JAMA

doi: 10.1001/jama.2010.1299pmid: N/A

Adjuvant Care After Resection of Pancreatic Cancer In the randomized European Study Group for Pancreatic Cancer (ESPAC)-3 trial, which assessed whether 6 months of adjuvant treatment with fluorouracil plus folinic acid or gemcitabine is superior in terms of overall survival following complete resection of pancreatic adenocarcinoma, Neoptolemos and colleagues Article found no survival advantage among patients who received gemcitabine compared with patients who received fluorouracil. In an editorial, O’Reilly Article discusses established and investigational adjuvant therapy for pancreatic cancer. Reuse of Nevirapine in HIV-Infected Children Nevirapine—used to prevent mother-to-child human immunodeficiency virus (HIV) transmission—has been associated with selection of drug-resistant viral mutations, and therefore, it is recommended that nevirapine-exposed infants be switched to protease inhibitor (PI)–based therapy. Given the limitations of indefinite use of PI-based regimens in young children, Coovadia and colleagues assessed whether reuse of nevirapine would be as effective as a PI-based regimen (ritonavir-boosted lopinavir) in maintaining viral suppression in a randomized trial that enrolled nevirapine-exposed children who had achieved viral suppression on the initial PI-based regimen. At the 1-year follow-up, the authors found lower rates of viremia (defined as >50 copies/mL) among children who were switched to nevirapine than among children who continued on the PI-based regimen. Article CLINICIAN'S CORNER Clinical Characteristics of Influenza A Strains In an analysis of data from a population-based active surveillance study of influenza cases in Wisconsin, Belongia and colleagues compared clinical characteristics of pandemic 2009 influenza A(H1N1) with illnesses caused by other influenza A strains. Among the authors' findings were that individuals with 2009 H1N1 infection were younger than those with 2007-2008 (H3N2) infection (median age, 10 years and 25 years, respectively) and that the risk of most serious complications was not elevated among adults or children infected with 2009 H1N1 compared with other recent seasonal influenza A strains. Article Pneumococcal Vaccine and Serotype 19A Acquisition A rapid increase in multiresistant pneumococcal serotype 19A has been observed coincident with widespread implementation of heptavalent pneumococcal conjugate vaccination (PCV-7) of infants. In a post hoc analysis of data from a randomized placebo-controlled trial of the effect of PCV-7 on pneumococcal carriage, van Gils and colleagues found that compared with unvaccinated controls, infants who received PCV-7 vaccination at 2, 4, and 11 months (a 2 + 1-dose schedule) had increased nasopharyngeal acquisition of pneumococcal serotype 19A in the first 2 years of life. Article Physician Clinical Performance Rankings In an analysis of data from a large academic primary care network, Hong and colleagues investigated the relationship between patient panel characteristics and physician quality rankings that were based on an aggregate of 9 commonly used Health Plan Employer and Data Information Set measures. The authors found that patient panels with greater proportions of underinsured, minority, and non–English-speaking patients were associated with lower physician quality rankings. Adjustment for differences in panel characteristics resulted in significant reclassification of physicians. Article A Piece of My Mind “Surgeons are blessed with steady hands for a reason: They reduce the trembling in the hands of worried family members, counteract pain and destruction, and alter creation for the better by fixing fault and disease within the body.” From “The Hands That Guide Me.” Article Medical News & Perspectives Advances in preventing HIV infection and concerns about faltering funding in the developing world were focal points at the XVIII International AIDS Conference. Article Vision Screening From the Archives Journals A June Archives of Ophthalmology article reported that visual acuity screening was effective in detecting clinically significant myopia but not hyperopia or astigmatism in a random sample of 12-year-old children. Bradfield discusses vision screening programs. Article Commentaries Public reporting of hand hygiene Article Health effects of the Gulf oil spill Article Genetic data and medical records Article Do IRBs protect research participants? Article Infectious Diseases and Immunology Call for Papers Authors are invited to submit manuscripts for an upcoming JAMA theme issue. Article JAMA Patient Page For your patients: Information about pancreatic cancer. Article

doi: 10.1001/jama.304.10.1043pmid: N/A

The Key and Critical Objectives of JAMA Key Objective To promote the science and art of medicine and the betterment of the public health Critical Objectives To maintain the highest standards of editorial integrity independent of any special interests To publish original, important, well-documented, peer-reviewed articles on a diverse range of medical topics To provide physicians with continuing education in basic and clinical science to support informed clinical decisions To enable physicians to remain informed in multiple areas of medicine, including developments in fields other than their own To improve health and health care internationally by elevating the quality of medical care, disease prevention, and research To foster responsible and balanced debate on issues that affect medicine and health care To anticipate important issues and trends in medicine and health care To inform readers about nonclinical aspects of medicine and public health, including the political, philosophic, ethical, legal, environmental, economic, historical, and cultural To recognize that, in addition to these specific objectives, THE JOURNAL has a social responsibility to improve the total human condition and to promote the integrity of science To achieve the highest level of ethical medical journalism and to produce a publication that is timely, credible, and enjoyable to read Editorial staff EDITOR IN CHIEF Catherine D. 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Patchin, MD (immediate past chair); Stephen R. Permut, MD, JD; J. James Rohack, MD; Carl A. Sirio, MD; Steven J. Stack, MD; Robert M. Wah (chair-elect), MD; Meredith C. Williams; Cecil B. Wilson, MD

