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MEDICAL BREAKTHROUGHS

Original research articles to keep consumers on top of their subject areas.

Top 6 Antiaging Breakthroughs

Drotumdi O

By Colette Bouchez Listen From the WebMD Archives Wanting to look young is not exactly a new idea -- the search for the fountain of youth has been going on for centuries. And while this past year didn’t deliver the perfect elixir, the year did introduce some scientifically solid, significant advances in anti-aging skin care. To home in on what can truly make a difference in your skin, WebMD asked medical experts to evaluate the cream of the crop. Antiaging Breakthrough No. 1: Fractional CO2 Laser Skin Resurfacing The antiaging breakthrough of the decade, according to many doctors, is a skin-resurfacing treatment known as CO2 fractional laser therapy. Combining the effectiveness of traditional carbon dioxide lasers -- long thought to be the gold standard in wrinkle removal -- with a new application technique, it delivers powerful results without the traditionally harsh side effects. "Essentially, you are getting all the benefits of laser resurfacing, still the best way to remove wrinkles, but you’re getting it without the downtime and without the horrendous complication rate," says David Goldberg, MD, director of Skin Laser and Surgery Specialists of New York and New Jersey and clinical professor of dermatology at the Mt. Sinai School of Medicine in New York City. Continue Reading Below you might like How does it work? The natural aging process, combined with exposure to sun and pollution, destroys collagen -- the main protein of connective tissue that keeps skin plump and line-free. Laser resurfacing uses beamlets of energy light to bore tiny holes in the skin, which works to put the body’s natural collagen production on fast-forward. Here’s what’s new: Fractional CO2 laser resurfacing does this in a way that prevents damage to the top layer of skin, offering maximum results with minimal recovery time. While laser resurfacing doesn’t come cheap -- the procedure will cost you about $5,000 -- it is quick, accomplished in one or two sessions, with about four days downtime. Goldberg says effects are thought to last eight to 10 years. According to the American Society for Dermatologic Surgery, patients with darker complexions may be at risk for pigmentation loss with any laser surgery. Common minor side effects for fractional laser resurfacing include redness and swelling that lasts about two days. Antiaging Breakthrough No. 2: The New Wrinkle Injections Wrinkle injection technology soared to new heights last year when the FDA approved four fillers: Perlane, Juvéderm, Artifill, and Radiesse. Along with Restylane, approved in 2003, each uses a slightly different substance to fill wrinkles. But according to Rhoda Narins, MD, professor of dermatology at NYU Medical Center in New York City, that’s just the beginning. "What’s really significant is that we can now use these fillers to volumize skin anywhere on the face, so you can really sculpt a lifted, youthful look without surgery," she says. Dermatologist Bruce Katz, MD, the director of Juva Skin and Laser Center in New York City, agrees. "Unlike a face-lift, which pulls the skin taut and tight, volumizing plumps up the skin so the look is youthful but more natural," he says. In even more good news about wrinkle injections, studies conducted by Frank Wang, MD, at the University of Michigan Medical School found that those containing hyaluronic acid (such as Restylane and Juvéderm) led to "robust collagen production" while also interfering with collagen breakdown. So not only do you get a filling effect, says Narins, but you also have an actual increase in natural collagen production. Currently, most fillers last up to one year, or longer. Only one -- Artifill -- offers permanent results, but not without concern. According to a published report by the FDA, it increases the risk of granulomas, bumps that form under the skin and may be permanent, as well as an increased risk of allergic reaction. Still, Narins says all currently approved wrinkle injections have been used in Europe for several years, and the track record on safety is generally good. Most often, side effects are mild, usually limited to redness or swelling at the site of injection, she adds. The cost of wrinkle-filling volumizers is between $600 and $1,000 per syringe. Antiaging Breakthrough No. 3: Antioxidants Topping the list of over-the-counter antiaging ingredients making the most noise these days are antioxidants. These skin-care nutrients fight aging by destroying free radicals, the unstable molecules that occur from sun exposure or pollution and that can literally gobble up the skin’s collagen supply. "Antioxidants are nutrients that, when topically applied, disarm and neutralize free radicals before they harm skin -- so they can play an important role in antiaging skin care," says Sumayah Jamal, MD, an assistant professor of dermatology and microbiology at NYU Medical Center in New York City. Scores of studies demonstrate the power of topical antioxidants (particularly CoQ10 and vitamins C and E) to rejuvenate and protect skin. However, the ingredient generating the loudest buzz in 2007 was clearly coffee berry, which some experts now believe is the single most powerful antioxidant discovered to date. Two independent studies found that the same plant that gives you your java jolt in the morning is ready to provide a powerful antiaging boost to your face. The research conducted by David McDaniels, MD, at the Institute of Anti-Aging Research in Virginia, and Zoe Draelos, MD, at Dermatology Consulting Service in North Carolina, reported that coffee berry extract significantly improved the appearance of fine lines and wrinkles without allergic reactions or skin irritations. Although Goldberg says it will be a few years before the full extent of coffee berry’s rejuvenating properties is known, he adds that it is "so powerful in its antioxidant rating that even if 1/1,000th of what’s applied gets into the skin it’s probably going to have an effect." Dermatologist Ken Beer, MD, director of Palm Beach Esthetic in Palm Beach, Fla., says he’s seen the science and he’s impressed: "I think this is going to be a major cosmeceutical ingredient." Other cosmeceuticals with new and powerful antioxidants include: Prescriptives Super Line Preventor Xtreme with seven antioxidants (1 ounce, $48) Neutrogena Antioxidant Age Reverse Day Lotion and Night Cream (1.7 ounces, $17.99 each) Lumene Vitamin + Energy Cocktail (1 ounce, $17.99) Clinique Continuous Rescue Antioxidant Moisturizer with eight time-release antioxidants (1.7 ounces, $39.50) Antiaging Breakthrough No. 4: Peptides Small proteins that stimulate the production of collagen, peptides have been on the cusp of antiaging skin care for a while. The excitement began several years ago with NIH-backed research on the ingredient Matrixyl (palmitoyl pentapeptide-3), showing its ability to stimulate collagen production in skin. Today, further studies on additional peptides continue to generate research news. According to Jamal, studies on formulations such as Argireline (acetyl hexapeptide-3) show they can produce a mild, Botox-like effect, inhibiting the release of neurotransmitters that keep facial muscles from forming wrinkles. Even newer peptide formulations act like growth factors, stimulating skin cells to make a quicker turnover, much like young skin. What’s new for peptides? Formulations that seem to yield overall improved results. "They are really getting the science down now, learning how to stabilize the peptides and at the same time inhibit collagenase [the breakdown of collagen] so we have better, more tailored peptide products," says Beer. Products containing the newest versions of that peptide technology include: Olay Regenerist Micro-Sculpting Cream with amino peptide complex (1.7 ounces, $29.99) Lumene Premium Beauty Rejuvenating Instant Serum (1 ounce, $29.99) Avon Anew Clinical Eye Lift (0.5 ounce, $28) Osmotics Blue Copper 5 Face Lifting Serum (1 ounce, $75) Emerge Bio-Peptide Night Repair Cream with 10% peptides (1.12 ounces, $43) Antiaging Breakthrough No. 5: Vitamin A Among the most medically studied topical antiaging treatments are the retinoids -- derivatives of vitamin A. They are offered as prescription treatments such as Retin A or Renova, but also available in weaker strengths in over-the-counter products, listed as the ingredient retinol. Retinoids are "thought to work on aging skin by increasing collagen production and decreasing collagen breakdown," says Jamal -- and a ream of studies backs her up. But while many doctors believed only the prescription-strength retinoids were powerful enough to cause significant change in the skin, 2007 was the year that idea changed. In a study published in the Archives of Dermatology in May, researchers from the University of Michigan found that 0.4% retinol lotion applied three times a week for 24 weeks yielded significant difference in skin wrinkling when compared with a similar lotion without retinol used on a separate group of people in the study. Even more surprising: The average age of study participants was 87, meaning it’s truly never too late to look younger. "For those who can’t or don’t want to have an office procedure for wrinkles, I suggest starting with retinol products, and if there are no problems, such as redness or irritation, you can work up to a prescription-strength Retin A product. But we now know that both have the power to produce measurable antiaging results," says Goldberg. Products containing retinol include: Vichy Reti-C Intensive Corrective Care (30 milliliters, $31) Neutrogena Healthy Skin Anti-Wrinkle Intensives with retinol and antioxidants (Serum, 1 ounce, $16.99; Eye Cream, 0.5 ounce, $16.99) Clinique Zero Gravity Repairwear Lift with retinol, antioxidants, and peptides (1.7 ounces, $52) L’Oreal Advanced RevitaLift Double Lifting Gel (1 ounce, $16.99) RoC Retinol Correxion Deep Wrinkle Serum (1 ounce, $19.99) Antiaging Breakthrough No. 6: Antiaging Sunscreens Among the most exciting new ways to fight skin aging are two dramatic breakthroughs in sun protection: Helioplex, a new technology that makes current sunscreen ingredients more effective, and Mexoryl SX (ecamsule), a new protective agent. Representing the first innovation in skin sun protection in more than 20 years, each is specifically designed to defend against the aging effects of short UVA rays. "They are truly the best we have, and they are a major, major advance in terms of antiaging protection," says Katz. Most of us know about the dangers of burning UVB rays, but you might be less aware of the damaging and aging effects of UVA. "These are the ones that go deep -- UVA rays cause the deep collagen and elastin damage that contributes to aging skin," says Katz. While most sunscreens effectively protect against UVB rays, protection from UVA was mostly limited to the "long" waves, with ingredients that were unstable and frequently degraded in the sun. But Mexoryl SX (ecamsule), a UVA-blocking sunscreen developed by L’Oreal, and Helioplex, a technology created by Neutrogena to stabilize traditional sunscreen ingredients avobenzone and oxybenzone, are proving not only to protect against the damaging short UVA rays, but to offer long-lasting protection without the need to constantly reapply. "They have been available in Europe for some time now, and there is no question they work -- and from an antiaging standpoint, they can be your best friend," says Goldberg. Even more exciting: In 2007 these sunscreen advances were combined with antioxidants and other antiaging ingredients in moisturizers and day creams that offer Fort Knox-level protection against the aging effects of the sun. Products containing the latest Helioplex technology include: Neutrogena Healthy Defense SPF 45 Daily Moisturizer (1.7 ounces, $11.99) Neutrogena Ultra Sheer Dry-Touch SunBlock SPF 70 (3 ounces, $9.99) Products containing Mexoryl SX include: Vichy Capital Soleil SPF 15 Sunscreen Cream (3.4 ounces, $29.99) L’Oreal Revitalift UV Moisturizer and Sunscreen (1.7 ounces, $22) LaRoche-Posay Anthelios SX (3.4 ounces, $29) Lancome UV Expert 20 (3.4 ounces, $35) Originally published in the November/December 2007 issue of WebMD the Magazine. WebMD Magazine - Feature Reviewed by Michael W. Smith, MD on October 10, 2007 Sources © 2007 WebMD, Inc. All rights reserved.

