainframe Contest as well as their System z Academic Initiative program. I envision a World Championship such as this generating momentum in academia and making educators take a second look at the mainframe in enterprise computing."
Dontrell Harris, a previous contestant, said his involvement resulted in an internship. "The Master the Mainframe Contest opened many doors for me... I was able to translate my knowledge of the mainframe and evolution of key computing workloads into a successful internship experience and hope to parlay those 'in demand' skills into a career upon graduation."
About the Author
Dian Schaffhauser is a senior contributing editor for 1105 Media's education publications THE Journal and Campus Technology. She can be reached at email@example.com or on Twitter @schaffhauser.
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Lowering technology, TCO at the same time your working to "future-proof" your education infrastructure is tricky but doable. This brief guide lays out the argument for re-examining how
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text:
Java For iPhone? Even Sun Doesn't Know
But probably more poisonous is the mystery around whether the iPhone will permit interpreters or application frameworks. Mozilla's Rob Sayre started the buzz with this post, which seems to be contradicted by Sun's determination to develop Java.
But will Sun actually be permitted to produce Java for the iPhone? Even Sun doesn't know. Eric Klein, Sun's VP for Java marketing had this to say:
"Our announcement was based on our excitement to build a JVM for the ?iPhone and the iTouch, as well as our assessment of Apple's publicly ?available information on the SDK and related business terms. If there ?are clauses in the iPhone beta SDK license agreement that potentially ?limit third party application� distribution, then these are items that ?we want to have a positive discussion with Apple about. Sun and Apple ?have an ongoing relationship around Java SE on Mac OS X and we look ?forward to further discussions with Apple about a JVM for iPhone and ?iTouch. Sun definitely plans to deliver a JVM for iPhone and iTouch if ?at all possible!"
Apple has gone back into silent mode, which is bad news. Application platforms do not generally thrive on confused silence - they thrive on clear guidance and guidelines, which Apple is not providing at the moment. But I have one big reason why Apple would permit Java, and one reason why they wouldn't (but one that Sun can turn around.)
PRO: A JVM does not actually have to call 'other code.' As everything runs within the Java sandbox, Java virtual machines could be seen as installing J2ME apps as 'updates' of 'themselves.' So the JVM would not be violating Apple's terms as it could be coded to incorporate any downloaded apps or midlets into its own package rather than leaving them lying around the filesystem.
CON: To my suspicious mind, the reason Apple wants to forbid other app frameworks is because they don't want any way to deliver paid content other than through the iTunes store. If you start allowing Java applets and Firefox extensions onto the iPhone, people will be able to buy them from GetJar.com or wherever and bypass Apple's 30% cut of revenues. Also, Apple wants to sign all apps for security reasons.
This is one that Sun could finesse through negotiations. J2ME uses certificates, of course. If Sun codes their JVM so that it only installs Apps with iTunes-provided certificates, and Apple lets Java apps be sold through iTunes, the problem is solved. Everybody gets what they want.
This would be great for everybody because there are thousands of J2ME apps already out there that could run on the iPhone, with some alteration. Apple could leverage this existing application base to provide a body of available apps for the phone even as the production of true, SDK-based "native apps" is still warming up.
What this emphasizes most of all is that if Apple wants to have a developer community for the iPhone, they need to start talking to them in a more interactive manner. They have to have known that slapping a slide up behind Steve Jobs mysteriously warning that "unforeseen" would be banned, whatever that means, would cause great tearing of hair and rending of garments in the developer world.


text:
I am a 25-year-old Model, Writer, Advocate and Dancer from London!
I teach a variety of Dance styles (Including Street Dance, Contemporary and Caribbean/Bollywood fusion), but my main focus and passion is Bollywood!
I can teach a 1 minute and 30-seconds Dance routine for your event, to help you to gain confidence or purely just for fun.
**Although my offer states a 1 minute+30 seconds dance routine. That is mostly for people looking to do a last minute routine for an event or people purely learning for fun.**
One hour with me teaching a single (one on one) is £30, but if you would like to perfect the routine it would take a few sessions (roughly 4 to 5) depending on your ability. Let me know a time and date that suits you and I will tell you my availability!
Go to the following link to Book a session: https://www.peopleperhour.com/hourlie/create-bollywood-inspired-dance-routine/431642
NOTE: It is vital that you visit the link to be able to book a session and not just get a ticket through eventbrite.
Thank you! Look forward to hearing from you all