Torpy, Janet M.

doi: 10.1001/jama.2010.1153pmid: 20823425

The energy and vitality of New York City's Lower East Side still exist, little changed since George Benjamin Luks (1867-1933) caroused on the area's bustling sidewalks. Hester Street (cover ) depicts the gritty urban scene, a market and all its inherent drama on display for an original audience that rarely, if ever, would have had reason to tread the streets and alleys of that colorful neighborhood filled with tenement houses. Today's Hester Street teems with curious tourists, local inhabitants, recent immigrants, and storefronts that spill their assortments of goods, reflecting the multiethnic atmosphere. There, one can savor homemade pasta and sip espresso, then half a block away pick up a bánh mì to devour while shopping for Asian vegetables or shiny fish—heads and all—lined up in their beds of ice, effluent dripping into makeshift drainage buckets. The essence of Hester Street in 1905 provided the perfect setting for Luks, who was painting as an urban realist, in the style of his colleagues and friends. Later termed the Ashcan School, and led by Robert Henri (JAMA cover, August 26, 2009), this group of independent artists grew into a conglomeration called The Eight; they exhibited their works in a small, nonjuried show in February 1908 at the Macbeth Gallery. The gallery, on Fifth Avenue, operated in a world far removed—although not geographically distant from—the microcosm of Hester Street. George Benjamin Luks (1867-1933), Hester Street, 1905, American. Oil on canvas. 65.6 × 91.1 cm. Courtesy of the Brooklyn Museum (http://www.brooklynmuseum.org/), Brooklyn, New York; Dick S. Ramsay Fund, 40.339. Luks, a Pennsylvania native, performed on stage—a vaudevillian—and later forged a successful career with the Philadelphia Press and the New York World, where he provided quickly drawn, spur-of-the-moment illustrations to accompany the newspapers' articles. With the advent of photography, need for Luks' services diminished, and he took his pen and ink in a different direction. Caricatures, satires, and even a self-portrait exist—but Luks, ever ebullient, emerged as a talented painter of portraits as well as of the genre scenes and realist works for which he is primarily remembered. John Sloan (JAMA cover, November 7, 2007), Arthur B. Davies, Everett Shinn, Maurice Prendergast, William J. Glackens, Ernest Lawson, Henri, and Luks, as The Eight, broke barriers and laid the groundwork for the modern art blockbuster, the New York Armory Show of 1913; their commitment to independence and to rejection of the tradition-bound National Academy of Design and its restrictive exhibit policies linked them together despite differences in lifestyle and in artistic temperament. Hester Street bursts with color, filled with snippets of human interaction in the busy market. The energy of the painting reverberates, underscoring Luks' cleverly placed vignettes. Reds and blues, accented with the more muted tones of conservative garb and the stained white of a well-worn apron, catch the eye. Luks' use of primary color does not distract from the density of his painting's characters, reflecting the crowded and cramped dwellings in the vicinity. Men, women, and children, vendors and customers, toys, flowers, carts, and stalls: Luks' scene pulsates, punctuated by tiny details inset to pique interest. The surrounds of Hester Street, in 1905, were occupied by Jews of eastern European descent. One can imagine Luks set this painting on a busy Friday morning, while preparations for the Sabbath were in full swing. The butcher's wares—no pork in this corner of the city—hang for inspection by the women who shop for the weekly celebration. The gentlemen stroll, conducting business; throughout the painting, Luks reveals the communication that oiled the wheels of commerce, growth, and, not least, relationships. George Luks' paintings and animated drawings reflect his lust for life. Unfortunately, that same joie de vivre, coupled with chronic overindulgence in strong spirits, led to Luks' premature death at the age of 66 years. Drunk, bellicose, and belligerent, “little old George Luks,” as the artist styled himself, was beaten to death in a barroom brawl. He died alone, ignored and neglected, on the ground: a sidewalk casualty similar to that which still occurs in countless contemporary urban neighborhoods. Luks' works and those of the other members of The Eight may have shocked and disturbed the early 20th-century audience, yet they heralded the shift in American art. Exploration of the intricacies and trappings of everyday working-class life freed popular artists, like Luks, from the constraints of idealism and pretension. Without a doubt, Luks' public shenanigans and robust personality enhanced interest in his paintings as much then as they do today: with Hester Street, he has left a moving, accurate, culturally sensitive—and visually stunning—portrait of a vibrant neighborhood that still enchants and beguiles its residents and its visitors.

Greenwald, Jeffrey

doi: 10.1001/jama.2010.1138pmid: N/A

LM is a 79-year-old widowed white man with a history of coronary artery disease and heart failure and 45 years of two packs per day smoking who complains of shortness of breath with wheezing worsening over the past 9 days. . . The patient is a 42-year-old G2P2 with a strong family history of breast cancer has had intermittent vaginal spotting and a 12-pound weight loss over the past 6 weeks. . . A blue 1999 Nissan Altima has been pulling to the left since the driver skidded into a curb on an icy corner one week ago. . . 12 y/o girl with a 9-yr h/o refractory complex partial seizures who's failed multiple med regimens now admitted for Wada testing after non-lateralizing cranial MRI 3 d ago. . . 2002 Ford F150 admitted for eval of electrical system due to difficulty turning over in AM and incr freq of stalling for 10 days. . . ’03 RX7 + high miles s/p recent clutch transplant c/o leaking oil ×2 weeks 68 y/o AAM c h/o HTN, MI s/p CABG×3 c MVR, IDDM, COPD, and IBD c/o BRBPR ×12hrs. . . ’88 beater s/p MVC on life support. . . 88 y/o WF s/p MVC headed for the junkyard. . .