20 New Biotech Breakthroughs that Will Change Medicine

Drotumdi O

From a spit test for cancer to a shot that helps your body re-grow nerves along your spinal cord, these new advances in the world of medicine blur the line between biology and technology—to help restore, improve and extend our lives.

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* 4. Cancer Spit Test

Forget biopsies—a device designed by researchers at the University of California-Los Angeles detects oral cancer from a single drop of saliva. Proteins that are associated with cancer cells react with dyes on the sensor, emitting fluorescent light that can be detected with a microscope. Engineer Chih-Ming Ho notes that the same principle could be applied to make saliva-based diagnostic tests for many diseases.

6. Prosthetic Feedback

One challenge of prosthetic limbs is that they're difficult to monitor. "You and I sense where our limbs are spatially without having to look at them, whereas amputees don't," says Stanford University graduate student Karlin Bark. Skin is sensitive to being stretched—it can detect even small changes in direction and intensity—so Bark is developing a device that stretches an amputee's skin near the prosthesis in ways that provide feedback about the limb's position and movement.

7. Smart Contact Lens

Glaucoma, the second-leading cause of blindness, develops when pressure builds inside the eye and damages retinal cells. Contact lenses developed at the University of California-Davis contain conductive wires that continuously monitor pressure and fluid flow within the eyes of at-risk people. The lenses then relay information to a small device worn by the patient; the device wirelessly transmits it to a computer. This constant data flow will help doctors better understand the causes of the disease. Future lenses may also automatically dispense drugs in response to pressure changes.

8. Speech Restorer

For people who have lost the ability to talk, a new "phonetic speech engine" from Illinois-based Ambient Corporation provides an audible voice. Developed in conjunction with Texas Instruments, the Audeo uses electrodes to detect neuronal signals traveling from the brain to the vocal cords. Patients imagine slowly sounding out words; then the quarter-size device (located in a neck brace) wirelessly transmits those impulses to a computer or cellphone, which produces speech.

9. Absorbable Heart Stent

Stents open arteries that have become narrowed or blocked because of coronary artery disease. Drug-eluting stents release medication that keeps the artery from narrowing again. The bio-absorbable version made by Abbott Laboratories in Illinois goes one step further: Unlike metal stents, it does its job and disappears. After six months the stent begins to dissolve, and after two years it's completely gone, leaving behind a healthy artery.

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10. Muscle Stimulator

In the time it takes for broken bones to heal, nearby muscles often atrophy from lack of use. Israeli company StimuHeal solves that problem with the MyoSpare, a battery-operated device that uses electrical stimulators—small enough to be worn underneath casts—to exercise muscles and keep them strong during recovery.

11. Nerve Regenerator

Nerve fibers can't grow along injured spinal cords because scar tissue gets in the way. A nanogel developed at Northwestern University eliminates that impediment. Injected as a liquid, the nanogel self-assembles into a scaffold of nanofibers. Peptides expressed in the fibers instruct stem cells that would normally form scar tissue to produce cells that encourage nerve development. The scaffold, meanwhile, supports the growth of new axons up and down the spinal cord.

12. Stabilizing Insoles

When Erez Lieberman's grandmother suffered a dangerous fall, he wanted to ensure it never happened again. "But it wasn't till a few years later at NASA that I found a way to channel that into something tangible," says the MIT graduate student. Using technology developed to monitor the balance of astronauts who have just returned from space, Lieberman's iShoe analyzes the pressure distribution of the feet. Doctors can use the insole to diagnose balance problems in elderly patients before falls occur.

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13. Smart Pill

California-based Proteus Biomedical has engineered sensors that track medication use by recording the exact time drugs are ingested. Sand-grain-size microchips emit high-frequency electrical currents that are logged by Band-Aid-like receivers on the skin. The receivers also monitor heart rate and respiration and wirelessly transmit the data to a computer. "To really improve pharmaceuticals, we need to do what is now common in every other industry—embed digital technology into existing products and network them," says David O'Reilly, senior vice president of corporate development.

14. Autonomous Wheelchair

MIT researchers have developed an autonomous wheelchair that can take people where they ask to go. The chair learns about its environment by listening as a patient identifies locations—such as "this is my room" or "we're in the kitchen"—and builds maps using Wi-Fi, which works well indoors (unlike GPS). The current model, which is now being tested, may one day be equipped with cameras, laser rangefinders and a collision- avoidance system.

* 18. Portable Dialysis

More than 15 million adult Americans suffer from diseases of the kidneys, which often impair the ability of the organs to remove toxins from the blood. Standard dialysis involves three long sessions at a hospital per week. But an artificial kidney developed by Los Angeles-based Xcorporeal can clean blood around the clock. The machine is fully automated, battery-operated, waterproof and, at less than 5 pounds, portable.

19. Walking Simulator

Stroke victims are being tricked into recovering more quickly with a virtual-reality rehabilitation program developed at the University of Portsmouth in Britain. As patients walk on a treadmill, they see moving images that fool their brains into thinking they are walking slower than they are. As a result, patients not only walk faster and farther, but experience less pain while doing so.

20. Rocket-Powered Arm

Adding strength to prosthetic limbs has typically required bulky battery packs. Vanderbilt University scientist Michael Goldfarb came up with an alternative power source: rocket propellant. Goldfarb's prosthetic arm can lift 20 pounds—three to four times more than current prosthetics—thanks to a pencil-size version of the mono-propellant rocket-motor system used to maneuver the space shuttle in orbit. Hydrogen peroxide powers the arm for 18 hours of normal activity.

Acute Myocardial Infarction after Laboratory-Confirmed Influenza Infection

Drotumdi O

 

  • Jeffrey C. Kwong, M.D.,
  • Kevin L. Schwartz, M.D.,
  • Michael A. Campitelli, M.P.H.,
  • Hannah Chung, M.P.H.,
  • Natasha S. Crowcroft, M.D.,
  • Timothy Karnauchow, Ph.D.,
  • Kevin Katz, M.D.,
  • Dennis T. Ko, M.D.,
  • Allison J. McGeer, M.D.,
  • Dayre McNally, M.D., Ph.D.,
  • David C. Richardson, M.D.,
  • Laura C. Rosella, Ph.D., M.H.Sc.,
  • Andrew Simor, M.D.,
  • Marek Smieja, M.D., Ph.D.,
  • George Zahariadis, M.D.,
  • and Jonathan B. Gubbay, M.B., B.S., M.Med.Sc.

Abstract

Background

Acute myocardial infarction can be triggered by acute respiratory infections. Previous studies have suggested an association between influenza and acute myocardial infarction, but those studies used nonspecific measures of influenza infection or study designs that were susceptible to bias. We evaluated the association between laboratory-confirmed influenza infection and acute myocardial infarction.

Methods

We used the self-controlled case-series design to evaluate the association between laboratory-confirmed influenza infection and hospitalization for acute myocardial infarction. We used various high-specificity laboratory methods to confirm influenza infection in respiratory specimens, and we ascertained hospitalization for acute myocardial infarction from administrative data. We defined the “risk interval” as the first 7 days after respiratory specimen collection and the “control interval” as 1 year before and 1 year after the risk interval.

