Consensus Criteria Predict Futile Prehospital Trauma Resuscitation

In 2003, the National Association of Emergency Medical Services (EMS) Physicians and the American College of Surgeons Committee on Trauma published guidelines on when to withhold or terminate prehospital resuscitation in traumatic cardiopulmonary arrest (TCPA). Using data from a level I trauma registry from 2003 through 2010, researchers studied prehospital TCPA patients aged 18 years for whom these guidelines were violated. Criteria to withhold or terminate care were (1) blunt trauma with apnea, pulselessness, and no organized electrocardiogram activity; (2) penetrating trauma with the preceding clinical presentation and no other signs of life; (3) 15 minutes of cardiopulmonary resuscitation without return of spontaneous circulation; or (4) EMS-witnessed TCPA followed by 15 minutes of unsuccessful resuscitation en route to the emergency department (ED).

Among 294 patients, mechanism of injury was blunt in 90 (31%) and penetrating in 204 (69%). Overall, 274 patients (93%) died in the ED, and 12 (4%) died during surgery. Of the 8 patients who reached the intensive care unit, 7 died in the ICU, and 1 (0.3%) survived but had a Glasgow Coma Scale score of 6 and was discharged to a long-term care facility.

Comment: The charges for hospital care for these 294 patients totaled nearly US$4 million, and the one surviving patient had a horrible outcome. These data strongly support the existing guidelines and the need to ensure that EMS personnel understand and adhere to them.

Source: Journal Watch Emergency Medicine

A New Way to Assess Risk in Upper Gastrointestinal Bleeding?

An assessment of five readily available measures in emergency settings could improve patient triage and outcomes.

Scoring systems based on clinical characteristics of patients with upper gastrointestinal bleeding (UGIB) pre- and postendoscopy can predict mortality and rebleeding, allowing for more-efficient use of resources through risk stratification. Now, researchers have developed a simple scoring system for clinicians to use when patients present with acute UGIB in emergency departments (EDs).

Using a large clinical database, investigators retrospectively identified risk factors associated with mortality among 29,222 patients admitted with UGIB through the EDs of 187 hospitals. They then retrospectively validated the results through a different cohort of 32,504 patients. Using recursive partitioning, investigators identified clinical characteristics that were associated with mortality, resulting in a treelike algorithm. To simplify the scoring calculation, they used the number of risk factors present rather than data generated from the algorithm.

This process identified five factors associated with increased risk for mortality: serum albumin <3.0 g/dL, an international normalized ratio >1.5, altered mental status, hypotension (systolic blood pressure 90 mm Hg), and age >65. Mortality increased with the number of risk factors present, as did length of hospital stay and cost. In the validation cohort, mortality increased from 0.3% with no risk factors (score, 0) to 24.5% with all five risk factors (score, 5). The predictive accuracy of the scoring system was high, with area under the receiver operating curve of 0.80 for the derivation cohort and 0.77 for the validation cohort.

The authors conclude that this risk stratification system is a simple way for ED clinicians to identify patients who require aggressive therapy.

Comment: Prior studies of scoring systems have demonstrated that endoscopic stigmata, bleeding volume, patient age, and comorbidities increase the risk for death in patients with acute UGIB. This new system came to the same conclusion but without the need for endoscopic data. The absence of a prospective validation cohort and data on rebleeding prevents meaningful comparisons with other scoring systems. However, the take-home message from all scoring systems is that older patients with high-volume bleeds and comorbidities are at much higher risk for poor outcomes than young, otherwise healthy patients with small-volume bleeds.

Source: Journal Watch Gastroenterology

17-Year-Old Girl Creates Nanoparticle That Kills Cancer

When I was seventeen, it was a very good year. Actually, that’s a flat out lie. When I was seventeen I was probably wallowing in self-important despair so trivial that now, years later, I can’t even remember if I was wallowing or not. The point I’m getting at here is that I wasn’t doing anything productive, much less anything that could save countless lives and contribute to a field of science that is more important now than it has ever been. That’s what Angela Zhang was doing, and now, she’s $100,000 the richer for it. Also, she can say she’s created a nanoparticle, one that kills cancer, for what that’s worth (Spoiler: It’s worth a lot).

The $100,000 Zhang earned comes with first prize in the Siemens Competition in Math, Science & Technology. Her project, “Design of Image-guided, Photo-thermal Controlled Drug Releasing Multifunctional Nanosystem for the Treatment of Cancer Stem Cells,” was apparently as complex, thorough, and revolutionary as it sounds.

The nanoparticle Zhang created is already being referred to as something of a “swiss army knife” in the area of cancer treatment. That’s not to say it’s dull and rusty because I you didn’t take care of it when I was you were out camping, but rather that it has a whole bunch of useful applications. The nanoparticle is delivered to tumors via the drug salinomycin where it kills cancer cells and deposits gold and iron-oxide materials to help with MRI imaging.