Zenilman, Ariela

doi: 10.1001/jama.2010.1291pmid: 20823426

Between the scrapes from paper cuts, the finger on which a ring is worn, and the color of nail polish, the hands of the human body tell a story. They are the most mysterious reflection of character. The hands that firmly grasp and shake another's in a sign of welcome are the same that clench with anger or quiver with anxiety. The evil caused and harm inflicted by one set of hands can also wipe the tears and pull at hair in grief and agony. Surgeons are blessed with steady hands for a reason: they reduce the trembling in the hands of worried family members, counteract pain and destruction, and alter creation for the better by fixing fault and disease within the body. A surgeon has the remarkable gift of a set of multifunctional and dexterous hands. I have always admired my father's hands. From a very early age I could tell his grace and dedication to detail were apparent in how he moved and touched, felt and experienced the world around him. As a small child, I knew that when my dad wasn't home, he was “operating,” which I initially understood to mean he drove a train or a bus. I certainly didn't know that he was an exquisite surgeon who would later show me the ropes of an ethical life, a strong sense of determination, and a fierce belief in balance throughout all aspects of life. My father's hands, though soft and smooth, spent the majority of their days wrist-deep inside the sanguine and crimson shades of living, breathing, feeling beings. His simultaneous ability to balance the stresses and isolating feelings of an operating room with the empathy and caring demeanor he exudes with patients reveals the importance of his job, as well as a tremendous amount about his character. His hands seemed inexplicably and effortlessly linked to his every thought: as a young child I always dreamed of having hands like his. My father's hands spent the weekends cleaning the swimming pool, barbecuing dinner, and fixing household appliances. At work, his hands changed character: covered with sterile gloves, their physical characteristics are hidden and the only hints of the wonders within are the delicate, deliberate, and careful procedures he performs seemingly effortlessly. If “superman” hands exist, my father has them: his hands magically transition from the careful, swift hands he shows during procedures into hands providing a soft, gentle touch to a family member after surgery. I remember as a child wondering if I had the hands to be a surgeon. I would twirl a pencil around my fingers and attempt to catch it on one and hold it there in steady balance. I remember when I first learned to crochet I would see how many stitches I could do before my thumb started to cramp, telling myself that the more tying I did on the growing blanket, the better I would be at directing my hands to suture a torn artery. Before I would serve the ball during varsity volleyball games, I would position my hand with the ball and repeat the motion that would obtain the maximum impact of the serve, and thus the greatest result. I watched as practice gave my hands meticulous motion with reproducible results. While researching in the microbiology lab, I observed how my hands progressively improved in delicate tasks. I started out pipetting, moved on to more advanced techniques, and soon my hands knew what they were doing without my strict instruction. While volunteering in the ambulance corps, I noticed the reflection of my character in my hands' abilities. I built confidence and talent in my technical skills and learned the basics of patient care. While I learned to not let my personal feelings or situation of shock affect my quality of care, my heart that empathized with the patient was always intact, and my hands reflected this caring and warm quality. I would get the famous adrenaline rush and neglect external distractions when I was on duty, letting my hands guide themselves in alleviating the suffering of my patients. They would take blood pressures and pulse rates while patting the shoulders of the worried patients, letting my natural demeanor take over to calm them. When I see my father's hands in their true form, I see hands of a multitude of personalities. I see hands that reach out to his children to embrace in a hug, hands that strum the air guitar when music is playing, and hands that reflect the underlying comic and cheerful aspects of his personality. I see the hands of a hero, the symbols of a dedicated human being upon whom many entrust their lives and the lives of their loved ones. I see hands and a life whose character I strive to mirror, not for their mere ability to correct an internal malfunction, but for their display of affection, humor, and love. His hands are a mere reflection of his heart, an attribute I hope to see in my hands as I follow in his footsteps. The power of medicine lies in physicians' ability to lay hands on patients. Medicine can truly change a life by the mere act of touch. The hands alone hold an incredible amount of power. I have watched as my father's hands accomplished what only celestial hands should, and I have come to understand the power human beings were given with a set of hands. Hands reflect ability, accomplishment, and passion. They express the character of the individual. With a role model to look up to, a handful of experiences, and a heart's desire to accomplish the extraordinary, I have learned to trust my instincts, follow my heart, and, most of all, not to underestimate the power of my own hands.