Results

We identified 364 hospitalizations for acute myocardial infarction that occurred within 1 year before and 1 year after a positive test result for influenza. Of these, 20 (20.0 admissions per week) occurred during the risk interval and 344 (3.3 admissions per week) occurred during the control interval. The incidence ratio of an admission for acute myocardial infarction during the risk interval as compared with the control interval was 6.05 (95% confidence interval [CI], 3.86 to 9.50). No increased incidence was observed after day 7. Incidence ratios for acute myocardial infarction within 7 days after detection of influenza B, influenza A, respiratory syncytial virus, and other viruses were 10.11 (95% CI, 4.37 to 23.38), 5.17 (95% CI, 3.02 to 8.84), 3.51 (95% CI, 1.11 to 11.12), and 2.77 (95% CI, 1.23 to 6.24), respectively.

Conclusions

We found a significant association between respiratory infections, especially influenza, and acute myocardial infarction. (Funded by the Canadian Institutes of Health Research and others.)

History of Medicine: PEPFAR — 15 Years and Counting the Lives Saved

Drotumdi O

In the long history of successful public health initiatives, such as those leading to the eradication of smallpox, the elimination of polio throughout most of the world, and the marked reduction globally in vaccine-preventable childhood diseases, few programs have matched the impact of one that began in 2003, the President’s Emergency Plan for AIDS Relief, or PEPFAR. This innovative program has had an unprecedented impact on the pandemic of HIV and AIDS.

The major scientific and clinical advances that made PEPFAR possible were the development and approval of highly effective combinations of antiretroviral medications that suppressed the replication of HIV. These drugs, generally administered in combinations of three or more, have transformed the lives of people living with HIV/AIDS, providing them with the possibility of a near-normal life expectancy and, in most cases, the ability to return to normal daily activities. Although HIV-infected people in resource-rich countries almost immediately benefited from these medications when they were licensed in the mid-1990s, a dramatic discrepancy in access to these drugs soon became apparent. More than 90% of all HIV infections were occurring in resource-limited countries, particularly in sub-Saharan Africa, where patients had little or no access to antiretroviral medications. Millions of people who could have been saved were needlessly dying.

PEPFAR was created by President George W. Bush, who felt strongly that as a resource-rich and privileged country, the United States was morally obligated to help people in low-income countries with diseases for which there were effective interventions that were unavailable to them. HIV/AIDS in the resource-limited world, particularly in southern and eastern Africa, was a stark example of such a disease. Early in his administration, Bush articulated his belief that the United States could and should design and implement a transformational and accountable program to address the HIV/AIDS pandemic in low-income countries. At that time, an estimated 30 million people were living with HIV/AIDS in Africa, where more than one third of adults in some countries were infected.1

After consulting scientific advisors, faith-based organizations, and others from both inside and outside his administration, Bush tasked trusted officials, including one of us (A.S.F.) and an inner circle of White House staff, with determining the feasibility of developing a program for the prevention, treatment, and care of people living with or at risk for HIV/AIDS in Africa and other low-income regions. The proposed goal would be to supply lifesaving drugs to HIV-infected people and provide the means of preventing new infections, such as the distribution of condoms to at-risk individuals.

In 2002, Bush sent members of his administration and federal officials, including one of us (A.S.F.), on a fact-finding mission to several of the hardest-hit African countries to determine whether such a program was feasible. In those countries, philanthropic and other organizations were efficiently and effectively providing antiretroviral drugs to small numbers of patients, and it was clear that patients there understood and embraced the critical need for treatment and adherence to treatment regimens. The firsthand observation of what was attainable in sub-Saharan Africa directly contradicted the notion expressed by some that HIV-infected people in southern Africa were incapable of adhering to a daily treatment regimen for a potentially lethal disease. When the delegation returned, the President, through his immediate staff, gave the go-ahead (to A.S.F. and Dr. Mark Dybul) to begin designing the program.

The challenge was to provide HIV prevention, treatment, and care for as many people as possible. Multiple versions and iterations of the proposed program were labored over by White House and other government officials, with the encouragement of the President and his senior staff. There were intense discussions concerning the size and magnitude of the program; which countries would be included; and how best to allocate effort and resources among prevention, treatment, and care; as well as several other considerations. After months of discussion and debate, Bush announced the formation of PEPFAR in his State of the Union Address on January 28, 2003. The original proposal for PEPFAR, authorized with strong bipartisan support from Congress under the United States Leadership Against HIV/AIDS, Tuberculosis, and Malaria Act of 2003, was for a program costing $15 billion over 5 years and aiming for ambitious goals, including preventing 7 million new HIV infections, treating 2 million HIV-infected persons, and providing care — including basic medical services, education, and social support — for 10 million HIV-infected people, including children who have lost one or both parents to AIDS.

Shortly after President Bush signed the legislation in May 2003, PEPFAR was officially launched in 14 countries in Africa and the Caribbean that were severely affected by HIV/AIDS: Botswana, Ethiopia, Guyana, Haiti, Ivory Coast, Kenya, Mozambique, Namibia, Nigeria, Rwanda, South Africa, Tanzania, Uganda, and Zambia. These countries collectively accounted for nearly 20 million HIV-infected men, women, and children.1 With the addition of Vietnam in July 2004, the PEPFAR partner countries were home to more than 50% of all HIV-infected people in the world.2 The program was an interagency effort spanning the administration and the U.S. government, coordinated by the Department of State.

PEPFAR has received continuous bipartisan support from Congress since 2003 and is the largest global health initiative for a single infectious disease that has ever been implemented. The amount of funds appropriated for PEPFAR in fiscal year 2017 totaled $6.8 billion to provide HIV/AIDS treatment, prevention, and support programs in more than 50 countries. Four PEPFAR directors — Ambassadors Randall Tobias (2003–2006), Mark Dybul (2006–2009), Eric Goosby (2009–2013), and Deborah Birx (2014–present) — reporting directly to the U.S. Secretary of State, have guided and shaped PEPFAR into a remarkable global health success. As of September 2017, PEPFAR-funded programs have provided 13.3 million HIV-infected men, women, and children with antiretroviral therapy; supported 15.2 million voluntary medical male circumcisions in eastern and southern African countries to reduce the risk of HIV transmission; averted nearly 2.2 million perinatal HIV infections; and provided care for more than 6.4 million orphans and vulnerable children.3

Major hurdles of lack of health systems, pervasive stigma and discrimination, and limited access to and uptake of treatment and prevention programs, as well as socioeconomic, cultural, and demographic barriers at the local, regional, and national levels, had to be overcome in order to realize these achievements. Recent PEPFAR data indicate that five African countries — Lesotho, Malawi, Swaziland, Zambia, and Zimbabwe — are on track to achieve the Joint United Nations Program on HIV/AIDS (UNAIDS) targets for treatment implementation by 2020.4

PEPFAR has also provided some of the critical workforce, organizational, and physical infrastructure to address other concerns — such as malaria, tuberculosis, maternal and child health, immunizations, and unanticipated infectious disease outbreaks — that affect the geographic areas where patients with HIV are treated. Specifically, the program has contributed to building sustainable health system capacity in host countries by investing in the critical infrastructure of laboratories and training more than 220,000 health care workers.5 With regard to international public relations, PEPFAR has done as much as or more than any other program in enhancing the humanitarian image of the United States and has firmly established it as a key player in the response to a historic global public health crisis.

Over the past 15 years, PEPFAR has demonstrated the transforming results that can be realized by strong government leadership in the global health arena. It is entirely possible to bring the HIV/AIDS pandemic to an end, and PEPFAR will undoubtedly play an essential role in this endeavor. However, it is vital that support for this transformative program continue both to meet the immediate challenge of HIV/AIDS and to serve as the model for the control and elimination of other globally devastating infectious diseases.

Treating and Preventing HIV with Generic Drugs — Barriers in the United States

Drotumdi O

 

  • Erika G. Martin, Ph.D., M.P.H.,
  • and Bruce R. Schackman, Ph.D.

Metrics

Combination antiretroviral therapy (ART) has dramatically improved survival rates among people with HIV and is a mainstay of HIV prevention; evidence shows that durable viral suppression prevents the transmission of infection. In addition, preexposure prophylaxis (PrEP) is an emerging approach to preventing HIV acquisition for certain high-risk groups. Generic ART medications offer the potential for treating and preventing HIV with fewer resources. Generic versions of lamivudine, abacavir, and efavirenz became available in the United States within the past 6 years at prices lower than their brand-name counterparts, a generic version of PrEP (emtricitabine and tenofovir disoproxil fumarate) was approved in 2016, and generic versions of tenofovir disoproxil are expected later in 2018. Yet most of the discussion about the availability of generic HIV drugs focuses on low- and middle-income countries.