text:
Career Paths in MIS
Application Developer | Systems Programmer | Computer Support Staff
Network Administrator | Data Administrator/Database Administrator | Web Developer
The Application Developer (A.K.A. Business Analyst)
The Applications Programmer/Analyst is the most likely place most computer science/IS
majors will begin their career. There are more business analysts in IS shops than any
other position. This person is responsible for identifying the requirements of business
professionals and encoding them into automated systems. The daily activities of an
application developer may include holding requirement-gathering sessions with the end user
and creating system specifications for application coding. It may involve writing 3rd and
or 4th generation languages to meet the system specifications or it may involve diagnosing
what happened last night in a processing cycle that did not complete successfully or that
completed with unexpected results. This position requires someone who has good listening
skills and can convert complex business rules and formulas into structured programming
language statements. This position requires someone with exceptional interpersonal skills
as they are called upon to interface with others within the IS organization as well as
other areas of the business.
Systems Programmer
The systems programmer is responsible for the operating system environment that the
application systems execute and are developed on. The daily activities of a systems
programmer include maintaining the operating system on many different platforms, planning
for upgrades to existing software platforms and identifying emerging hardware and software
products that influence the development environment. The systems programmer typically
tries to minimize the amount of code he/she has to develop. By using software packages
like IBM's SMPE to manage several thousand components that make-up an operating system,
the systems programmer is continually checking on software pre-requisites and
co-requisites to ensure seamless compatibility among the many components of an operating
environment. This position requires someone with exceptional organization skills, someone
with the ability to organize extremely well, and someone who has the aptitude to evaluate
individual needs while keeping in mind the whole picture. Systems programmers usually work
with other members of the IS organization.
Computer Support Staff (Operator, Help Desk, Systems
The computer support person is responsible for keeping everything running. This
includes everything from mounting tapes, to monitoring screens for exception alerts and
ensuring that the printers have a continuous supply of paper. It also includes manning the
help desk, which receives questions ranging from connectivity problems, authorization
failures, and "user" errors. This is a highly specialized area of IS in the
sense that Master Terminal Operators responsible for on-line availability have completely
different sets of skills that must be mastered than the operators that monitor and are
responsible for batch cycle jobs running to completion. This position may require shift
work, and can become monotonous but never dull. There are a tremendous number of
activities that must be performed to maintain a data center and the computer support staff
must be proficient in many of them regardless of their primary area of responsibility.
These positions require someone that is flexible and tireless. They must be able to take
direction well and be able to analyze many different situations that arise. Computer
support personnel often feel that they "don't get no respect" because without
them the data center would not function, but they aren't recognized as being very
technical. Computer support folks usually interface with other members of the IS
organization about processing problems and are called upon to answer the business user's
questions about the results of application processing.
Network Administrator
The network administrator is becoming very important as companies move into client
server processing. The multiple platforms now available, the move toward open systems and
the many different protocol choices make the network administrator's job very similar to
the systems programmer's job. The network administrator is responsible for monitoring
through put across the organization's communication lines. The daily activities of a
network administrator may involve running a diagnostic program on a communication line to
determine performance bottlenecks or it may involve installing a new operating system on a
LAN operating machine. The network administrator frequently answers questions about
network traffic to end-users as well as IS staff. Understanding the basics of the seven
layers of the Open Systems Initiative (OSI) protocol stack is essential to the network
administrator. Knowing the details of how the hardware and software that implements each
layer operates is where the network administrator gets his leverage. The network
administrator is involved in the planning of the IS architecture to support the business.
By calculating BAUD rate estimates, the network administrator attempts to avoid
performance bottlenecks. This position requires someone that is analytical but more
importantly, has the ability to remember large amounts of detailed information.
Data Administrator, Data Base Administrator
The data administration (DA) staff is involved in the establishment and enforcement of
development standards. The data base administrator (DBA) is responsible for the
performance of the data resource within an organization The DA also is involved in the
logical modeling of the data and process requirements of most application development.
Performance and tuning is done at a very physical level for the DBA. Data administrators
and DBAs are usually CASE tool experts that are involved in the analysis and design phases
of applications. Daily activities include system walk-thru's with business analysts,
participation in business user interviews along with business analysts to help capture
information needs, and modeling activities including encyclopedia/repository
reconciliation. These positions require someone who can think in very abstract terms and
maintain a consistent level of abstraction. These positions are perhaps the most
technically challenging positions in the organization. Good communication skills are
required, as are good negotiation skills. Frequently the administrator must convince the
application development staff to adopt a course of action that involves additional
overhead for their project because it is good for the overall development environment.
Data administrators are responsible for maintaining strategic objectives for the IS
organization more so than most other positions whose focus is frequently tactically
focused. Data Base administrators are responsible for the daily operational and tactical
objectives for the IS organization.
Web Developer
The Internet developer, a.k.a. Web developer, is arguably the most visible position in
the IS organization today. The WEB developer is concerned with access to company data from
very diverse and uncontrolled sources. In addition to evaluating the development
requirements that every business analyst receives, the WEB developer must focus on the
presentation of the data to ensure it's consistency with the Internet standards as well as
the standards defined by his organizations home page. The WEB developer must have a
working knowledge of the firewall procedures put in place to protect corporate data and
system resources from outside corruption. A balance must be maintained between sharing
information with the target population, whether that is internal Intranet users or
external Internet users, and protecting sensitive corporate assets. This position requires
someone with good visual development skills and the ability to remain flexible in an
increasingly dynamic environment. This position also requires someone that can maintain a
technical edge while developing applications that meet the stated business need for
globalization of the corporate data asset. An individual that has a good history of
business applications analysis would be a good candidate if they also possessed the visual
development skills mentioned earlier. A unique challenge to the WEB developer is trying to
meet the needs and expectations of the general public around the world. Normally,
application development staffs strive to meet the expectations of their corporate sponsors
and this requirement is no less for the WEB developer. But in addition, the WEB developer
is in competition in a global marketplace.