Stephenson, Joan

doi: 10.1001/jama.2010.1292pmid: 20823427

Vienna, Austria— As scientists, clinicians, policy makers, patients, and others gathered here for the XVIII International AIDS Conference (IAC), activists waving signs declaring “No Retreat, Fund AIDS” brought to mind demonstrations at IACs in past years. The message during those earlier protests was that few people living with HIV/AIDS in poor countries hardest hit by the pandemic were benefiting from the transformative power of antiretroviral drugs. (Photo credit: Steve Forrest/IAS/Workers' Photos) Demonstrators at the XVIII International AIDS Conference protested cutbacks by several developed countries in funding for treatment of people living with HIV/AIDS in poorer nations. In the decade or more since those days, the effort to roll out antiretroviral therapy (ART), funded by wealthier nations, has brought treatment to an estimated 5.2 million patients in low-income and middle-income nations in sub-Saharan Africa and elsewhere, according to the World Health Organization (WHO). Now, however, the recent global economic crisis and shrinking donations from donors make the already elusive goal of bringing ART to all who need treatment in these countries recede even further. Although such concerns remained a persistent thread throughout the conference, attendees were also buoyed by encouraging new research findings, notably the first demonstration of a vaginal microbicide that appears to offer some protection against HIV infection. New treatment guidelines New HIV treatment guidelines announced during the conference also reflect a growing appreciation that evidence demonstrates that earlier treatment of HIV saves lives. The WHO revised its HIV treatment guidelines, greatly increasing the number of individuals in the developing world who are eligible to receive HIV treatment. The agency is now recommending initiating ART for asymptomatic patients when their level of CD4 cells dwindles to 350/μL or less, rather than to 200/μL or less, the previous threshold for starting treatment. It also urges countries to progressively phase out the use of the nucleoside reverse transcriptase inhibitor stavudine, which can have long-term and nonreversible toxicity, to less-toxic alternatives, such as zidovudine and tenofovir. The move to earlier treatment is based on evidence that earlier treatment reduces opportunistic infections and saves lives, said Gottfried Hirnschall, MD, MPH, director of the HIV department for WHO. An International AIDS Society–USA panel also cited increasing evidence indicating that longstanding, uncontrolled HIV replication and immune activation “lead to a chronic inflammatory state, resulting in end-organ damage and comorbid conditions not previously thought to be associated with HIV infection.” As a result of this new evidence, the panel revised their guidelines for ART in developed-world settings, described during a press briefing on the first day of the conference and published simultaneously in JAMA (Thompson MA et al. JAMA. 2010;304[3]:321-333). Specifically, the panel recommended initiating treatment in “highly-resourced countries” when the level of CD4 cells drops to 500/μL instead of the previous threshold for initiating therapy, 350/μL, said panel member Melanie A. Thompson, MD. An estimated 15 million individuals with HIV living in the developing world will now qualify under the new WHO guidelines for HIV treatment, which would initially increase the overall cost of bringing ART to patients in those regions. However, said Hirnschall, it will eventually lead to cost saving because patients with HIV will require less treatment for other infections. In addition, initiating ART earlier in the course of the infection will not only save lives, it will also have prevention benefits, he said. Because treatment reduces viral load, he noted, it means that individuals with HIV infection are less likely to transmit the infection. Microbicide proof of concept Perhaps the most compelling news emerging from the conference was the report that for the first time, a vaginal microbicide (a gel containing the antiretroviral drug tenofovir) reduced the risk of HIV infection in women by an estimated 39% compared with a placebo gel. These findings were presented by researchers in South Africa and published simultaneously in the journal Science (Karim QA et al. Science. doi: 10.1126/science.1193748; published online July 19, 2010). A standing ovation by the audience that capped the presentation of results from the CAPRISA 004 trial reflected a feeling of long-awaited triumph after many years of failed attempts to develop a protective microbicide against HIV infection. “Today, we celebrate the proof-of-concept of microbicides,” said Gita Ramjee, PhD, MSc, of the HIV Prevention Research Unit of the South African Medical Research Council, who chaired the session in which the results were presented. “As someone who has been working on multiple clinical microbicide trials in South Africa for over a decade, these groundbreaking results from CAPRISA 004 mean a lot to me personally and give hope to women in South Africa and elsewhere.” Developing an effective microbicide against HIV infection has been one of the holy grails of HIV prevention research. The vast majority of all HIV infections among women worldwide are due to heterosexual intercourse. Because of biological factors, women are more likely than their male partners to acquire HIV infection during sex. And in societies in which women are economically and socially dependent on men, they are even more vulnerable because they often have limited power to refuse sex or to negotiate the use of condoms. An effective microbicide that could be used without the knowledge of a male partner could provide such women with a powerful preventive strategy. CAPRISA 004, a phase 2b randomized, double-blinded, placebo-controlled trial, assessed the effectiveness and safety of a vaginal gel formulated with 1% tenofovir (a nucleotide reverse transcriptase inhibitor) in 889 sexually active women at risk for HIV infection at 1 urban and 1 rural site in South Africa. All participants were given a supply of single-use applicators (prefilled with tenofovir gel or placebo gel) and were instructed to apply a first dose of the product 12 hours or less before sexual intercourse and as soon as possible within 12 hours afterward (and no more than 2 doses in 24 hours). Both groups also received condoms, risk-reduction counseling, and treatment of symptomatic sexually transmitted infections, explained Quarraisha Abdool Karim, PhD, of the Centre for the AIDS Program of Research in South Africa (CAPRISA), in Durban, who presented the findings of the study with her husband and coinvestigator, Salim Abdool Karim, MBChB, PhD. During the 30-month trial, the researchers assessed HIV serostatus, sexual behavior, and gel and condom use at monthly visits. Overall, HIV incidence was 5.6 per 100 women-years among those who received tenofovir gel vs 9.1 per 100 women-years among those who received placebo gel, which translates to an estimated 39% reduction in HIV infection in women using the tenofovir gel. Among those with high adherence (those who used the gel for more than 80% of coital acts), HIV infection was reduced by about 54%. Among women with intermediate adherence (used the gel 50%-80% of the time), the gel reduced HIV infection by about 38%; among those with low adherence (used the gel less than half the time), the infection rate was reduced by about 28%. The gel's protective effect appeared to be independent of sexual behavior, condom use (condoms were reportedly used in about 80% of coital acts), and herpes simplex virus type 2 (HSV-2) infection. In addition, there was no statistically significant increase in the