Costs for a 30-Day Supply of ART Regimens Recommended by the Department of Health and Human Services.*

ART accounts for 60% of the projected $326,500 discounted lifetime medical cost of HIV treatment in the United States.1 A 2013 study estimated nearly $1 billion in savings in the first year if all eligible U.S. patients for whom brand-name was prescribed efavirenz at the time (when it was a component of a leading ART regimen) switched to a regimen with generic efavirenz.2 Our analysis of four regimens currently recommended by the Department of Health and Human Services (HHS) shows in more detail the potential cost savings associated with switching to generic regimens (see table). For example, switching from a brand-name to a generic formulation of the three-drug combination of dolutegravir, abacavir, and lamivudine (regimen 1) would yield a 25% reduction in both the wholesale acquisition cost (generating savings of $667) and the federal supply schedule cost (generating savings of $553) for a 30-day supply. The wholesale acquisition cost approximates what private insurers pay for a drug, and the federal supply schedule cost approximates what government programs pay.

Greater use of generic ART in the United States could provide some relief to government programs that already face severe budgetary pressures and serve the majority of people with HIV and those at the highest risk for infection. Moreover, if proposed health policy reforms — such as allowing private insurers to exclude people with preexisting conditions or converting Medicaid to a block-grant program — are enacted and people with HIV lose their current public or private health insurance coverage, there will be more pressure on the AIDS Drug Assistance Program (ADAP). A payer of last resort, ADAP provides access to drugs for low-income people who are uninsured or underinsured. ADAP funding has been flat for the past 15 years despite increased demand as people with HIV live longer and more people are diagnosed with HIV infection. Finding new sources for cost savings is particularly important as states and local communities scale up efforts to increase rates of diagnosis, linkage to HIV care, and viral suppression as part of initiatives such as New York State’s Ending the Epidemic, San Francisco’s Getting to Zero, and Houston’s Roadmap to Ending the HIV Epidemic.

Can the United States realize billions of dollars in savings from the availability of generic ART medications? Although we believe such savings are theoretically possible, numerous legal, clinical, and market factors create barriers to the widespread adoption of generics in the United States as well as uncertainty about actual cost savings.

A key barrier to uptake of generics is modification of brand-name products coupled with aggressive marketing of modified products. Manufacturers have used various strategies to delay generic competition, such as developing coformulations with medications that have longer patent lives (e.g., coformulating tenofovir disoproxil fumarate with emtricitabine), changing inactive drug components (e.g., adding a new binding agent to the combination of efavirenz, emtricitabine, and tenofovir to resist degradation), filing for approval for additional indications that introduce new patent claims and extend market exclusivity (e.g., obtaining FDA approval to market lamivudine to treat hepatitis B virus), and obtaining patents on pediatric formulations (e.g., patenting the combination of lopinavir and ritonavir). In promoting their brand-name products, manufacturers may emphasize the side effects of older products as compared with newer brand-name alternatives, thereby increasing the general mistrust of generics. For example, efavirenz has been linked to increased suicidality3; because of the strength of this evidence, it is no longer a recommended first-line therapy in the current HHS guidelines despite the infrequency of suicides. There continues to be persistent skepticism among clinicians, pharmacists, and patients regarding the performance and safety of generic medications in general as compared with their brand-name counterparts.4

Because all first-line ART regimens contain three or four medications, often coformulated, the staggered availability of generic versions of each component will probably require replacing coformulated tablets with multiple individual pills, which creates several obstacles for both clinicians and patients. First, there is a perception — but no strong evidence — that increasing the number of pills in a once-daily regimen will adversely affect adherence and viral suppression. In keeping with systematic reviews on the general acceptability of generics,4 a recent study found that a substantial minority of French HIV physicians and their patients were unwilling to prescribe or use generic medications — and that the majority were unwilling if switching to generics resulted in an increased pill burden.5 In addition, patients taking multiple pills could potentially face higher costs if they had separate copayments for each medication rather than one copayment for a combination pill, which could affect their willingness or ability to refill prescriptions on time.

Another complication is the fact that the financial incentives for switching to generics vary among payers. HIV care is financed through a complex patchwork of public and private payers, including private insurance, Medicaid, Medicare, and state ADAPs. Payers don’t incur identical costs for ART. As shown in the table, although there are cost savings associated with all generic-substitution regimens, not all substitutions yield meaningful price reductions. For example, although switching to a generic formulation of dolutegravir, abacavir, and lamivudine (regimen 1) would lead to a 25% reduction in the cost of a 30-day supply for both private and government payers, doing the same for dolutegravir, tenofovir disoproxil fumarate, and emtricitabine (regimen 2) would yield savings of $364 for private insurers but only $5 for public payers.

Furthermore, some clinics are eligible for the federal 340B drug-pricing program, which provides access to discounted medications, and ADAPs have negotiated rebates, price freezes, and medication prices that are lower than mandatory government rates for Medicaid. Currently, HIV-program pharmacies eligible for 340B pricing can generate substantial revenue by dispensing brand-name ART and obtaining full reimbursement from payers, which provides a disincentive to use generics. ADAP managers also have other priorities in addition to encouraging generic substitution, such as adapting to rapid changes in the federal health insurance landscape, managing funding cuts, and establishing programs that provide access to PrEP for HIV-negative persons.

After more than three decades of progress in HIV prevention and treatment, we have reached an era when the “end of AIDS” is conceivable, and many communities in the United States are mobilizing around ambitious new goals for linkage to and retention in care, rates of durable viral suppression, and PrEP use. The availability of generic ART medications might help address some budget shortfalls, particularly in states that didn’t expand their Medicaid programs, where ADAPs must stretch their budgets to cover uninsured people with HIV and federal funding cuts are anticipated. However, many factors will delay widespread adoption. Although information and education about generics can improve health professionals’ and patients’ confidence in generic substitution, there is limited evidence on which interventions are most effective at improving perceptions of generic drugs.4 Generic ART will not be a panacea for government programs serving people with HIV and those at risk. We believe it is important to continue to advocate for sufficient funding for public-insurance programs that can provide access to all medications needed for HIV treatment and prevention.

Disclosure forms provided by the authors are available at NEJM.org.

Author Affiliations

From the Rockefeller Institute of Government and the Department of Public Administration and Policy, University at Albany, State University of New York, Albany (E.G.M.); and the Department of Healthcare Policy and Administration, Weill Cornell Medical College, New York (B.R.S.).

Adjunctive Glucocorticoid Therapy in Patients with Septic Shock

Drotumdi O

Adjunctive Glucocorticoid Therapy in Patients with Septic Shock

  • Balasubramanian Venkatesh, M.D.,
  • Simon Finfer, M.D.,
  • Jeremy Cohen, M.D., Ph.D.,
  • Dorrilyn Rajbhandari, R.N.,
  • Yaseen Arabi, M.D.,
  • Rinaldo Bellomo, M.D.,
  • Laurent Billot, M.Sc., M.Res.,
  • Maryam Correa, Ph.D.,
  • Parisa Glass, Ph.D.,
  • Meg Harward, R.N.,
  • Christopher Joyce, M.D., Ph.D.,
  • Qiang Li, M.Sc.,
  • Colin McArthur, M.D.,
  • Anders Perner, M.D., Ph.D.,
  • Andrew Rhodes, M.D.,
  • Kelly Thompson, R.N., M.P.H.,
  • Steve Webb, M.D., Ph.D.,
  • and John Myburgh, M.D., Ph.D.
  • et al.,
  • for the ADRENAL Trial Investigators and the Australian–New Zealand Intensive Care Society Clinical Trials Group*

 

A full list of investigators in the ADRENAL Trial is provided in the Supplementary Appendix, available at NEJM.org.

 

 

January 19, 2018
DOI: 10.1056/NEJMoa1705835

Metrics

Comments open through January 26, 2018

Abstract

Background

Whether hydrocortisone reduces mortality among patients with septic shock is unclear.

Methods

We randomly assigned patients with septic shock who were undergoing mechanical ventilation to receive hydrocortisone (at a dose of 200 mg per day) or placebo for 7 days or until death or discharge from the intensive care unit (ICU), whichever came first. The primary outcome was death from any cause at 90 days.

Results

From March 2013 through April 2017, a total of 3800 patients underwent randomization. Status with respect to the primary outcome was ascertained in 3658 patients (1832 of whom had been assigned to the hydrocortisone group and 1826 to the placebo group). At 90 days, 511 patients (27.9%) in the hydrocortisone group and 526 (28.8%) in the placebo group had died (odds ratio, 0.95; 95% confidence interval [CI], 0.82 to 1.10; P=0.50). The effect of the trial regimen was similar in six prespecified subgroups. Patients who had been assigned to receive hydrocortisone had faster resolution of shock than those assigned to the placebo group (median duration, 3 days [interquartile range, 2 to 5] vs. 4 days [interquartile range, 2 to 9]; hazard ratio, 1.32; 95% CI, 1.23 to 1.41; P<0.001). Patients in the hydrocortisone group had a shorter duration of the initial episode of mechanical ventilation than those in the placebo group (median, 6 days [interquartile range, 3 to 18] vs. 7 days [interquartile range, 3 to 24]; hazard ratio, 1.13; 95% CI, 1.05 to 1.22; P<0.001), but taking into account episodes of recurrence of ventilation, there were no significant differences in the number of days alive and free from mechanical ventilation. Fewer patients in the hydrocortisone group than in the placebo group received a blood transfusion (37.0% vs. 41.7%; odds ratio, 0.82; 95% CI, 0.72 to 0.94; P=0.004). There were no significant between-group differences with respect to mortality at 28 days, the rate of recurrence of shock, the number of days alive and out of the ICU, the number of days alive and out of the hospital, the recurrence of mechanical ventilation, the rate of renal-replacement therapy, and the incidence of new-onset bacteremia or fungemia.