text:
Beneath each sparkling gemstone, graceful waves form a subtle detail within the sterling silver setting, a sophisticated and stylish reference to the waters that surround Martha's Vineyard. These post-style earrings are available in two sizes and many gemstone choices, making it easy to accessorize a range of outfits and occasions.
• Cushion cut citrine are 7mm in diameter


text: Howdy John, and thanks for the reply. On Mon, 2003-01-06 at 09:36, John Burton wrote: > > Ummm...'all "computin" ain't equal'. While checkpoint files might not be > useful for what you do, they save thousands of machine and man hours in > my business. With all kidding aside, I can see how (in some applications) check-point files are and absolute necessity. My only beef with the situation is that a large amount of time is being spent doing IO on a "maybe." I do, however, see how they can be useful. > Apparently you are not current on cluster technology, or you wouldn't be > proposing something that is common knowledge. As I've said from the beginning, I'm a complete and total neophyte when it comes to parallel processing and beowulf. I'm a contractual software engineer, and I specialize in data-acquisition and process-control software for the oil biz. I also work part time for Stewart Technology Associates. (If interested, check out www.stewart-usa.com, although be forewarned that it's a pretty geeky site :^). One of the reasons I'm on this list is to look at the feasibility of using a beowulf cluster for computational fluid dynamics. Rather than send the work down road or have the calculations take a few days to run on a single PC, I'd like to do this internally and setup an in-house cluster on some old PCs we have hanging around. When I'm not busy doing all of that, I'm usually visiting my family in Louisiana, and I also do some network administration in the business world for some friends that own local businesses. With networking comes the added responsibility of computer security, of course, which I also help to implement at STA in Houston. I've also been known to take on embedded-control projects or design a bit of hardware to solve a given task. BTW, I'm also on the list to see if I can learn a bit about cluster administration. So, if the oil biz falls off in a serious way, I might be able to find a decent job quickly. For the most part, though, I'm here for FUN, and I enjoy brainstorming with the learned folks here to see if I my "somtimes old news to the experienced" ideas have any form of validity. If it's old hat, no big deal. If not, then maybe I might come up with an idea that could actually help someone. Let's just say that doing this is a creative outlet that also helps me to understand all of this stuff quickly. Unfortunately, though, some may see this as mucking up the signal-to-noise ratio, raising the noise floor to an unappreciated level." In many respects, they'd be correct! :^). I can only say that this isn't my intention, and I'm only doing this to see if my layman ideas and thought processes are at least in the ballpark when it comes to parallel processing and beowulf. > 10Base-T is too slow for typical parallel application. Switched > 100Base-T is almost as inexpensive. Great. This is good to know. OTOH, I was trying to think of ways to put really antiquated gear to use. After all, and from what I've been reading, doing things cheaply is what beowulf is all about. > In my world a check point file is a "snapshot" of the state of running > process at a given time. This "snapshot" is complete enough to restart > the process at that point should it fail at a later point. OK. Thanks for the explanation, and that was the way I was thinking about it when Donald and I were discussing this earlier. Best Regards, Randall -- Randall Jouett Amateur Radio: AB5NI


text:
Arab - Laugh Out Loud Pt. 2 (Responds To World Star Haters) + Claims He Aint Steal No Beat. Dude Gave It To Him
Arab Money Gang TV reports "Response video to Laugh out loud (I didn't steal the beat he gave it to me) Twitter.com/arabsodmg S.O.D. Money Gang Boss Money Records "
Please click the "Report" button below if the video on this page is not working properly.
Comments will only be displayed by verified emails. No Spamming or Racism.