overall rate of adverse events, although the women who received the tenofovir gel had an increased incidence of mild, self-limiting diarrhea (approximately 17% vs 11%). Among those who acquired HIV infection during the trial, there was no statistically significant difference in viral load at the time HIV was detected and no tenofovir-related resistance mutations. There also was no reported increase in risky sexual behavior, an effect known as risk compensation, in which individuals who believe an intervention might provide protection will reduce their use of proven preventive measures, such as condoms. However, the effectiveness of the tenofovir gel appeared to decline, from a 50% reduction in HIV infection at 12 months to a 39% reduction after 30 months, the researchers reported. The investigators believe this effect is linked to decreased adherence; the women who became infected with HIV during the trial were returning substantially fewer used gel applicators. In contrast, those women who maintained high levels of adherence for the entire duration of the trial maintained the 54% reduction in risk. Reducing hsv infection Researchers from the CAPRISA 004 trial also discovered that the tenofovir gel has another effect that could provide further protection against HIV: it helps prevent HSV-2 infection, the most common cause of genital ulcer disease. HSV-2 infection affects about 50% to 60% of South African adults, and those with HSV-2 infection have twice the probability of acquiring HIV, noted Salim Abdool Karim. Because a precursor molecule from which tenofovir is derived is the fundamental building block of other antiviral agents, including a drug used to treat HSV-2 infection (cidofovir), the CAPRISA 004 researchers decided to see if use of the tenofovir gel could help prevent women who were not infected with HSV-2 from acquiring the infection. The researchers collected samples at the beginning and end of the study, which were then tested for HSV-2. Of 434 women who were not infected with HSV-2 at the beginning of the study, 208 received the tenofovir gel and 226 received the placebo gel. Among these initially uninfected women, the HSV-2 incidence rate was 9.9 per 100 women in the tenofovir group vs 20.2 in the placebo group. Taking into account 4 indeterminate samples, the data indicate “an effectiveness that ranges from 47% to 51%,” said Salim Abdool Karim. Although it is reasonable to hypothesize that lowering the overall prevalence of HSV-2 would have a long-term effect on HIV, CAPRISA 004 was not designed to demonstrate that, Karim added, but it is biologically plausible. “Additional studies are urgently needed to confirm, and indeed, to extend the findings” of the tenofovir gel's effectiveness in protecting against HIV and HSV-2 infection, he said. In addition, finding ways to improve adherence levels and sustain them is also important. “This is an extraordinarily important proof of concept,” said Anthony Fauci, MD, director of the National Institute for Allergy and Infectious Diseases (NIAID), in a press briefing following the session in which the tenofovir gel findings were presented. “We still have work ahead,” he added. “We can do better—we haven't hit a wall on this; there are adherence issues, there are issues of application.” Some useful information may be forthcoming from an ongoing placebo-controlled trial, the Vaginal and Oral Interventions to Control the Epidemic (VOICE) trial, funded by NIAID and other agencies at the US National Institutes of Health. The trial is expected to enroll 5000 women in 4 African countries (South Africa, Uganda, Zimbabwe, and Malawi) and will test the safety and efficacy of 1% tenofovir gel used daily, regardless of when participants have sex. The study is also evaluating the use of oral antiretroviral drugs (tenofovir alone or combined with emtricitabine), a strategy known as oral preexposure prophylaxis, or PrEP, for the ability of these regimens to reduce HIV acquisition. It remains to be seen if the level of protection from 1% tenofovir gel demonstrated in the CAPRISA 004 trial is sufficient, if adherence can be improved, and how the product would fare when used outside of a clinical trial. But if the study's findings are confirmed and tenofovir gel is made widely available to the women who need it, it “has the potential to alter the course of the HIV epidemic,” said Salim Abdool Karim. “Mathematical models estimate that if we could implement tenofovir gel in a way similar to the way in which we did it in the trial, we could prevent 1.3 million new HIV infections and more than 800 000 deaths over the next 20 years in South Africa alone.” Targeting tb Results from another trial, conducted in Cambodia, provides guidance to clinicians treating patients who are coinfected with both TB and advanced HIV. The lung infection, the number one killer of persons with HIV, causes about 450 000 deaths each year in HIV-infected patients, according to the WHO. (Photo credit: Zephyr/www.sciencesource.com) The deaths of many patients who have both tuberculosis (TB) and advanced HIV disease might be prevented by starting antiretroviral therapy 2 weeks after starting TB treatment. Despite the need to get both infections under control, clinicians have delayed initiating HIV treatment for up to 8 weeks after starting TB treatment to reduce the likelihood of TB-HIV drug interactions, as well as the risk of a potentially fatal condition called immune reconstitution inflammatory syndrome (IRIS). IRIS may occur when the damaged immune system begins to recover and the patient experiences a worsening of a preexisting, sometimes unrecognized infection, frequently TB. But other data have also suggested that for HIV-TB–coinfected patients who have a severely weakened immune system, initiating ART sooner than 8 weeks after the start of TB treatment would decrease the risk of illness and death by helping the immune system fight both infections. To help resolve the issue of whether the benefits of earlier ART treatment outweigh the risks of IRIS, researchers funded by NIAID and the French National Agency for Research on AIDS and Viral Hepatitis launched a phase 3 randomized trial called CAMELIA (Cambodian Early versus Late Introduction to Antiretroviral Drugs). They enrolled 661 HIV-TB–coinfected Cambodian men and women (median age, 35 years) at 5 sites in Cambodia, all of whom had never been treated for HIV, had received no TB treatment or had started it no more than 1 week before enrollment, and had fewer than 200 CD4 cells/μL. (The median CD4 cell count was 25/μL, indicating extremely poor immune function.) Participants were randomized to begin receiving ART (daily stavudine, lamivudine, and efavirenz) either 2 weeks or 8 weeks after beginning TB treatment and were followed up for 50 weeks after the enrollment of the last participant. By completion of the follow-up period, the earlier treatment reduced mortality by about 34% compared with the later treatment; 59 of the 332 participants who started ART 2 weeks after starting TB treatment had died (a rate of 8.28 deaths per 100 person-years) vs 90 of the 329 participants who started ART 8 weeks after TB treatment began (a rate of 13.77 per 100 person-years), reported Francois-Xavier Blanc, MD, of Bicetre University Hospital in France. IRIS did occur significantly more frequently in the early-treatment group (110 cases, including 5 fatal) compared with the late-treatment group (48 cases, including 1 fatal), a nearly 2.5-fold difference. “But most of the time it was quite easy to manage” and not unexpected, said Blanc. “We can speculate that initiating [highly active antiretroviral therapy] 2 weeks after the onset of TB treatment could potentially save 150 000 of the 450 000 annual HIV/TB-related deaths,” Blanc said.