Conclusions

Among patients with septic shock undergoing mechanical ventilation, a continuous infusion of hydrocortisone did not result in lower 90-day mortality than placebo. (Funded by the National Health and Medical Research Council of Australia and others; ADRENAL ClinicalTrials.gov number, NCT01448109.)

Introduction

Sepsis, which has been identified by the World Health Organization as a global health priority, has no proven pharmacologic treatment, other than the appropriate antibiotic agents, fluids, and vasopressors as needed; reported death rates among hospitalized patients range between 30% and 45%.1-6 Glucocorticoids have been used as an adjuvant therapy for septic shock for more than 40 years.7 Nonetheless, uncertainty about their safety and efficacy remains.

Randomized, controlled trials that were conducted in the 1980s showed that the use of high-dose methylprednisolone (30 mg per kilogram of body weight) was associated with higher morbidity and mortality than control.8,9 Two randomized, controlled trials that examined the effect of lower-dose hydrocortisone (200 mg per day) on mortality among patients with septic shock showed conflicting results,10,11 although each trial showed an earlier reversal of shock in patients who had been treated with hydrocortisone than in control patients.

Subsequent systematic reviews and meta-analyses have not provided compelling evidence for or against the use of hydrocortisone in patients with septic shock.12-14 Current clinical practice guidelines recommend the use of hydrocortisone in patients with septic shock if adequate fluid resuscitation and treatment with vasopressors have not restored hemodynamic stability; however, the guidelines classify the recommendation as weak, on the basis of the low quality of available evidence.15

The uncertainty about the efficacy of glucocorticoids in reducing mortality among patients with septic shock has resulted in widespread variation in clinical practice.16 Reports of potential adverse effects associated with glucocorticoids, including superinfection and metabolic and neuromuscular effects, have compounded clinical uncertainty.11 We designed the Adjunctive Corticosteroid Treatment in Critically Ill Patients with Septic Shock (ADRENAL) trial to test the hypothesis that hydrocortisone results in lower mortality than placebo among patients with septic shock.17

Methods

Trial Design and Oversight

Our trial was an investigator-initiated, international, pragmatic, double-blind, parallel-group, randomized, controlled trial that compared intravenous infusions of hydrocortisone with matched placebo in patients with septic shock who were undergoing mechanical ventilation in an intensive care unit (ICU). We conducted the trial in Australia, the United Kingdom, New Zealand, Saudi Arabia, and Denmark.

The trial management committee designed the trial. The trial sponsor (the George Institute for Global Health, Australia) coordinated all the operational processes and conducted all the statistical analyses. Trained research coordinators collected data at each site and entered the information into a Web-based database. Data monitoring and source-data verification were conducted according to a prespecified monitoring plan (Table S1 in the Supplementary Appendix, available with the full text of this article at NEJM.org).

Before enrollment was completed, we published the trial protocol (available at NEJM.org) and statistical analysis plan.17,18 Approval from a human research ethics committee was obtained for all the sites before enrollment of the patients. Previous written informed consent or written consent to continue was obtained for all participants, according to the legal requirements in each jurisdiction. The authors vouch for the accuracy and completeness of the data and statistical analyses and for the fidelity of the trial to the protocol.

Neither Pfizer (which supplied hydrocortisone) nor Radpharm Scientific (which supplied placebo) had any input into the design or conduct of the study, data collection, statistical analysis, or writing of the manuscript. Mater Pharmacy Services (Brisbane, Australia) was responsible for acquisition of the drugs and the blinding processes. There was no contractual arrangement between the trial sponsor, the George Institute for Global Health, and either Pfizer or Radpharm Scientific. All contractual arrangements were between Mater Pharmacy Services and the George Institute for Global Health.

Patients

Eligible participants were adults (≥18 years of age) who were undergoing mechanical ventilation, for whom there was a documented or strong clinical suspicion of infection, who fulfilled two or more criteria of the systemic inflammatory response syndrome,19 and who had been treated with vasopressors or inotropic agents for a minimum of 4 hours up to and at the time of randomization. Patients were excluded if they were likely to receive treatment with systemic glucocorticoids for an indication other than septic shock, had received etomidate20 (a short-acting anesthetic agent with adrenal-suppressant properties) during the current hospital admission, were considered to be likely to die from a preexisting disease within 90 days after randomization or had treatment limitations in place, or had met all the inclusion criteria for more than 24 hours. Detailed inclusion and exclusion criteria and the alignment of these criteria with the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3)21 are provided in Tables S2A through S2C in the Supplementary Appendix.

Randomization and Trial Regimen

We concealed the randomized trial-group assignments using a minimization algorithm by means of a password-protected, encrypted, Web-based interface. Randomization was stratified according to participating center and according to medical or surgical admission. Surgical admissions were defined as patients being admitted to the ICU from the operating room or the recovery room; all other admissions were considered to be medical admissions.

Patients were assigned to receive an intravenous infusion of hydrocortisone (Pfizer) at a dose of 200 mg per day or matching placebo (Radpharm Scientific). Blinding regarding the trial regimen was ensured by the supply of hydrocortisone and placebo in identical, masked vials. The integrity of the trial-group assignment was confirmed by an independent person who assessed a random sample of hydrocortisone and placebo packs from 10% of the trial population (Table S3A in the Supplementary Appendix). The trial regimen was reconstituted to produce a concentration of 1 mg per milliliter of hydrocortisone or an equivalent volume (in milliliters) of placebo. The trial dose volume was set at 200 ml, which was administered by means of continuous intravenous infusion over a period of 24 hours for a maximum of 7 days or until ICU discharge or death, whichever occurred first. A description of the blinding process and of the preparation and reconstitution of the trial regimen is provided in Table S3B in the Supplementary Appendix.

The patients, treating clinicians, and trial personnel were unaware of the trial-group assignments and sequence. All other aspects of the patients’ care were conducted at the discretion of the treating clinicians.

Outcomes

The primary outcome was death from any cause at 90 days after randomization. Secondary outcomes included death from any cause at 28 days after randomization, the time to the resolution of shock,22 the recurrence of shock, the length of ICU stay, the length of hospital stay, the frequency and duration of mechanical ventilation, the frequency and duration of treatment with renal-replacement therapy, the incidence of new-onset bacteremia or fungemia between 2 and 14 days after randomization, and the receipt of blood transfusion in the ICU. Definitions of the secondary outcomes are provided in Table S4 in the Supplementary Appendix.

Statistical Analysis

We determined that a population of 3800 patients would provide the trial with 90% power to detect an absolute difference of 5 percentage points in 90-day all-cause mortality from an estimated baseline mortality of 33%, at an alpha level of 0.05.6 This calculation allowed for a rate of withdrawal and loss to follow-up of 1%.

The primary-outcome result is presented as the odds ratio for death, with corresponding 95% confidence intervals, analyzed with the use of a logistic-regression model with adjustment for stratification variables, with admission type (medical or surgical) as a fixed effect and trial site as a random effect. Additional sensitivity analyses were performed by adding the following covariates to the main logistic-regression model: sex; age; Acute Physiology and Chronic Health Evaluation (APACHE) II score, assessed on a scale from 0 to 71, with higher scores indicating a higher risk of death23; the time from the onset of shock to randomization; and the use of renal-replacement therapy in the 24 hours before randomization.

The primary outcome was also examined in six prespecified subgroups, which were defined according to the following baseline characteristics: admission type (medical vs. surgical); dose of catecholamine infusions (norepinephrine or epinephrine at a dose of <15 μg per minute vs. ≥15 μg per minute); primary site of sepsis (pulmonary vs. nonpulmonary); sex (male vs. female); APACHE II score (<25 vs. ≥25; a score of ≥25 has been used as a cutoff point to identify patients at a higher risk for death24,25); and the duration of shock according to four intervals of 6 hours each between 0 and 24 hours before randomization (<6 hours, 6 to 12 hours, 12 to 18 hours, or 18 to 24 hours). The secondary binary and continuous outcomes were analyzed with the use of logistic regression and linear regression, respectively, with adjustment for stratification variables. The rate of death in a time-to-event analysis was reported with the use of Kaplan–Meier plots, and differences in survival were tested with the use of a Cox proportional-hazards model26 that included the randomized trial group, admission type, and a random effect for trial site.

The times to the resolution of shock and ventilation and the times to discharge from the ICU and the hospital were analyzed by means of two approaches: with death treated as a competing risk27 and with results described with the use of cumulative incidence function; and as a post hoc analysis with data from patients censored at the time of death and with results described with the use of Kaplan–Meier plots. Differences in the time to event (e.g., resolution of shock, cessation of ventilation, and ICU or hospital discharge) were tested with the use of the same Cox model that was used for the analysis of time to death.