text:
ABO Virtual
Mitchells & Butlers, 27 Fleet Street, Birmingham, B3 1JP 0121 498 4000
Mitchells & Butlers, 27 Fleet Street, Birmingham, B3 1JP 0121 498 4000
Winter is now a distant memory and we're celebrating longer evenings, and summer sunshine (fingers crossed), with some delicious new treats. Our chefs and mixologists have been working hard to bring you some exciting new menus, so get the gang together and get a 'catch up' booked in the diary at ABO Virtual
Our new Nutritious Power-foods are perfect for summer! We've partnered with registered nutritionist Sarah Jackson to create four healthy summer dishes that add vital nutrients to your diet. All of the power-foods are vegan and you can add different proteins to the dish if you wish!
Why not try our Avocado & Black rice salad, which features 2 of your 5 A Day, and is rich in vitamin B6. We love ours topped with salmon for that extra Omega-3 kick!
If you're after something seriously tasty but equally healthy our new Power of Five is 5 of your 5 A Day (!!), and 300 calories or less. Enjoy pan-fried greens and vegetables with our favourite miso sauce, which is topped with a rice noodle cracker.
Hump day has never looked so fabulous…. To celebrate our new menu, we're treating you to 2-4-1 on all Nutritious Power-foods dishes every Wednesday. It's the perfect lunch-time break from the office or post-shopping refuel. Simply join us on Wednesday and order two of the power-food dishes and you'll get the least expensive item for free*!
We've got a brand new selection of tasty tipples and refreshing cocktails to add to your summer catch ups too!
Our new Gin Tonicas are a celebration of the traditional G&T. Originating in Spain, this is a premium style of serve, which combines gin, tonic water, bitters, herbs, spices and fruits to perfectly complement the gin botanicals. It's the perfect drink to sip this summer.
If you're staying on the wellness train then our new range of twisted tonics are a refreshing low-alcohol alternative. Try our Elderflower & Cucumber twisted tonic for a deliciously crisp and cool summer drink.


text:
GETUID(2) BSD Programmer's Manual GETUID(2)
getuid, geteuid - get user identification
#include <sys/types.h> #include <unistd.h> uid_t getuid(void); uid_t geteuid(void);
The getuid() function returns the real user ID of the calling process. The geteuid() function returns the effective user ID of the calling pro- cess. The real user ID is that of the user who has invoked the program. As the effective user ID gives the process additional permissions during execu- tion of "set-user-ID" mode processes, getuid() is used to determine the real user ID of the calling process.
The getuid() and geteuid() functions are always successful, and no return value is reserved to indicate an error.
getgid(2), setreuid(2), setuid(2)
The getuid() and geteuid() functions conform to IEEE Std 1003.1-1988 ("POSIX"). MirOS BSD #10-current June 4, 1993 1
Generated on 2017-04-03 16:26:17 by $MirOS: src/scripts/roff2htm,v 1.88 2017/01/29 00:51:06 tg Exp $
These manual pages and other documentation are copyrighted by their respective writers;
their source is available at our CVSweb,
AnonCVS, and other mirrors. The rest is Copyright © 2002–2017 The MirOS Project, Germany.
This product includes material provided by mirabilos.
This manual page's HTML representation is supposed to be valid XHTML/1.1; if not, please send a bug report — diffs preferred.