Not only is this impressive in its own right, but let me remind you this girl is 17. She’s got a lot of time ahead of her. She spent about 1,000 hours developing this particle since 2009 (when she must have been 15) and she wants to continue to study chemical engineering, biomedial engineering, or physics. She hopes to someday be a research professor. Thank god, because if she said she wanted to be a poet, we might have a problem on our hands.

If she’s accomplished this by 17, there’s virtually no doubt we’ll see some further innovations coming from Zhang in the future. In the meantime, just take a moment to think about what you’ve done with your life. But only a moment; any longer than that and it starts to get depressing.


Are scientists afraid of revolution?

By far, one of the most sensational science stories of 2011 has been that of the allegedly faster-than-light particles reported by the subterranean physics laboratory under the Apennine mountains in Italy. When the news broke this past September, it instantly triggered speculation (some of it a bit overheated) that the discovery might upend physics, force a rewrite of Einstein’s theory of special relativity, reveal particles traveling backward in time, and undermine concepts of cause and effect.

Physicists around the world were quick to temper such speculations by pointing out that the reported results were almost certainly a mistake. Last week, however, the Italian team announced that a rerun of the experiments carefully designed to eliminate a source of possible error had only confirmed the earlier results.

Yet physicists aren’t satisfied. They keep on citing reasons why the faster-than-light particles would conflict with theory. Even colleagues at the same Italian physics facility have declared that the observations must be wrong.

So why aren’t scientists accepting the verification of these seemingly impossible faster-than-light particles? Are they just refusing to acknowledge that the concepts on which they built their careers are wrong? Are they rebelling against a “paradigm shift” in their field, as the historian Thomas Kuhn put it in The Structure of Scientific Revolutions? And does their behavior lend credence to the idea often spread by cold fusion enthusiasts, climate change deniers, intelligent design theorists, UFO believers and others that researchers are more interested in protecting mainstream scientific orthodoxy than in finding the truth?

Not at all. In fact, the scrutiny of these supposedly faster-than-light particles is an example of how science is supposed to work and helps to demonstrate why such conspiratorial criticisms are wrong.

Faster than expected

First, a quick recap of exactly what the strange faster-than-light results are. Fourteen hundred meters beneath the Italian mountain for which it is named, the Laboratori Nazionali del Gran Sasso (Gran Sasso National Laboratory) is conducting an experiment called OPERA (Oscillation Project with Emulsion-tracking Apparatus). OPERA detects and measures neutrinos, ethereally aloof particles that have long been understood to shoot unperturbed through matter at the speed of light. OPERA’s detectors are set up to catch a beam of neutrinos generated by a powerful accelerator at the CERN laboratory in Geneva. In less than three milliseconds, the neutrinos zip 730 kilometers through the earth’s crust, which filters out other, unwanted particles in transit.

Sifting through the data, however, the OPERA team repeatedly saw that the neutrinos appeared to be arriving 60 billionths of a second sooner than expected. They were therefore moving 0.00025 percent faster than light — a tiny but jarring discrepancy because Einstein’s special relativity theory established that no particle could be accelerated to beyond light speed.

It’s worth noting that the OPERA experiment is not the first one to find evidence of faster-than-light (or superluminal) neutrinos. Back in 2007, the MINOS neutrino project associated with Fermilab in Illinois published a similarly curious result, but the support for that conclusion was thin and few scientists were persuaded by it. The observations by the OPERA team presented in September were far more robust and compelling (the team claims that the result has a statistical significance of “6 sigma,” meaning that the odds of it being a fluke are less than one in half a billion). And the latest, more rigorous repetition of the experiments adds that much more evidence that the effect might be real.

This OPERA ain’t over …

But the OPERA results are still far from constituting proof for superluminal neutrinos, revolutionary as those would be. First, the re-do of the experiment was only a very limited test of the first’s findings. One criticism of the first OPERA evidence was that the way of measuring precisely when neutrinos left Geneva and arrived at Gran Sasso was in effect slightly mushy. The improved system in the second round of experiments used sharper, shorter bursts of neutrinos whose timing was more certain.

Yet that change fixes only one source of potential error. Scientists have also called into question, for example, whether relativistic effects in the GPS system that helps to clock the neutrinos might be biasing the measurements, or whether distance between the CERN and OPERA setups might be slightly shorter than believed. (The distance would only have to be off by about 22 meters over the 730-kilometer distance to account for the discrepancy; of course, the distance is supposedly measured to an accuracy within 20 centimeters.) All these possibilities need to be ruled out before the results stand firm.