Physiological data were averaged over the period of days 1 to 14 and compared with the use of a repeated-measure, linear mixed model and were presented as overall mean differences with corresponding 95% confidence intervals. Post hoc analyses were performed with the use of a separate calculation of the mean differences over the period of days 1 to 7 (duration of trial regimen) and days 8 to 14. The proportions of patients who had adverse events and serious adverse events were compared with the use of Fisher’s exact test.

All the analyses were conducted on an intention-to-treat basis with no imputation of missing data. For secondary outcomes, a post hoc Holm–Bonferroni procedure was applied to control for multiple testing.28 All the analyses were conducted with the use of SAS software, version 9.4 (SAS Institute).

Two prespecified interim analyses were performed by an independent statistician when 950 patients (25%) and 2500 patients (66%) could be assessed with regard to the primary outcome at 90 days. These analyses were reviewed by an independent data monitoring committee.

Results

Patients

From March 2013 through April 2017, we identified 5501 eligible patients, of whom 3800 were enrolled in the trial at 69 medical–surgical ICUs. The ICUs were in Australia (45 sites), the United Kingdom (12), New Zealand (8), Saudi Arabia (3), and Denmark (1).

Of the 3800 patients enrolled, 1898 were assigned to receive hydrocortisone and 1902 to receive placebo. A total of 114 patients (3.0%) either withdrew (24 patients) or did not have informed consent obtained (90), and 28 of the remaining 3686 patients (0.8%) were lost to follow-up at 90 days. Thus, the trial included 3658 enrolled patients, of whom 1832 in the hydrocortisone group and 1826 in the placebo group were included in the analysis of the primary outcome (Figs. S1 and S2 and Table S5 in the Supplementary Appendix).

Table 1. Table 1. Characteristics of the Patients at Baseline.

The characteristics of the patients at baseline were similar in the two groups (Table 1). The mean (±SD) age of the patients was 62.3±14.9 years in the hydrocortisone group and 62.7±15.2 years in the placebo group; the percentages of male patients were 60.4% and 61.3%, respectively; the median APACHE II scores were 24.0 (interquartile range, 19.0 to 29.0) and 23.0 (interquartile range, 18.0 to 29.0), respectively; and the percentages of patients with surgical admission were 31.2% and 31.8%, respectively. The primary site of infection was similar in the two groups and was predominantly of pulmonary origin among patients with a medical diagnosis and of abdominal origin among patients with a surgical admission (Tables S6 and S7 in the Supplementary Appendix).

Trial and Concomitant Regimens

The assigned trial regimen was received by 1834 of 1837 patients (99.8%) in the hydrocortisone group and by 1838 of 1843 (99.7%) in the placebo group. The median time from randomization to the commencement of the trial regimen was 0.8 hours (interquartile range, 0.4 to 1.6) in the hydrocortisone group and 0.8 hours (interquartile range, 0.4 to 1.5) in the placebo group (P=0.28). There was no significant between-group difference in the cumulative duration of the trial regimen (median, 5.1 days [interquartile range, 2.7 to 6.8] in the hydrocortisone group and 5.6 days [interquartile range, 2.9 to 6.8] in the placebo group; P=0.09). The overall mean rate of adherence to the dosing protocol was 95.2±11.3% in the hydrocortisone group and 94.9±12.1% in the placebo group (P=0.34) (Table S8 and Fig. S3 in the Supplementary Appendix).

Between days 1 and 14 after randomization, 138 of 1853 patients (7.4%) in the hydrocortisone group and 164 of 1860 (8.8%) in the placebo group received open-label glucocorticoids (P=0.13). The use of inotropes, vasopressors, etomidate, statins, and antimicrobial therapies did not differ significantly between the groups (Tables S8 and S9 in the Supplementary Appendix).

Between days 1 and 7, patients in the hydrocortisone group had a higher mean arterial pressure than did those in the placebo group (difference, 5.39 mm Hg; P<0.001), as well as a higher plasma lactate level (difference, 0.08 mmol per liter; P=0.02) and a lower heart rate (difference, −6.6 beats per minute; P<0.001). There were no significant between-group differences in the daily peak dose of norepinephrine among patients who were receiving vasopressors between days 1 and 14. (Details are provided in Fig. S4A through S4E in the Supplementary Appendix.)

Primary Outcome

Table 2. Table 2. Outcomes.Figure 1. Figure 1. Rate of Survival and the Risk of Death at 90 Days, According to Subgroup.Panel A shows Kaplan–Meier estimates of the survival rate among patients receiving hydrocortisone or placebo. The P value was calculated with the use of a Cox proportional-hazards model that included the randomized trial group, admission type (medical or surgical), and a random effect of trial center. Panel B shows the odds ratio of death at 90 days in the six prespecified subgroups. The size of the square representing the odds ratio reflects the relative numbers in each subgroup, and horizontal bars represent 95% confidence intervals. P values are for heterogeneity of the effect of the trial regimen on the primary outcome in each subgroup. Scores on the Acute Physiology and Chronic Health Evaluation (APACHE) II are assessed on a scale from 0 to 71, with higher scores indicating a higher risk of death (a score of ≥25 has been used as a cutoff point to identify patients at a higher risk for death).23-25 Data on admission type were missing for 1 patient in the placebo group; on the catecholamine dose for 15 in the hydrocortisone group and for 26 in the placebo group; on the APACHE II score for 2 and 2, respectively; and on the time from shock onset to randomization for 7 and 7, respectively.

At 90 days after randomization, 511 of 1832 patients (27.9%) who had been assigned to receive hydrocortisone had died, as had 526 of 1826 (28.8%) who had been assigned to receive placebo (odds ratio, 0.95; 95% confidence interval [CI], 0.82 to 1.10; P=0.50) (Table 2, and Table S10 and Fig. S5 in the Supplementary Appendix). There was no significant between-group difference in the rate of death in the time-to-event analysis during the 90 days after randomization (hazard ratio, 0.95; 95% CI, 0.84 to 1.07; P=0.42) (Figure 1A).

There was no significant heterogeneity in the effect of the trial regimen on the primary outcome in the six prespecified subgroups (Figure 1B). A post hoc sensitivity analysis that excluded patients who had received open-label glucocorticoids did not alter the primary outcome result (odds ratio, 0.96; 95% CI, 0.82 to 1.12; P=0.59).

Secondary Outcomes

Figure 2. Figure 2. Cumulative Incidence Function of Time from Randomization to Resolution of Shock.The cumulative incidence function plot was created by treating death as a competing risk.

There was no significant between-group difference in mortality at 28 days (Table 2, and Table S10 in the Supplementary Appendix). The time to the resolution of shock was shorter in the hydrocortisone group than in the placebo group (median, 3 days [interquartile range, 2 to 5] vs. 4 days [interquartile range, 2 to 9]; hazard ratio, 1.32; 95% CI, 1.23 to 1.41; P<0.001) (Figure 2, and Fig. S6A and S6B in the Supplementary Appendix).

The time to discharge from the ICU was shorter in the hydrocortisone group than in the placebo group (median, 10 days [interquartile range, 5 to 30] vs. 12 days [interquartile range, 6 to 42]; hazard ratio, 1.14; 95% CI, 1.06 to 1.23; P<0.001) (Fig. S6C and S6D in the Supplementary Appendix). After adjustment for multiple comparisons, there was no significant between-group difference in the number of days alive and out of the ICU (P=0.047; threshold level for significance after adjustment for multiple comparisons, P=0.005) (Table 2, and Table S11 in the Supplementary Appendix).

Patients in the hydrocortisone group had a shorter duration of the initial episode of mechanical ventilation than did those in the placebo group (median, 6 days [interquartile range, 3 to 18] vs. 7 days [interquartile range, 3 to 24]; hazard ratio, 1.13; 95% CI, 1.05 to 1.22; P<0.001), but taking into account episodes of recurrence of ventilation, there were no significant differences in the number of days alive and free from mechanical ventilation (Table 2, and Fig. S6G and S6H in the Supplementary Appendix).

There were no significant between-group differences with respect to the rate of recurrence of shock, the time to hospital discharge, the number of days alive and out of hospital, the rate of recurrence of mechanical ventilation, the duration and rate of use of renal-replacement therapy, and the rate of development of new-onset bacteremia or fungemia (Table 2, and Fig. S6E and S6F in the Supplementary Appendix).

Fewer patients in the hydrocortisone group than in the placebo group received a blood transfusion (37.0% vs. 41.7%; odds ratio, 0.82; 95% CI, 0.72 to 0.94; P=0.004). Among the patients who received a transfusion, there was no significant between-group difference with respect to the mean total volume of blood transfused (Fig. S7 in the Supplementary Appendix).

Adverse Events

Table 3. Table 3. Adverse Events.

A total of 33 adverse events was reported in the trial population, with a higher percentage in the hydrocortisone group than in the placebo group (1.1% vs. 0.3%, P=0.009). There were 6 serious adverse events, with 4 occurring in the hydrocortisone group and 2 in the placebo group (Table 3). The list of protocol violations and the results of the interim analyses are presented in Tables S12 and S13, respectively, in the Supplementary Appendix.