text:
Parent Directory | Revision Log
|Links to HEAD:
|(view) (download) (annotate)
Move test for MERGE_TYPE from check-reqs_pkg_setup() to check-reqs_run().
Output binary prefixes for units according to IEC 80000-13, as calculations are 1024 based. Fix documentation of check-reqs_get_unit function, and other minor fixes.
Fixing units
Fixing binpkg behaviour
naive bump of all EAPI-specific checks in eclasses to permit EAPI=5 where EAPI=4 was previously allowed
Update the wording in the failed case.
Add the updated check-reqs eclass as per gentoo-dev discussion.
fix random bugs in eclass documentation, and convert to new @AUTHOR tag
Actually print out the path that check-reqs is testing; bug #300662
USE ${T} rather than ${PORTAGE_TMPDIR} to check for sufficient space on disk (bug #139798). Document check-reqs.eclass for eclass-manpages thanks to mren on bug #210921.
Add check_reqs_conditional function
*** empty log message ***
Remove ECLASS= and INHERITED= which haven't been necessary for a long time now
Remove ECLASS= and INHERITED= which haven't been necessary for a long time now
nicer variable names
new toy to play with
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text:
Job Title: Teen Outreach Program Leader
Purpose: The Teen Outreach Program Leader directly engages the teenage community of St. Charles County through programs and book discussions at residential and outreach centers including the Juvenile Detention Center. Each Program Leader will manage one or more Teen Outreach Program to include program facilitation and/or lead book discussions at the location.
Location: Multiple sites throughout St. Charles County, but responsibilities will be assigned from the Administrative Office located at 77 Boone Hills Dr. St. Peters, MO 63376.
Key Responsibilities:
Reports to: Extension Services Specialist
Length of Appointment: The Teen Outreach Program Leaders will serve for at least one year and can stay on as a permanent position.
Time Commitment: Two programs per month (mutually agreed upon time by Teen Outreach Program Leader and partner residential center contact) for up to two hours each time. Additional time may be needed to pick up and return materials to a library branch.
Support: Training/orientation for this position will be provided. In addition, the Extension Services Specialist will be available for questions and assistance.
Age Requirement: 18 years or older
Dress Code: Business Casual


text:
In order to grant our guests a pleasant stay and to offer them 100% happiness and satisfaction, our "Ultimate All Inclusive" concept starts with a warm welcome by offering our guests a traditional Turkish dessert called "cezerye" and a glass of Turkish sweet drink called "sherbet". Then it continues with wide range of food and drinks for 24 hours. Our A' la Carte restaurants require reservation and they are free of charge for once during seven night's accommodation.
Fee-paying Food & Beverage Services: Room service (24 hours), brandy, 12 and 15 years old whiskeys, local and foreign bottled luxury wines, energy drinks and fresh fruit juices.


text: This skull may have better teeth than you. Craig Rodway/Flickr hide caption toggle caption Craig Rodway/Flickr Shots - Health News Ancient Chompers Were Healthier Than Ours February 24, 2013 By examining ancient dental plaque, researchers have concluded that prehistoric humans' diets made for healthier mouths. The addition of flour and sugar to modern diets may have set the stage for a near-constant state of oral disease.


text:
This Day in Sports History — August 3
Here are just some of the notable sports moments that happened on August 3:
1921 — Baseball commissioner, Judge Kenesaw Mountain Landis banned eight members of the 1919 Chicago White Sox from baseball for life for their roles in allowing the Cincinnati Reds to win the 1919 World Series. (More info.)
1928 — American Ray Barbuti won the 400-meter race at the Summer Olympics in Amsterdam. It was the only individual gold medal the US won in those games. (More info.)
1936 — African-American athlete Jesse Owens won the gold medal in the 100-meter race after German leader Adolf Hitler earlier proclaimed the Aryans a superior race. (More info.)
1944 — At just 16 years and eight months old, Tommy Brown played shortstop for the Brooklyn Dodgers against the Chicago Cubs in Ebbets Field in New York. (More info.)
1949 — The Basketball Association of America and the National Basketball League merged to form the National Basketball Association. (More info.)
1959 — The American League beat the National League, 5-3, in the second MLB All-Star Game of the year at the Memorial Coliseum in Los Angeles. (More info.)
1960 — The Cleveland Indians traded manager Joe Gordon to the Detroit Tigers for manager Jimmy Dykes. (More info.)
1984 — American gymnast Mary Lou Retton became the first US woman to win the Olympic gold medal in the all-around at the Los Angeles Games. (More info.)


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The radness is happening again this Saturday near Canada in the USA at Sunday River! Last year we had such a bitchin' time out in Maine that we had to do it again with more riders, bigger prizes and even funner features…it's gonna be bananas! Join Lib Tech Rippers Jesse Burtner, Ted Borland, Brandon Reis and Sam Hulbert as well as GNU weirdos Max Warbington and Gus Warbingtonfor a bitchin' day of freedom fueled progression on a ridiculously creative canvas of snow. Think mini-pipe, skatepark, bmx track with all your best homies.
We're also bringing back our ONE HUNDRED $10 TRICKS…yep, we're giving out a grand in cash one trick at a time…land some tricks and stack some paper kids. Oh yeah…almost forgot…we're also going to give one Bitchin' Boarder an invite and plane ticket to LIB TECH'S HOLY BOWLY this April in Park City, Utah…BOOM!
A big shout to Sunday River, Snowboarder Magazine, Eastern Boarder and Crab Grab for the support!
No Entry Fee!
Registration is from 9-10:30AM
Snowboards Only / Helmets Required / 18 and under requires parents signature / Valid lift ticket or season's pass required
One Bitchin' Boarder gets an invite & plane ticket to LIB TECH'S HOLY BOWLY!
Facebook Event Page: https://www.facebook.com/events/1387910834812166/


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KIST/PU Advances in detection systems for biology: Classifying signals from fluorescence and scatter
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08 Dec 2011 | Papers | Contributor(s): J. Paul Robinson
Biology-driven advances in photonic detection systems have been dramatic in the last several years. Three specific aspects are of particular interest: molecular detection, cellular detection, and whole-organ or small-animal imaging. Each area of study requires specific probes, detectors, and...