Another problem is that the OPERA team performed both the initial measurements and the more recent ones. No one questions the credibility or competence of the OPERA researchers, but independent verification is needed because the scientists might unwittingly be introducing the same skew repeatedly into the experiments. Replication of the results by different scientists is the acid test. Indeed, spokespeople for the MINOS facility have said that it may be able to run a preliminary test next year.

For the OPERA results to be strongly vindicated, they need as many independent, rigorous verifications as possible because “extraordinary claims demand extraordinary evidence,” in the words of the late astrophysicist and skeptic Carl Sagan. Frustrated proponents of unorthodox science sometimes complain that Sagan’s standard begs the questions of what constitutes “extraordinary evidence,” but no matter what, more than one repetition is necessary for something this amazing.

Of course, those same disgruntled and suspicious critics might also claim that all these rationales for more proof are beside the point — that the ugly truth is the physicists don’t want to see the edifice of Einstein’s physics toppled. That argument, however, is built on a misunderstanding of why scientists hold the views that they do.

The inconvenient facts

Faster-than-light particles don’t seem unlikely just because they are at odds with theories that physicists are loath to give up. Rather, they are at odds with huge amounts of observational and experimental data that gave rise to those theories.

Ring of debris surrounding the remnants of supernova 1987A. (Credit: NASA/ESA/P. Challis and R. Kirshner, Harvard-Smithsonian Center for Astrophysics)

For example, one of the stunning vindications of modern astrophysics involved the supernova 1987A: shortly before that star exploded in 1987, it released a burst of neutrinos precisely when models of stellar collapse predicted that it should. But if neutrinos actually move faster than light by the margin OPERA suggests, those neutrinos should have arrived at Earth four years earlier than they did.

Similarly, the theoretical refutation of the OPERA results that Nobel laureate Sheldon L. Glashow and Andrew G. Cohen have offered is that any superluminal neutrinos from CERN should have shed almost all their energy by the time they reached Gran Sasso because of a phenomenon called bremsstrahlung radiation. Bremsstrahlung is observed whenever charged particles interact with matter.

Perhaps some extenuating complexities can explain these discrepancies: maybe neutrinos from CERN and those from stars move at different velocities, and maybe superfast neutrinos may uniquely avoid radiating away their energy. But for now, the more parsimonious explanation is that the OPERA results are wrong.

What’s almost absurd, however, is to think that scientists would steer away from iconoclastic discoveries to protect their professional standing. But the career of any scientist who has the evidence to knock down pillars of his or her field isn’t ruined — it’s made.

The physicists who first prove the existence of faster-than-light particles are instantly in the history books. That credential looks pretty good to tenure committees and granting agencies. The same would be true for any climate scientist who could truly, conclusively prove that worries about climate change from industrial greenhouse gases were groundless, or for any biologist who could knock off evolution as the best explanation for living things’ traits. They wouldn’t be blackballed by their professions: they would be among the most famous scientists alive and able to name their own appointments.

Moreover, revolutions in science aren’t just good for the leaders of the revolution. The demonstrated existence of faster-than-light particles would mean that other new physics remains to be discovered, and lots of new work needs to be done to fit the older observations into the new paradigms. Those opportunities would be welcomed by legions of physicists looking to make their mark. Indeed, the OPERA results have already inspired a number of scientific papers.

Einstein’s theory of special relativity sits on a pedestal of honor, not on an altar. Plenty of physicists would be glad to knock it off and put something else in its place. But it may take something more substantial than OPERA’s superluminal neutrinos to bring it down.

Source:Smart planet.

New spray illuminates hard-to-spot tumors within minutes

Researchers have developed a way to light up tiny, hidden tumors with a fluorescent spray.

Within minutes, doctors can track down residual cancer that spread and scattered throughout the body – helping to ensure that no tumors are left behind during surgery.

The main ingredient in the new spray probe is a green dye called gGlu-HMRG, which triggers a chemical reaction when it comes into contact with some cancer cells. Nature News explains:

it glows after being transformed by an enzyme that sits in the cell membrane of ovarian cancer cells. It is activated during passage into the cell, so the probe only starts to glow once inside the diseased tissue.

Current tumor imaging procedures can take up to several hours or even days. “Our probe is actuated in minutes or even seconds – that’s very important for the surgeon, who can’t necessarily wait 20 minutes,” says study researcher Hisataka Kobayashi of the National Institutes of Health.

  1. The team observed ‘rapid fluorescence’ in less than 10 minutes after adding the dye to ovarian cancer cells in the lab.
  2. Then they tried the spray on mice with human ovarian tumors. Within a minute of spraying the probe directly onto tissue inside the body, they observed bright fluorescent regions in the abdominal cavity where the cancerous lesions were (pictured).
  3. Now that they’re clearly identifiable, the small tumors were quickly removed from the living mice using tweezers.