Voelker, Rebecca

doi: 10.1001/jama.2010.1288pmid: 20823428

A recent alarm warning against complacency in polio vaccination has come from an unlikely place: Canada. Infectious poliomyelitis, eradicated in much of the world during the past 2 decades, remains endemic only in Nigeria, India, Afghanistan, and Pakistan. But a new outbreak last spring in Tajikistan has resulted in 452 laboratory-confirmed cases of wild poliovirus type 1 and 20 deaths. At least 7 related cases have been reported in the Russian Federation. (Photo credit: WHO) The first polio outbreak in a World Health Organization–certified polio-free region has sparked a warning for renewed vigilance in maintaining high vaccination rates. The outbreak is the first to strike a World Health Organization (WHO)–certified polio-free region. Tajikistan is in the WHO European Region, which was certified polio-free in 2002. Tajikistan's outbreak, imported from northern India, prompted a bluntly worded editorial in the Canadian Medical Association Journal (CMAJ). The Journal 's public health section editor, Noni MacDonald, MD, and its editor-in-chief, Paul Hébert, MD, wrote that the Tajikistan outbreak “should be clanging alarm bells” throughout polio-free regions, including developed countries in North America and Europe (MacDonald N and Hébert P. CMAJ. 2010;182[10]:1013). “The threat now is more than theoretical,” Hébert said in an interview. “The risk is, including in the United States, largely because we seem to have let our guard down” in maintaining high vaccination rates. The editorial noted that the percentage of children in Ontario who have been immunized against polio during the past decade has ranged between the high 70s and low 80s. The WHO recommends vaccination coverage of at least 90% to prevent transmission. The agency reported that polio vaccine coverage in Tajikistan was 83% in 2005, but increased to 93% in 2009. School requirements for polio vaccination help maintain high coverage rates in the United States. Even so, the National Immunization Survey in 2007-2008 reported that 9 states had polio immunization rates below 90%. Idaho's 86.5% was the lowest (http://www2a.cdc.gov/nip/coverage/nis/nis_iap.asp?fmt=r&rpt=tab21_pol_race_iap&qtr=Q3/2007-Q2/2008). Samuel Katz, MD, chair of the WHO Polio Research Committee and chair emeritus of pediatrics at Duke University School of Medicine in Durham, NC, called it “disappointing” that so many states' vaccination rates were below the 90% threshold. Katz noted that because most young parents and health professionals have never seen polio unless they worked overseas, immunization may not be as high a priority as it should. “Parents have concerns if [vaccination] is safe, or even necessary, and physicians may be a little less convincing that it is necessary to get kids immunized if they’ve never seen it,” he said. The last indigenous case of wild poliovirus transmission in the United States was in 1979, according to the US Centers for Disease Control and Prevention (CDC). The United States and Canada are included in the WHO Region of the Americas, which was certified polio-free in 1994. Until polio is eradicated, Katz and others said, outbreaks in developed countries are possible but unlikely to spread. “Most countries, really all countries, in the developed world are protected by herd immunity given by vaccination, so it's unlikely that the introduction of a wild polio virus would cause a major epidemic in those countries,” said Stanley Plotkin, MD, professor emeritus of pediatrics at the University of Pennsylvania School of Medicine in Philadelphia. Steven Wassilak, MD, a medical epidemiologist with CDC's Global Immunization Division, agreed with the need for vigilance in maintaining high polio immunization rates. “Several countries have allowed their vaccination rates to slip substantially,” he said. But Wassilak rejected the CMAJ editorial's contention that the WHO should be more proactive in warning countries of the dangers of low immunization rates than simply posting case numbers at http://www.polioeradication.org. He noted that a new strategic plan from the WHO and its polio eradication partners calls for local governments in high-risk countries to become more involved and accountable in maintaining high immunization rates. “Those plans already have derived some benefits,” he said. An example is Nigeria, where polio is endemic. As of August 2, the WHO reported that Nigeria had 6 cases of polio compared with 365 at the same time last year. India, also an endemic country, had 25 cases compared with 163 at the same time last year. Yet Pakistan, another endemic country, has 34 cases compared with 25 last year. “We can't see progress in Pakistan to date,” Wassilak said. “But we have made progress in the global fight.”