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A few months back, I came across this cake on RedChillies' blog and promptly bookmarked it. It looked like one of those recipes that I just had to try out immediately and I did- the very next day, and with fantastic results. Since then I've made this cake many times.
I most recently baked a loaf of this bread/cake a few weeks back for my sister and brother-in-law when we visited them in Montreal. It was a big hit and was enjoyed by all.
My recipe is adapted from RedChillies' recipe, which in turn is inspired by this recipe on Sify Food.
I replaced the butter in the original recipe with oil and used almonds instead of walnuts in this recipe although I have used walnuts at other times. I like to use brown sugar instead of the granulated sugar that the original recipe calls for.
1 cup canned mango pulp (you can find this at most Indian grocery stores)
1 cup + 1 Tbsp semolina/rava/sooji
½ cup + 2 Tbsp brown sugar
½ tsp powdered cardamom
1 tsp baking powder
¼ cup oil
A pinch of salt
¼ cup slivered almonds (reserve a few for sprinkling on top of the batter)
Preheat the oven to 375 degrees F. Line a bread pan with foil and grease with oil/butter.
Mix together the mango pulp, semolina, sugar, cardamom powder, oil, salt, almonds, and baking powder. Let the batter stand for 10 minutes and then pour it into the greased pan. Sprinkle some almonds on top of the batter and bake at 375 degrees F for 25- 27minutes (check after 25 minutes).
Cool, slice and serve.
Thursday, August 6, 2009
Eggless Mango Cake
Cooked by TBC on Thursday, August 06, 2009
Labels: cake, Mangoes, Semolina, Sweet Treats
39 Burps:
- sunny said...
It's Looks Like Yummy..... I love to Eat Cake..I also Have Good Cakes Recipes Find out These Recipes....
- August 7, 2009 at 1:18 AM
- Nags said...
mango and cake in one dish! yum :D
- August 7, 2009 at 1:49 AM
- Nupur said...
A cake with only sooji and mango pulp as the base?? Very intriguing! I love the color :)
- August 7, 2009 at 7:41 AM
- Rajitha said...
I am making this tomorrow...for once i have everything at home....will let you know how it turns out...
- August 7, 2009 at 9:16 AM
- Sakshi said...
Is it really so easy as you make it sound? eggless ha now that's tempting me to try this out.
- August 7, 2009 at 10:13 AM
- RAKS KITCHEN said...
Mango and brown sugar makes a divine combo! Wish I cud bake like you just like that!!
- August 7, 2009 at 10:31 AM
- Vani said...
Looks moist and delicious, TBC!
- August 7, 2009 at 10:51 AM
- Soma said...
When i saw this in the reader, i was thinking i saw this somewhere & bookmarked it! Looks awesome. I was thinking fresh mangoes, but the little we get i do not want to use it in cooking. what a stunning color!
- August 7, 2009 at 10:53 AM
- Lisa said...
I can understand why you bookmarked this recipe! It looks so moist and sticky at the same time.
- August 7, 2009 at 11:50 AM
- Ranjani said...
What a gorgeous hue..this cake's got me craving mangoes now!
- August 7, 2009 at 5:10 PM
- rekhas kitchen said...
mango cake looks nice and moist yum.
- August 8, 2009 at 5:36 AM
- RedChillies said...
Hey TBC, so glad that you tried it and liked it. It tastes awesome isn't it? Love this recipe from SIFY.
Call it strange coincidence but I made the same cake yesetrday, but using bananas instead. I will post it soon.
- August 8, 2009 at 10:15 AM
- Siri said...
this is such a simple recipe TBC. I am surely gonna try!
- August 8, 2009 at 7:48 PM
- karuna said...
wowowo for an eggless cake tht looks so fluffy.
love the nice bright yellow colour.
- August 8, 2009 at 11:56 PM
- shyam said...
ohoho... here's a gorgeous recipe to try! What a fantastic photo!
- August 9, 2009 at 2:46 PM
- Mandira said...
looks fantastic.. love the color too!
- August 11, 2009 at 11:24 AM
- Vaishali said...
Looks delicious. I use whole-wheat pastry flour or all-purpose flour in my mango bread and muffins, and the use of rava sounds unusual but delicious. I can imagine the absence of gluten would give it a more tender texture...?
- August 11, 2009 at 3:51 PM
- Srivalli said...
That looking so delicious tbc!
- August 12, 2009 at 12:50 AM
- A_and_N said...
The colours are brilliant! Beautiful.
- August 12, 2009 at 9:27 AM
- Parita said...
Love the color, looks refreshing! Bookmarked!
- August 12, 2009 at 10:50 AM
- TBC said...
Thanks everybody!
Will respond to the comments later in the day. :)
- August 12, 2009 at 1:09 PM
- TBC said...
Nags- yum indeed! :D
Nupur- I too was skeptical before I tried it, but turns out that they work really well together.:)
Rajitha- how was it? did it work for you?
Sakshi- yes, it is! Go for it then! :D
Rak's kitchen- there's nothing to it- really! It is not as difficult as you think it is. :)Pick something pretty basic and simple to start with.
Vani- Red Chillies' recipe works pretty well.:)