The team’s working on producing a compound suitable for human studies and for other cancers, like gastric, colon, liver, and uterine cancer.

Source: Science Translational Medicine


Many Women Don’t Get Breast Reconstruction After Mastectomy

Older Women, Those on Medicare Less Likely to Have Reconstruction Immediately
surgical instruments

Dec. 8, 2011 (San Antonio) — Despite the psychological and cosmetic benefits, fewer than 1 in 4 women with insurance have breast reconstruction immediately after having a mastectomy to treat their breast cancer.

Women who are on Medicare or Medicaid, who are older, who are black, and who are treated at rural or non-teaching hospitals are even less likely to have immediate reconstructive surgery. Research has shown that breast reconstruction improves patients’ psychological and sexual well-being.

The vast majority women would rather have reconstruction at the time of mastectomy so they don’t have to undergo a second surgery later, says Dawn Hershman, MD, who headed up the study. She is an assistant professor of medicine and epidemiology at Columbia University Medical Center in New York City.

“For all those reasons, we were surprised to see that although the use of immediate reconstruction has increased over the past decade, the rates still remain so low,” she tells WebMD. The study involved more than 100,000 insured women with breast cancer who underwent mastectomy between 2000 and 2010.

Private Insurers Cover More

The research was presented at the 2011 San Antonio Breast Cancer Symposium. Among the findings:

  • Overall, 42% of women younger than 50 and 17% of women 50 and older underwent immediate reconstruction over the 10 year period.
  • The percentage of women opting for immediate reconstruction increased steadily from 15% in 2000 to 33% in 2010.The largest increase came from women under 50 (from 29% to 60%) and women with private insurance (from 25% to 55%).
  • Women with very early breast cancer known as ductal carcinoma in situ, or DCIS, were more likely to undergo immediate reconstruction than those with cancers that had invaded the breast.

Women with private insurance are more likely to have a greater portion of the cost covered, says Patricia Ganz, MD, director of prevention and control research at UCLA Jonsson Comprehensive Cancer Center.

While the price tag of mastectomy remained stable over the decade, the cost of immediate reconstruction tripled, Hershman says. The hospital stay — for mastectomy plus the plastic surgery — runs about $15,000 if a woman opts for implants and $17,000 if breasts are rebuilt using tissue from her body, she says.

“Not everyone wants or should have [reconstructive surgery]. But there should be universal access regardless of type of insurance,” Hershman says.


First Solid Signs of the Higgs Boson Could Be Announced Next Week

It’s just about time to put up or shut up for the most sought-after elementary particle, the famed Higgs boson. Next week, physicists working with the world’s biggest atom smasher—the Large Hadron Collider (LHC) at the European particle physics laboratory, CERN, near Geneva, Switzerland—will report the latest results of searches for the Higgs, the key to physicists’ explanation of how all particles get their mass. Nobody expects a definitive claim of discovery, but given the amount of data the LHC has produced in 2 years of running, some physicists say that—if it’s there—the Higgs should begin to emerge from “background” particle collisions like a sapling rising above the grass.

“You should start to see something,” says Dmitri Denisov, an experimenter at Fermi National Accelerator Laboratory (Fermilab) in Batavia, Illinois. In fact, if no sign of the Higgs appears, then its existence may come into question, says Michael Peskin, a theorist at SLAC National Accelerator Laboratory in Menlo Park, California. “If the Higgs is really not there, that could certainly be discovered with the current data set,” he says.

The LHC feeds two enormous particle detectors, called ATLAS and CMS, that are designed to detect the Higgs as it pops out of collisions of high-energy protons and quickly decays into familiar particles. The mass of the Higgs remains to be determined, although previous searches have restricted it to above 114 giga-electron volts (GeV), or about 122 times the mass of a proton, and ruled out a small range of higher masses. This summer, the ATLAS and CMS teams reported data that, taken together, show that the Higgs does not exist in the range from 141 GeV to an untenably high 476 GeV. That paints the Higgs into a corner from 114 to 141 GeV.

Researchers now have twice as much data. In the units physicists use, each experiment now has 5 inverse femtobarns of data. That’s still not enough to make an incontrovertible discovery. Physicists measure the strength of a signal, such as the number of candidate Higgs decays, in multiples of the uncertainty in the measurement, denoted sigma. That yardstick reveals the chances that random backgrounds could create a fake signal as big. For example, the chances of spotting a spurious three-sigma signal are 0.14%. The standard for a discovery is five sigma, as the chances that background processes will produce such a large signal are 1 in 3.5 million. To achieve such sensitivity, ATLAS and CMS would need 10 to 15 inverse femtobarns of data each.