Discussion

We found that the administration of hydrocortisone did not result in lower 90-day mortality than placebo among patients with septic shock. This effect did not differ in any of the six prespecified subgroups. We observed a more rapid resolution of shock and a lower incidence of blood transfusion among patients who received hydrocortisone than among those who received placebo. Patients who had been assigned to receive hydrocortisone had a shorter time to ICU discharge and earlier cessation of the initial episode of mechanical ventilation than did those who had been assigned to receive placebo. There were no significant between-group differences with respect to mortality at 28 days, the rate of recurrence of shock, the number of days alive and out of the ICU or hospital, the duration and rate of recurrence of mechanical ventilation, the rate of use of renal-replacement therapy, or the rate of new-onset bacteremia or fungemia. Patients who had been assigned to receive hydrocortisone had more adverse events than did those who had been assigned to receive placebo, but these events did not affect patient-centered outcomes.

Our pragmatic trial was designed with statistical power to detect a clinically plausible effect on mortality. To reduce bias, we used a central randomization process and ensured the concealment and blinding of trial-group assignments, which were independently verified. We published our statistical analysis plan before unblinding.

We chose 90-day mortality as a patient-centered primary outcome and specifically targeted a population of patients who had high requirements for vital organ support (use of mechanical ventilation and ≥4 hours of vasopressor therapy before randomization) and a substantial risk of death. The trial was successful in enrolling the intended population.

A high proportion of eligible patients received the trial intervention as planned, and few enrolled patients were lost to follow-up. The ratio of patients who underwent randomization to those who were eligible for inclusion was high: 0.69:1, a ratio that approaches that seen in other large-scale trials.29 The inclusion of 69 sites in five countries increases the external validity of the results.

Our trial differs from previously published trials in several respects.10,11 We administered hydrocortisone by means of continuous infusion, because such a plan has been shown to attenuate the inflammatory response and reverse shock.30 Practice guidelines for septic shock suggest that infusions may minimize potentially harmful metabolic effects of glucocorticoids.15,31 A tapering strategy was not used for the discontinuation of glucocorticoids, because a beneficial effect of these agents on survival was previously reported without tapering.10 A recent study that compared abrupt cessation with a tapering strategy showed no benefits from tapering.32 We did not perform corticotropin testing, because its interpretation in critically ill patients is controversial33-35 and such testing is not recommended in current clinical practice guidelines.15 We excluded patients who had received etomidate before randomization. We did not administer fludrocortisone, because it has been shown previously to be ineffective.36

Our trial had limitations. Within the context of a large pragmatic trial, we collected data on only adverse events that had been judged by the treating clinicians to be related to the trial regimen, and we did not adjudicate this judgment. This approach may weaken the inferences about adverse events. We did not collect data regarding all possible secondary infections, and we recorded only bacteremia and fungemia, which are less subject to diagnostic error or ascertainment bias. We did not adjudicate the appropriateness of antibiotic therapy. We used rates of recurrence of ventilation as a surrogate for myopathy but did not assess long-term neuromuscular weakness.

Our trial provides evidence about the role of hydrocortisone as an adjunctive treatment in patients with septic shock. Although we did not observe a significant difference between the hydrocortisone group and the placebo group with regard to 90-day mortality, some secondary outcomes were better in the group that received the active treatment. Our observation of the hemodynamic effects of hydrocortisone is consistent with those in previous studies.37-39 These hemodynamic effects may represent a beneficial role of hydrocortisone. There was a lower incidence of transfusion in the hydrocortisone group than in the placebo group, a finding that may be regarded as hypothesis-generating. A detailed cost–benefit assessment of these results was not done, but such an analysis may inform clinicians about the overall cost-effectiveness of hydrocortisone in patients with septic shock.

In conclusion, in patients with septic shock who were undergoing mechanical ventilation, the administration of a continuous infusion of hydrocortisone did not result in lower mortality at 90 days than placebo.

Funding and Disclosures

Supported by project grants from the National Health and Medical Research Council of Australia (grant nos., 1004108 and 1124926) and the Health Research Council of New Zealand (grant no., 12/306), by indirect funding from the National Institute of Health Research in the United Kingdom, and by Practitioner Fellowships from the National Health and Medical Research Council of Australia (to Drs. Finfer, Bellomo, and Myburgh).

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

This article was published on January 19, 2018, at NEJM.org.

We thank the patients and their families for their participation in this trial and the intensive care unit clinical and research staff at all the participating sites.

Author Affiliations

From the George Institute for Global Health, University of New South Wales (B.V., S.F., D.R., L.B., M.C., P.G., M.H., Q.L., K.T., J.M.), St. George Clinical School, St. George Hospital (J.M.), Sydney Medical School, University of Sydney (B.V., S.F., J.M.), and Royal North Shore Hospital (S.F.), Sydney, the Princess Alexandra Hospital (B.V., C.J.) and Royal Brisbane and Women’s Hospital (J.C.), University of Queensland, and the Wesley Hospital (B.V., J.C.), Brisbane, Austin Hospital (R.B.), the School of Medicine, University of Melbourne (R.B.), and the Australian and New Zealand Research Centre (R.B.), School of Public Health and Preventive Medicine (R.B., S.W., J.M.), Monash University, Melbourne, VIC, and Royal Perth Hospital (S.W.) and the School of Medicine and Pharmacology, University of Western Australia (S.W.), Perth — all in Australia; King Saud Bin Abdulaziz University for Health Sciences, King Abdullah International Medical Research Center, Riyadh, Saudi Arabia (Y.A.); the Department of Critical Care Medicine, Auckland City Hospital, Auckland, New Zealand (C.M.); Rigshospitalet, University of Copenhagen, Copenhagen (A.P.); and St. George’s University Hospitals NHS Foundation Trust, St. George’s University of London, London (A.R.).

Address reprint requests to Dr. Venkatesh at the Department of Intensive Care, Wesley Hospital, 451 Coronation Dr., Auchenflower, Brisbane, QLD 4066, Australia, or at bvenkatesh@georgeinstitute.org.au.

A full list of investigators in the ADRENAL Trial is provided in the Supplementary Appendix, available at NEJM.org.

 

Supplementary Material

ProtocolPDF3669KB

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References (39)

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    Close References

    Comments (8)

    Top 10 Most Important Medical Discoveries

    Drotumdi O


    Medicine is an ever-evolving field. New breakthroughs are being made all the time, but there are some discoveries that will always stand out as changing human thinking forever. Thanks to medicine, diseases have been eradicated, babies have been created and illnesses that used to be serious are now relatively mild. So, be grateful for living in the 21st century as we take a look at the Top 10 Most Important Medical Discoveries.

    10. Anesthetic

    If you’ve ever visited a museum of naval history, you will inevitably have come across a display that shows how they used to do surgical procedures on board ships in the 1800s. Amputations were done on a table, with the injured man biting on a piece of wood to stop from screaming. You probably shuddered then and are probably shuddering now.

    Fortunately, the late 19th century saw the discovery of anesthetia, which numbs all sensation in the patient. An early anaesthetic was cocaine, first isolated by Karl Koller. It was an effective numbing agent, but as we now know it is also addictive and open to abuse. Around the same time, chloroform was also being used to numb pain (as demonstrated by John Snow during one of Queen Victoria’s births), but this too had potentially lethal side-effects. Luckily, today’s anesthetics are both effective and safe.

    9. Birth Control

    Another huge difference that occurred in the late 19th century was the drop in birth rate as people started choosing to have smaller families. In the UK, for instance, the birth rate was 35.5 births per 1,000 people in 1870 and was down to 29 per 1,000 in 1900. This was, in part, due to better education about sex and reproduction but it was also due to better methods of birth control.

    In the US, the “birth control movement” started a few years later, when a group of radicals, led by Emma Goodman (above), decided to start educating their fellow women about contraception to try and control the number of unwanted pregnancies. Their campaign was eventually successful and the Planned Parenthood Federation of America was formed in 1942. Birth control remains unpopular with some religious groups, but it has had a profound and undeniable social effect.

    8. MMR

    Another controversial one now, with the combined vaccine for measles, mumps and rubella. It was licensed in 1971, by Maurice Hilleman and immediately had a significant effect on the number of measles cases reported, with hundreds of thousands in the US during the 1960s (1966 saw 450,000) reduced to thousands by the 1980s.

    The controversy occurred much later, in 1998, when Andrew Wakefield was paid by lawyers to find a way to discredit the MMR. He did this effectively, by publishing a paper claiming that there was a link between the MMR vaccine and autism. The research has since been entirely discredited, but the effects on vaccination rates was devastating, with the officially eliminated disease reoccurring in the US. Similarly, in the UK the number of measles cases had dropped to 56 in 1998 and was up to 1348 in 2008. There is also an epidemic in the UK in 2013, largely around Wales. MMR rates are now increasing again, thanks to emergency vaccination programs and it can be safely said that the MMR is a significant medical breakthrough.