Soma- I have actually tried using fresh mangoes too. The end product does not have the mango flavor that you get when you use the canned pulp. The mangoes I get here are pathetic to say the least, and don't smell or taste like mangoes. So, unless you get mangoes that are really good (like the ones we get back home in India), I'd recommend that you stick with the canned pulp.
Lisa- this one's a keeper for sure! :D
Ranjani- what are you waiting for? Go get some before the season's over.:)
Rekha's kitchen- thank you.:)
RC- it IS a fabulous cake!:)
My normally fussy sister gave it a pretty good rating.:D
Bananas instead of mangoes? Hmmm...I'll stick witht the mangoes. I find that bananas, even in very small amounts, have a very overpowering flavor in baked goods. Have to see what you did with the bananas though.:)
Siri- please do! Tell me how you liked it,ok? :D
- August 12, 2009 at 11:30 PM
- TBC said...
Karuna- thank you.:D
Shyam- thank you. :D I visited you blog recently and when I got back to mine, I saw your comment here.;)
Mandira- thank you. :)
Vaishali- Yes, the rava helps make the cake soft and moist. As for the taste of the cake- it almost tastes like a sheera made using mangoes. :)
Srivalli- thank you.:)
A & N- how are you doing? how's the diet going? :D
I'm glad you like the cake.:)
Parita- thank you.:) Hope you like it as much as we did.
- August 12, 2009 at 11:51 PM
- Siri said...
Hey TBC, I was just browsing through RC's Eggless Mango Cake on web and found the following link:
I am not sure if you have contributed ur post to this website or they copied w/o lettting you know. Just wanted to bring to your notice!
- August 14, 2009 at 1:01 PM
- Aparna said...
Love the crumb. Its made with semolina and that's new to me. Anything mango is always good as far as I'm concerned.
- August 16, 2009 at 7:10 AM
- Divya Kudua said...
Mangoes are gone so maybe I can try it out with Pineapple instead..??Looks delicious..I've bookmarked it from Rc's too..:)
- August 16, 2009 at 12:37 PM
- kitchen queen said...
Your eggless mango cake looks yummy in the picture and mouth watering.Hearing about this for the first time. you can visit my blog view my recipes and give ur comments
- August 23, 2009 at 3:55 PM
- TBC said...
Kitchen Queen- thanks. :)
Will definitely stop by your place soon.
- August 24, 2009 at 10:32 PM
- Namratha said...
Sounds and looks very good T, will be trying soon!:)
- August 25, 2009 at 9:35 PM
- Anonymous said...
Now if only we could high lite and/or print out the recipe and use it, ourselves. I am not finding a link or anything, that would allow me to print it out. But it does look good! One more thing, what is semolina/rava/sooji?
- September 24, 2009 at 10:54 PM
- TBC said...
Anon- why the anonymous comment?
I'm glad you like what you see here.
Yeah, I do not have a "print recipe" button for my recipes. How about bookmarking the recipe though?
Also, there is a link to what rava/semolina/sooji is in the ingredient list. Maybe you need to go over the list once more?
- September 25, 2009 at 8:44 AM
- evolvingtastes said...
Hi TBC,
After having bookmarked the recipe ages ago, I made it recently and blogged about it here:
It is just so lovely. Thanks a bunch for sharing!
- July 21, 2010 at 1:17 PM
- TBC said...
Evolvingtastes- I'm glad you liked the recipe. Thanks for the feedback.:)
- July 25, 2010 at 10:55 AM
- Manju said...
Love the color of the cake...can almost smell the aroma! Am going to try it today. Had a quick question - I noticed that the quantity of butter/oil is half of the original recipe. Is that intentional or a typo? If intentional, do you think it made the cake dry? Thanks a bunch!
- March 23, 2011 at 10:18 AM
- TBC said...
Manju, I did cut down on the fat in the original recipe- I used only 1/4 cup and my cake turned out fine. It was also the simplest cake I'd ever made. Try it and let me know how it turns out for you.
- March 23, 2011 at 11:33 AM
- Manju said...
I tried this cake a few days ago - the taste is amazing! Had a few problems (my own fault)- I doubled the recipe but it appears that I didn't use a big enough container. The cake was soft and uncooked in the middle. So, this is what I did: I cut slices from whatever was cooked and firm and kept aside. I then scooped out the soft/uncooked part,put it in a dish and steamed for 20 min and then cut slices from that. Perfect! I'm definitely going to try this again but the right way this time. Thanks for a great recipe!
- March 29, 2011 at 9:17 PM
- TBC said...
Manju- Thanks for the feedback. Too bad that it did not turn out as expected for you. I'm not sure why though. Better luck next time!
- May 22, 2011 at 9:41 PM
- BaKaSoor said...
Tried this yesterday. Absolutely loved it. :) Thanks so much!
- April 23, 2012 at 2:30 PM
- TBC said...
BaKaSoor- Thank you for letting me know. Glad you liked it!
- April 23, 2012 at 5:30 PM