Still, as a data set grows, a signal “shouldn’t go from nothing to five sigma in one shot,” Denisov says. So with the data they have now, ATLAS and CMS should start seeing signs of the Higgs, if it’s there. The two teams will report their latest results at a special seminar at CERN on 13 December.

If both experiments report excesses of Higgs candidates in the same mass range, many physicists will take that result as evidence of Higgs. And rightly so, says Gordon Kane, a theorist at the University of Michigan, Ann Arbor. “All the knowledgeable theorists will immediately believe it is [there] if there are coincident 2-sigma signals,” he says.

Others are more cautious. “We have seen lots of 3-sigma signals [of other things] that have gone away,” says Marcela Carena, a theorist at the University of Chicago in Illinois. In fact, in July both ATLAS and CMS reported small excesses of Higgs candidates in the same low-mass region. By August, with more data, those excesses had weakened.

Alternatively, both ATLAS and CMS could see no sign of an excess. That outcome would undermine the case for the Higgs, at least as it is described by physicists’ standard model. That would be “incredibly important,” Peskin says. However, other versions of the Higgs could still exist, he says.

The standard model assumes that empty space is filled with a Higgs field, akin to an electric field, that drags on particles to give them inertia, the essence of mass. That field is made up of Higgs bosons much as an electric field consists of photons. The standard model also assumes that there is only one type of Higgs and that it’s the only particle waiting to be discovered. If other new particles exist, then they could interact with the Higgs and alter its decays to make it harder to detect, Peskin says. So killing off the standard-model Higgs would not ax the entire Higgs “mechanism” for giving particles mass. Physicists might have to look for years to find a non-standard-model Higgs, however.

More ambiguous results are possible: CMS could see something and ATLAS not, or vice versa. The least-revealing result may be the most likely, says Jacobo Konigsberg of the University of Florida, Gainesville, who works on the CMS experiment. With 5 inverse femtobarns of data, neither CMS nor ATLAS may be able to rule out the Higgs in the mass range between 114 and about 130 GeV, he says, leaving a window in which it might or might not exist. Indirect evidence suggests that the Higgs should have a relatively low mass, so “the room that’s left is where it’s likely to be,” Konigsberg says.

Given the rate at which the LHC has been cranking out data, physicists say they will surely discover or rule out the standard-model Higgs within a year. “2012 will be the year of the Higgs,” says Rob Roser, an experimenter at Fermilab. But that prospect won’t stop people from jumping to conclusions based on the data presented next week. “It’s going to be overinterpreted within 24 hours,” Peskin predicts. The chances that he’s wrong are 1 in 3.5 million.



On 1 December, U.S. President Barack Obama headed a star-studded event, “The Beginning of the End of AIDS,” that attracted heavyweights such as former presidents George W. Bush and Bill Clinton, the president of Tanzania, the head of Coca-Cola, and the rock stars Bono and Alicia Keys. The cause for the occasion held at George Washington University in Washington, D.C., was World AIDS Day, but as Obama noted, this year’s theme was far more ambitious than any in the past. Over the past 2 years, four large-scale studies of interventions to prevent HIV have worked, and for the first time, the goal of ending AIDS epidemics in some locales—and, in time, the world—seems like a possibility, provided, of course, that there’s political will and money. To that end, the Obama Administration a few weeks earlier had declared a global priority of “creating an AIDS-free generation.”

But there’s a vast difference between a study having success and thwarting HIV in the real world. “This is truly an exciting time, but it’s a complicated time,” says Anthony Fauci, who heads the U.S. National Institute of Allergy and Infectious Diseases in Bethesda, Maryland. “If we implement a combination of known prevention modalities, we could probably have a significant impact on the epidemic even before we have a vaccine.” Yet he stresses that the impact of proven interventions might vary from place to place because the epidemics have different features.


Daunting funding issues face any campaign to ramp up HIV prevention. Just 2 weeks ago, for instance, the Global Fund to Fight AIDS, Tuberculosis and Malaria, low on money, scuttled a round of new grants. But funding aside, it’s a challenge to figure out how best to combine the available interventions. Many mathematical modelers and HIV/AIDS researchers have begun to explore and intensely debate a variety of strategies. “We’re fortunate to have several prevention interventions that are efficacious, but the next step is to factor in the nuances of each of these local epidemics,” says Wafaa El-Sadr, an epidemiologist at Columbia University.

Several large clinical trials under way or in the works should reveal which new prevention strategies best bring down incidence in a population versus simply protecting an individual. El-Sadr suggests that, in parallel, countries begin to apply new combinations of proven strategies today with a trial-and-error mindset. “It has to be an iterative process of using the information at hand and being willing to adjust and modify,” she says.