Kuehn, Bridget M.

doi: 10.1001/jama.2010.1289pmid: 20823429

As the US government works to implement health care reform, it has committed more than $1.1 billion to funding comparative effectiveness research that may help guide decision making. In doing so, the United States has joined other nations that are looking toward comparative effectiveness data as a means to improve health care quality. Several other countries have already established systems to develop comparative effectiveness data, assess that data, and translate it into policy. Since 1999, the National Institute for Health and Clinical Excellence (NICE) has been fulfilling this role in the United Kingdom. Kalipso Chalkidou, MD, PhD, director of NICE's international program, spoke with JAMA recently about how the National Health Service (NHS) in England and Wales uses comparative effectiveness data. (Photo credit: Duncan Rand) Kalipso Chalkidou, MD, PhD, director of the international program at the United Kingdom's National Institute for Health and Clinical Excellence (NICE). NICE assesses comparative effectiveness data to guide policy making. JAMA:Why was NICE created? Dr Chalkidou: The idea was to try to address inappropriate variation in the type and quality of health services people were receiving, which was a big problem back then and still is, though things have improved. The second goal was to improve the uptake of new technologies [by instructing the NHS to pay for them]. In fact, we do have the data to show we have done exactly that in many areas. Additional reasons for the creation of NICE were improving quality of care, making sure guidelines were available for professionals across the board, and ensuring that any additional money going into the health service is used efficiently. JAMA:How does NICE fulfill this mission to improve care and efficiency? Dr Chalkidou: We use local and international evidence and the local cultural values of England and Wales as inputs into a process that is transparent, consultative, and independent from interference from central government, hospitals, patients, clinicians, the pharmaceutical industry, or the health care industry in general. The output is actionable policy and practice recommendations. The idea is to translate evidence into policies. JAMA:How are topics selected for evaluation, and how are they evaluated? Dr Chalkidou: We have different sources of potential topics. We have a horizon scanning center, based at a university and funded by the department of health, that looks at pharmaceutical company pipelines to identify what we should be looking at. We have a Web site where basically anybody can suggest a topic. We have a network of consultants who work regionally with clinicians, administrators, and patients, and we get a lot of suggestions from them. There's a process for NICE staff to suggest topics. There are also policy priorities indicated by our government. All of these things get fed through to topic selection panels manned mostly by clinicians, though there are other stakeholders—industry representatives, patient representatives, academics, epidemiologists, and economists. They have a set of criteria and a process for identifying the key priorities. The minister of the department of health approves the selected topics. JAMA:How are NICE guidelines developed? Who is involved? Dr Chalkidou: Before NICE was established, the royal colleges and the professional associations were responsible for developing guidelines. The government would give money to the organizations to develop guidelines. But this was perceived to be problematic. Every group had its own priorities. There was a lack of consistency in the process of developing the guidelines, reflected in different formats, different ways of appraising the evidence, and different ways of engaging with people. A lot of the time there was very little public engagement. There was also a perception that these guidelines might not be that independent. Now the government directs funds through NICE to the professional organizations. NICE takes the role of a quality assurer. We set out how the guidelines will be developed and for what problems. We set requirements—for instance, on how many patients to involve and how to involve them. Every guideline that comes out has the stamp of the professional association or college and NICE. JAMA:How are cost considerations figured into NICE recommendations? Dr Chalkidou: There is a lot of science on how economic analysis can inform decision making. The first hurdle is clinical effectiveness—the technology or service has to be demonstrated to work. After that, given the likelihood it could work and the margins of the clinical benefit, is it worth the extra cost? It's not an exact science. It's not as if there is a figure that comes out of the model and the decision is made automatically. Our committees have a lot of flexibility. One of our first appraisals considered a drug for flu-like symptoms in otherwise healthy adults. The drug seemed to work and was relatively inexpensive, about £5 [approximately $7.62] per day for 5 days. However, the magnitude of the clinical benefit was a reduction in symptoms by half a day, 2 days instead of 2.5. So the committee felt it was not clinically worth the overall cost and the increased number of visits to family physicians. Some things are approved even though they are a lot less cost-effective than what we tend to approve. For example, we looked at a drug for a malignancy of the lungs caused by asbestos exposure in miners and shipyard workers. At the time these people were working, nobody knew this was a cause of cancer. It's a difficult disease. This drug is not curative, but it extends life by 2 to 3 months. Even though it was not cost-effective, the committee felt it was something worth paying for. JAMA:Has NICE reduced health care costs in England and Wales? Dr Chalkidou: NICE published its first guidance in 2002, the year that the government announced the biggest funding boost for the NHS in its history. There was a 50% real increase in NHS funding, about an extra £100 billion (approximately $156 billion), between 2002 and 2009. So, the first 10 years of NICE have been years of investment in the NHS, and we’ve been asked to come up with good investments. The coming decade will be years where we have to help the system make efficiency savings because the money is running out and we won't be able to continue the funding increases. They will be testing times for NICE and the health system to try to identify, in an evidence-based way, things that we shouldn't be doing, and things we should be doing more efficiently. JAMA:What is the process for appealing a decision by NICE? Dr Chalkidou: People can be involved throughout the process, from selecting the topic all the way to publishing the final recommendation. Appeal is the final step, if somebody disagrees. We get appeals from manufacturers that feel their products ought to have been covered and from patients and professional organizations that think a drug should be made available. We get an increasing number of appeals from local public insurers, who basically feel something is unaffordable and doesn't offer as much value as alternatives for their populations in their areas. The appeal process gives us an opportunity to address their concerns and to revisit the guidance. The appeals are heard by an independent committee led by the chair of NICE, who is not involved in the guidance development process itself. We also have representatives of NHS, industry, clinicians, and other representatives of NICE on the committee. About half of NICE's decisions on technologies are appealed. Decisions can and do change, and in about 1 in 3 cases the appeals are upheld, at least partly. If the appeal is upheld, the committee [that came to the original decision] is asked to have another look. The change the committee makes could be minor—rewriting to make sure people understand what they are saying—or substantive. For example, if the committee looks at another piece of evidence that it hadn't realized was there, the actual decision could change. If an appeal is upheld, it can delay publication of the guidance about 2 months, but it is important and fair to allow people to raise their concerns. JAMA:What would you say are the key elements of a successful comparative effectiveness program? Dr Chalkidou: It is context-specific. Something that is important to success in the United States might not work in England or Japan. I think our model has some good aspects to it. The principle of independence is very important. It is also really important to be responsive, to show people how you do what you do, what type of evidence you consider, how you evaluate the evidence, and how you reach the final decision. Engagement is really important. It is important to be scientific in your methods, the way you evaluate the evidence and the way you do the economic evaluation. If you lose your science, you lose your credibility. JAMA:Are their any lessons to be learned from NICE's experience? Dr Chalkidou: Allowing policy makers to have a say is hugely important. We talk about evidence-based policy making, but setting the priorities for research is undertaken by a different group of people. To close the loop, we need to make sure policy makers have a say to make sure research is policy relevant. JAMA:Do you think the experience at NICE has implications for the United States as we begin to promote more comparative effectiveness research? Dr Chalkidou: One thing worth thinking about in the United States is whether you will take the step from research to policy. It's not clear whether it will happen. It would have to happen in a unique and America-specific way, but it will have to happen. Otherwise you send all the money to research, but don't have the mechanisms for translating and implementing this research into practice. It's one thing to disseminate and make things available, but to get people to use these things is a different story. JAMA:Are there other considerations unique to the United States? Dr Chalkidou: Some general principles should be applicable; how you implement them would be different. We have a pay-for-performance scheme for general practitioners. About 20% of the salaries of primary care practitioners can be made up of rewards for doing things that are evidence-based. NICE is now responsible for setting metrics for measuring clinicians' performance. I’m not sure you could have such a framework across the United States. You have different insurers, sometimes paying for care for very different population groups. There are differences, but the principle of using evidence and values to inform and reward good practice, or not reward bad practice, is the same.