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Like several theater artists with connections to bonnie Scotland, David Greig seems to have the golden ticket of the moment. This thrilling scribe — perchance you saw his grand piece "The Strange Undoing of Prudencia Hart" last fall at the Chicago Shakespeare Theater — also has written the book to the much-anticipated new musical version of "Charlie and the Chocolate Factory," which begins previews in London in a couple of weeks.
But he's tricky. He tends to write in a singular fusion of the narrative and the dramatic; his characters love to tell their own stories, even as they find themselves in the heart of them. You have to tease out the throughline. And his works have to be directed with zest and passion.
Neither of those latter two qualities are sufficiently on display in Writers' Theatre's disappointingly flat, safe and prosaic production of "Yellow Moon," what should be an edgy, frenetic, 80-minute piece about a couple of alienated Scottish teenagers who take off together to make trouble, somewhat akin to a modern-day Bonnie and Clyde.
The boy, Stag Lee McAlinden (portrayed by Josh Salt), is the boisterous product of a broken family and one of those dangerous, cute teenage boys dreaded by the parents of quiet teenage girls the world over. The girl, Leila (Ashleigh LaThrop), is a good girl from a migrant family who knows how to keep the rules, until she lets loose. The immature pair has no clue what they are doing, of course, or even how to relate to each other. At one point, Stag declares his intention to make a career as a pimp, and Leila still sticks around. But they find in each other a refuge from the cruelties of the world. And as they embark on a trip across the heather in search of both a father and self-discovery, they're filled with desire.
Frankly, there was more sexual tension on Thursday night at one of the stoplights on Green Bay Road than in the little room behind Books on Vernon in Glencoe, a tiny venue that should have been ideal for a piece that demands an intimate setting. As the adults in the piece and the main storytellers, accomplished actors John Lister and Karen Janes Woditsch have their moments and surely know how to unspool Grieg's dramatic poetry. But although LaThrop and Salt are attractive young actors, they seem to have no connection whatsoever to each other, no sense of young lovers against the world, no feeling for the dangerous sexual politics of follower and leader. They're supposed to be hot-blooded young people striking out alone for the first time, yet there is barely a flicker of illicit mutual passion.
And thus with the entire production shorn of any sensual or dangerous teenage undertow, "Yellow Moon," a fine piece of writing, does not rise and fall as it should. Director Stuart Carden, who might have paid more attention to these problems, should call these actors back in the room and make it known that unless they connect to each other, we surely cannot connect to them, however rich the language coming from their mouths.
When: Through Aug. 4
Where: Writers' Theatre at Books on Vernon, 664 Vernon Ave., Glencoe
Running time: 1 hour, 20 minutes
Tickets: $35-$60 at 847-242-6000 or writerstheatre.org


text: Ok i like changing my Avatar alot but lately im getting pissed cause im a computer retard. Every Avatar i want needs to be resized or something to fit on Tobys new forum. I remember back in the day we all had bigger avatars. Can we go back to this. Some peoples Avatars are so small you cant see them or read them so i would like everyones thoughts on this