Eric Goosby, who heads the multibillion-dollar U.S. President’s Emergency Plan for AIDS Relief (PEPFAR), says his group is closely analyzing models now. “We see it as a definite opportunity to change the way we do business and move us all toward higher impact interventions,” Goosby says. “We’re taking this as seriously as you can.”

Flood of success

Nearly all of the earliest HIV prevention trials failed badly or yielded confusing results. For instance, efforts to reduce HIV transmission by treating other sexually transmitted infections worked in one large study and failed in others. The first clear success was the demonstration in 1994 that antiretroviral (ARV) drugs could prevent HIV-infected mothers from transmitting the virus to their babies if both received them. So-called harm-reduction strategies, including needle exchange, can protect injecting drug users from HIV. But neither of those interventions slows sexual transmission, the route of spread for most of the world’s 34 million HIV-infected people.

In 2005, a study finally proved unequivocally that a biomedical intervention could block sexual transmission: A large, randomized, controlled trial in South Africa found that male circumcision offered 60% protection to uninfected heterosexual men. But it was four subsequent triumphs during the past 18 months that made ending the epidemic seem an achievable goal.

The first was a South African study of a strategy called topical pre-exposure prophylaxis (PrEP), which showed in July 2010 that a vaginal gel laced with an anti-HIV drug could cut transmission to uninfected women by 39%. That November, another trial in six countries of an oral PrEP that combined two anti-HIV drugs taken daily showed 44% efficacy in uninfected men who have sex with men. In May, a nine-country trial known as HPTN 052 had a downright spectacular result. The study recruited “discordant” heterosexual couples. One long-term partner was uninfected at the start whereas the other had a known HIV infection and a relatively intact immune system with 350 to 550 CD4 cells per milliliter (600 to 1200 is normal; fewer than 200 is AIDS). Half of the infected people received treatment immediately; the other half waited until their CD4 counts fell below 250. Earlier treatment reduced the risk of transmitting HIV by 96%. Although observational studies had long suggested that reducing viral levels made a person less infectious, the ongoing HPTN 052 trial proved once and for all that “treatment as prevention” (TasP) works. A different study with discordant heterosexual couples in Kenya and Uganda reported 2 months later that if infected people remained untreated and their uninfected partners instead took the two-drug oral PrEP, transmission dropped by 73%.

With these successes has come a dilemma. “We’ve got more things we could spend our money on than ever before but less to spend,” says epidemiologist Timothy Hallett, who has done extensive mathematical modeling of the epidemic with Geoffrey Garnett at Imperial College London (ICL). “It’s a real crunch time.”

Hallett and his ICL colleague Íde Cremin have taken a stab at modeling the impact of combining several proven biomedical interventions. They focused on KwaZulu-Natal, South Africa, which has an annual HIV incidence of nearly 3%. The model assesses the drop in incidence that would occur by 2025 as various interventions are scaled up starting in 2013. First, putting 75% of infected people who have fewer than 200 CD4 cells on ARVs and increasing male circumcision to 65% reduces incidence in the model by 1%. If infected people start treatment an average of 2 years after testing positive instead of waiting for their CD4s to fall below 200, incidence decreases another 1%. If 60% of 15-to-24-year-olds—a particularly high-risk group there—uses PrEP, incidence drops another half-percent. In the final analysis, incidence plummets to almost 0.5% . “We can cut down the epidemic with 1000 cuts rather than one fatal blow,” Hallett says.

Brian Williams and colleagues at the South African Centre for Epidemiological Modelling and Analysis at the University of Stellenbosch looked at the same question but assessed a different outcome: reducing an individual’s risk of infection. According to their calculations, if 60% of men in a given population were circumcised and 80% of infected men and women were taking ARVs, the risk of someone becoming infected would drop by 55%. Reducing risk by 85% would require 90% of infected people on ARVs, 10% on daily PrEP, 80% male circumcision, and 25% of uninfected women using a vaginal microbicide before and after sex. Williams emphasizes that every one of these interventions other than circumcision depends on the person properly using their medication. “The key to success is compliance,” Williams says.

Limitations galore

Variable compliance is but one of many reasons each of the recently proved biomedical prevention interventions may work better in clinical trials—and in models based on them—than when governments attempt to apply them in public health programs. Trained specialists who can run diagnostic tests and provide medicines are already in short supply in many low- and middle-income countries. Uninfected people could undermine the effectiveness of TasP, PrEP, or circumcision if they presume they are invulnerable and engage in riskier behaviors. Widespread use of ARVs could increase drug resistance, crippling both TasP and PrEP.

Some say models are being used naïvely. “People need to get a more realistic view,” says Sally Blower, a mathematical modeler at the University of California, Los Angeles. “Too many think, ‘Treatment as prevention: good.’ It’s just not right.”