Mitka, Mike

doi: 10.1001/jama.2010.1284pmid: N/A

Citing a record 1742 drug recalls in 2009, a 400% increase from 2008, Sen Michael Bennet (D, Colo) introduced legislation designed to enhance the ability of the Food and Drug Administration (FDA) and the pharmaceutical industry to ensure that medications are safe and effective regardless of where they are manufactured. The bill (S 3690 [http://thomas.loc.gov]), introduced August 3, would enhance the FDA's ability to track and monitor foreign manufacturing sites and give the agency additional recall power and enforcement options, such as assessing civil penalties. The bill also requires companies to institute quality management plans to ensure quality and safety of their drugs, plans that would include stronger supplier oversight and document which entities are involved in the manufacturing supply chain for their drugs. In addition, the bill would give the FDA new oversight of over-the-counter (OTC) drugs and prevent the agency from relegating such drugs to a lower-risk category for site inspection because of their OTC status.

Mitka, Mike

doi: 10.1001/jama.2010.1283pmid: N/A

Private-sector innovation aimed at treating rare and neglected pediatric diseases may be spurred on by a Senate bill introduced August 4. (Photo credit: Office of Senator Sherrod Brown) Sen Sherrod Brown (D, Ohio) introduced legislation intended to spur drug development for rare and neglected pediatric diseases. The bill (S 3697 [http://thomas.loc.gov]), introduced by Sen Sherrod Brown (D, Ohio) and cosponsored by Sen Sam Brownback (R, Kan) and Al Franken (D, Minn), amends provisions of the Food and Drug Administration Amendments Act that established an incentive for pharmaceutical companies to develop innovative therapeutics for neglected tropical diseases. Under the law, a company that develops new drugs and biologics for neglected tropical diseases is eligible for a “priority review voucher” that entitles it to expedited review of another drug submitted for approval. The bill extends the same voucher program to rare and neglected pediatric diseases. In a press release, Brown said the National Institutes of Health estimates that there are more than 6000 rare diseases, as defined by the Orphan Drug Act; other diseases, such as tuberculosis, malaria, and dengue fever, are not rare but are neglected because they primarily affect poor populations in developing nations. Of these rare and neglected diseases, fewer than 300 are currently of interest to the pharmaceutical industry, Brown noted.