Loud debates about the limits of TasP have been raging since The Lancet published a model 3 years ago that proposed that testing and treating every infected person in the world could “eliminate” the epidemic in 10 years. In a paper published online 26 November 2008, World Health Organization epidemiologist Reuben Granich, Williams, and colleagues used data from South Africa, which has more HIV-infected people than any country, to create a scenario that involved testing the entire population for HIV once a year and treating every positive individual. Within 10 years, they concluded, the annual rate of new infections would drop from about 2% to below 0.1%.

Critics said treating all of South Africa—let alone the world—was unrealistic, both technically and financially. Many questioned the testing scheme, too. Rochelle Walensky, an HIV/AIDS epidemiologist at the Massachusetts General Hospital in Boston, said she found the Granich model “provocative and motivating” but worried that it set benchmarks that no country could meet. A study she led evaluated a pilot test-and-treat program in Washington, D.C. Although individuals benefited, “suggestions that a test and treat strategy might be sufficient to eradicate the HIV epidemic create public expectations that cannot be realized,” the study team wrote in the 15 August 2010 issue of Clinical Infectious Diseases.

Walensky says it’s extremely difficult to test an entire population, do so repeatedly, then start all positive people on treatment, and see that they take ARVs as prescribed. “We’re nowhere near 100% coverage for testing once, let alone annually,” Walensky says. “When you offer tests, people don’t necessarily take them, and when they get positive results, they don’t necessarily start treatment.”

Myron Cohen of the University of North Carolina, Chapel Hill, who heads HPTN 052, raises another caveat. Cohen contends that a disproportionate amount of transmission occurs from recently infected people who have high viral loads but do not yet produce the antibodies that standard HIV tests detect. Even if a program managed to start all HIV-positive people in a community on ARVs, it would miss the acute or recent infections. A model that Cohen and co-workers described in the 16 July issue of The Lancet—using behavioral and viral load data collected in Lilongwe, Malawi—calculated that acutely infected people were high transmitters for up to 5 months after becoming infected, accounting for 38% of the transmissions. “If the contribution of acutely infected people to incidence is very large, we might be very disappointed by the results of combination prevention,” Cohen says. Hallett and co-workers at ICL showed with a model in AIDS and Behavior in May that acute infection likely has a major impact on a community’s prevalence if many people have overlapping, or “concurrent,” sexual partners, as is common in parts of sub-Saharan Africa and in communities of men who have sex with men. In their model, increasing concurrency from 10% of the population to 12% led HIV prevalence to jump from 3% to 11%.

In the past, some dismissed the Granich model because TasP had never proved its worth in a rigorous study. HPTN 052 has ended that argument. But Blower and others have now turned their sights on the limits of HPTN 052.

Online on 11 October in the journal AIDS, Blower and Columbia’s El-Sadr applied HPTN 052’s design in a model, targeting discordant couples in Malawi, Lesotho, Ghana, and Rwanda. The number of infections prevented varied dramatically according to population size. Malawi, population of 15.3 million, benefited the most; Lesotho, with only 2 million, the least. The rate of new infections, a different measure of effectiveness, also varied considerably among countries. Because Lesotho had the highest HIV prevalence and the greatest percentage of discordant couples, it benefited the most. “One really needs to be very specific and look at the population at hand in order to figure out where does this strategy fit,” El-Sadr says.

Blower says it does not make sense for countries to target discordant couples with TasP. She says the best strategy is to test and treat in geographic hot spots that have the highest prevalence .

Scaling up use of oral PrEP, another part of the combination package, raises its own issues—the first being who has priority? Some 7.6 million HIV-infected people in the world need ARVs for survival but have no access to the drugs. Scientists and policymakers alike agree that infected people should receive the lifesaving drugs before the uninfected.

It’s also unclear how much oral PrEP protects women: Two studies have shown it reduces transmission, and two studies have shown no effect. “I really don’t know whether it works in women,” Cohen says. Confusion similarly surrounds topical PrEP, or microbicide-laced gels: On 25 November, a large study reported that it had no effect, putting a question mark on earlier positive data from South Africa.

Several potential flaws dogging PrEP and TasP—including compliance, repeated testing, and drug resistance—could be mitigated by male circumcision. But for it to work, men must first choose to be circumcised, and the procedure has to be properly done. A study published 29 November in PLoS ONE asked 241 applicants to the Lesotho Defence Force whether they were circumcised. Trained clinicians examined the 64 who said yes. Of these, 50% either were not circumcised or had portions of foreskin left—an HIV-infection risk. The men who misreported their status were seven times more likely to have been cut by a “traditional” circumciser as part of an initiation rite, which the researchers stress is common in sub-Saharan Africa.

Blower says each country will ultimately have to figure out the best combination of interventions for its population. The “mantra” is that the more interventions we use, “the more synergy we get,” Blower says. “It isn’t true.” If the measures are simply redundant, “synergy might not occur for decades, or you might not get it at all.”

The road forward

Whatever the limitations of the overall scheme, each component of combination prevention makes solid scientific sense. And the abundant enthusiasm on display at the World AIDS Day event in Washington shows that ending AIDS has become something of a movement. But as many speakers at that event stressed, the research successes being celebrated come in the midst of a financial crisis that has many countries worrying whether they can maintain, let alone expand, the HIV/AIDS programs they have in place.

PEPFAR and other programs have begun to look for smart ways to transfer alreadyallocated funds to support the new opportunities, and they’ve turned to modelers such as South Africa’s Williams to identify the most cost-effective interventions. Williams says male circumcision should be used as widely as possible. “It’s a no-brainer,” he says. “It’s very cheap, and you do it once and it’s for life.” Giving uninfected people ARVs as oral PrEP, on the other hand, he says, would have the most bang for the buck with groups at the highest risk of infection. Treating infected people to prevent spread, he argues, would have the greatest impact: “If you want to stop transmission, the core of it has to be treatment as prevention.”

Models only point out routes to ending AIDS, and many will surely differ from the one proposed by Williams. But for the first time since AIDS surfaced 31 years ago, many researchers believe the destination itself is no longer a mirage.





Universal Alignment

Could the cosmos have a point?

The universe has no center and no edge, no special regions tucked in among the galaxies and light. No matter where you look, it’s the same—or so physicists thought. This cosmological principle—one of the foundations of the modern understanding of the universe—has come into question recently as astronomers find evidence, subtle but growing, of a special direction in space.

The first and most well-established data point comes from the cosmic microwave background (CMB), the so-called afterglow of the big bang. As expected, the afterglow is not perfectly smooth—hot and cold spots speckle the sky. In recent years, however, scientists have discovered that these spots are not quite as randomly distributed as they first appeared—they align in a pattern that points out a special direction in space. Cosmologists have theatrically dubbed it the “axis of evil.”

More hints of a cosmic arrow come from studies of supernovae, stellar cataclysms that briefly outshine entire galaxies. Cosmologists have been using supernovae to map the accelerating expansion of the universe (a feat that garnered this year’s Nobel Prize in Physics). Detailed statistical studies reveal that supernovae are moving even faster in a line pointing just slightly off the axis of evil. Similarly, astronomers have measured galaxy clusters streaming through space at a million miles an hour toward an area in the southern sky.

What could all this mean? Perhaps nothing. “It could be a fluke,” says Dragan Huterer, a cosmologist at the University of Michigan at Ann Arbor, or it could be a subtle error that has crept into the data (despite careful efforts). Or, Huterer says, perhaps we are seeing the first signs of “something amazing.” The universe’s first burst of expansion could have lasted a little longer than we thought, introducing a tilt to it that still persists today. Another possibility is that at large scales, the universe could be rolled up like a tube, curved in one direction and flat in the others, according to Glenn D. Starkman, a cosmologist at Case Western Reserve University. Alternatively, the so-called dark energy—the bewildering stuff accelerating the universe’s expansion—might act differently in different places.

For now, the data remain preliminary—subtle signs that something may be wrong with our standard understanding of the universe. Scientists are eagerly anticipating the data from the Planck satellite, which is currently measuring the CMB from a quiet spot 930,000 miles up. It will either confirm earlier measurements of the axis of evil or show them to be ephemera. Until then, the universe could be pointing us anywhere.

Source: Scientific American



Does Recurrent Clostridium difficile Infection Mean Reinfection or Relapse?

Even after months, most recurrences appear to be relapses.

Both nosocomial and community-acquired Clostridium difficile infections are becoming common enough that when patients have repeated infections, distinguishing between relapse and reinfection often is difficult. Making this distinction can be important both for tracking and for management.

Researchers used a polymerase chain reaction assay to type organisms from 134 paired stool isolates obtained from 102 patients with recurrent C. difficile infections who were seen during 30 months at a single New York City hospital; 24 patients had three or more episodes. Among stool isolates obtained 2 to 8 weeks apart, 88% yielded identical strains, which suggested relapse rather than reinfection; among isolates obtained 8 weeks to 11 months apart, 65% yielded identical strains. Similar patterns were seen among the patients with more than one recurrence: Among the 17 patients with four or more episodes, 11 had the same strain isolated for all episodes.

Comment: These data suggest that recurrent C. difficile infection often represents relapse rather than reinfection, no matter how long between episodes. However, as the authors point out, even patients who are treated and completely asymptomatic can continue to shed organisms into the environment and thus can transmit infection horizontally to themselves, confounding the usual semantics of infection.

Source:Journal Watch General Medicine