    7. X-Ray

    A medical procedure that is now so common that we take it for granted, the X-Ray was discovered by accident. Its inventor was Wilhelm Conrad Röntgen and on 8 Nov, 1895 he discovered that his cathode ray tube could produce some unusual images. A week later, he x-rayed his wife’s hand and the resulting image was close to our modern x-rays – her bones and wedding ring were clearly visible, but flesh was not. He named it “X-ray” as the x stood for “unknown”, but they are occasionally known as Röntgen rays in his native Germany. He was awarded the first Nobel Prize in 1901 and his invention continues to be used in hospitals everywhere.

    6. Insulin

    Another breakthrough that is used on a daily basis by diabetics, insulin is the life-saving hormone that keeps our blood sugars in check. Diabetics are either missing this hormone entirely (with type 1 diabetes) or produce it but not in a way their bodies can use (type 2). It was first isolated in 1921, by scientists from the University of Toronto, who were later awarded the Nobel Prize for their discovery. The following year, a 14-year-old called Leonard Thompson (above) became the first human to receive artificial insulin after coming close to a diabetic coma. He rallied after his second dose (the first was found to be impure) and lived another 13 years.

    It’s hard to imagine, given that diabetics can now live very normal lives, but Type 1 Diabetes used to be a terminal disease. Apart from diet management, there was nothing that could be done to combat the disease. Nowadays, it still isn’t curable but is manageable thanks to insulin – just as well, given that obesity rates are rising, and diabetes rates with them. Insulin could become the most useful drug in the world…

    History Of Most Importand Medical Breakthroughs

    Drotumdi O

    Written by Alex Koyfman
    Posted August 14, 2015
    • Save

    The advent and advancement of medical science ranks as one of the top three main influencers of the general advancement of the human species, alongside agriculture and industrialization.

    Since the dawn of history, study of the human body, the diseases that attack it, and the remedies that can combat those diseases has been a constant obsession for some of our greatest thinkers and problem solvers.

    In their drive to ward off the inevitable facing each and every human being from the moment of birth, doctors and scientists from the classic era all the way through today have been making steady progress.

    But it's the breakthroughs — those rare moments in history that mark major turning points in the way medicine is practiced and perceived — that propel all of human civilization past major historical milestones.

    Here are five of the most important advancements ever made by medical science. In one way or another, each and every one of us — you included — owes our lives to these technical achievements.

    Vaccines

    Viruses have led to some of mankind's deadliest, most widespread calamities, and they continue to do so as biological evolution presents medical science with new problems each and every year.

    But some of the biggest battles have already been won.

    Dr. Edward Jenner first introduced the idea of vaccinations in 1796, when he successfully prevented a young English boy from getting smallpox.

    vaccine

    The idea was simple enough: Introduce a benign strain of a virus into the human body so that the immune system can develop a natural response.

    Thanks to this simple but groundbreaking procedure, smallpox — the single-biggest killer of people in the 20th century — has been virtually eradicated from the face of the Earth.

    Vaccination took another step forward thanks to Louis Pasteur, whose work with vaccines for such infectious diseases as rabies and anthrax contributed greatly to the widespread acceptance of vaccination as a standard preemptive medical practice in the 20th century.

    Today, vaccination is prevalent in most of the developed world, with infants acquiring artificial immunity to a host of diseases before ever leaving the maternity ward — and contributing significantly to the steady rise in life expectancy since the turn of the 20th century.

    Clean Water and Sanitation

    Anybody who's seen the inside of a modern operating room would quake at the sight of how things used to be not so long ago.

    Bare-handed amputations, scalpels being reused without sterilization, and open wounds exposed to unsanitized instruments were just a few elements of surgical procedures up to the beginning of the 20th century.

    first operation

    Nobody could have predicted how something as simple and apparent as sanitation could change the way high-risk, invasive procedures and hospital protocol are tackled.

    Although impossible to quantify the raw numbers of lives saved, considering the death rates of patients going under the knife in the post-Civil War era and the post-World War I era, it's not a stretch to assume that millions owed their lives to better hospital conditions.

    And it goes beyond the hospital and battlefield triage.

    Water, the most fundamental molecular component of all life, has gone through a technological revolution of its own.

    In the early 20th century, as many as 15% of infant deaths were attributed to unclean water. Today, that statistic is down more than 50-fold.

    Antibiotics

    Vaccination was just one prong of fortifying our immune systems against the never-ending onslaught of new microbes and parasites.

    Antibiotics, which came about by accident less than 90 years ago, rank alongside the most important breakthroughs of all time.

    And this accident didn't require billions in research. In fact, the cost of the experiment that has saved hundreds of millions of lives was probably less than $5 in today's money.

    alexfleming

    In 1928, Sir Alexander Fleming left a Petri dish of Staphylococci bacteria uncovered and later noted that the bacteria had been killed by a mold which had contaminated the sample.

    Upon further studying the mold, he discovered it was from a family called Penicillium notatum.

    The mold gave the name to the first antibiotic, penicillin, and the rest was history. It is now estimated that at least 200 million lives were saved by this one medical breakthrough.

    Extrapolating that through the generations, there's a very good chance that you would have never been born had this simple treatment not been administered to one of your ancestors.

    Today, antibiotics are used to treat a laundry list of bacterial illnesses, preventing complications and untold numbers of fatalities every single year.

    Radiological Imaging

    Whether it's at the dentist's office or at the hospital, most of us have had at least a couple experiences with X-rays.

    But before the first X-ray image was ever taken, doctors had to make their diagnoses by one of two means: either working from external clues on the surface of the body or through exploratory surgery.

    Neither was very reliable. One was often deadly.

    Since that first eerie image was taken in 1895 (pictured below), however, radiology has become a science unto itself.

    firstxray

    By 2010, it was estimated that over 5 billion X-ray imaging studies have been conducted worldwide.

    In 2006, as much as 50% of total ionizing radiation exposure in the U.S. came from these devices.

    And there is no end in sight, as computer and super-conductor technology continues to push forward this branch of medical science.

    With modern imaging like CT (computer tomography) and MRI (magnetic resonance imaging), the level of detail we can see has gone up orders of magnitude.

    Today's best equipment can digitally dissect the human body into slices fractions of a millimeter thick, allowing for radiologists and surgeons to spot tumors, aneurysms, blood clots, and a host of other potential problems before they escalate.

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    Molecular Pharmacology

    People have been taking pills for centuries, with most of them doing next to nothing or nothing at all.

    However, when the pharmaceutical industry merged with the science of molecular engineering, things really started to change.

    With today's technology, the engineering, patenting, and modification of complex molecules has opened new doors both to curing diseases and to the study of how the human anatomy reacts to those compounds.

    molebio

    Chemical engineers and molecular biologists are now able to hybridize the effects of certain drugs with other drugs to create synergistic new products that can then be modeled in computer simulations before a single living organism undergoes trial testing.

    Drugs can also, for the first time, be tailored to interact with their target cells on an exclusive basis, allowing for medications that are less dangerous, less invasive, and more effective at isolating specific problems.

    Moving forward, this branch of medical science will work more and more alongside the rising field of nanotechnology, making the pills we take smarter, safer, more effective, and more versatile.

    Fortune favors the bold,

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    Alex Koyfman

    follow basic@AlexKoyfman on Twitter

    Coming to us from an already impressive career as an independent trader and private investor, Alex's specialty is in the often misunderstood but highly profitable development-stage microcap sector. Focusing on young, aggressive, innovative biotech and technology firms from the U.S. and Canada, Alex has built a track record most Wall Street hedge funders would envy. Alex contributes his thoughts and insights regularly to Tech Investing Daily. To learn more about Alex, click here.

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    Time Line of Medicine and Medical Discovery

    Drotumdi O

    From Wikipedia, the free encyclopedia

    Jump to: navigation, search

    Timeline of the history of medicine and medical technology.[a]

     

    Contents

     [hide] 

     

    Antiquity[edit]

    • 3300 BC – During the Stone Age, early doctors used very primitive forms of herbal medicine.[1]
    • 3000 BC – Ayurveda The origins of Ayurveda have been traced back to around 4,000 BCE.[2]
    • c. 2600 BC – Imhotep the priest-physician who was later deified as the Egyptian god of medicine.[3][4]
    • 2500 BC – Iry Egyptian inscription speaks of Iry as [eye-doctor of the palace,] [palace physician of the belly,] [guardian of the royal bowels,] and [he who prepares the important medicine (name cannot be translated) and knows the inner juices of the body.][5]
    • 1900 BC – 1600 BC Akkadian clay tablets on medicine survive primarily as copies from Ashurbanipal's library at Nineveh.[6]
    • 1800 BC – Code of Hammurabi sets out fees for surgeons and punishments for malpractice[5]
    • 1800 BC – Kahun Gynecological Papyrus
    • 1600 BC – Hearst papyrus, coprotherapy and magic[7]
    • 1551 BC – Ebers Papyrus, coprotherapy and magic[8]
    • 1500 BC – Saffron used as a medicine on the Aegean island of Thera in ancient Greece
    • 1500 BC – Edwin Smith Papyrus, an Egyptian medical text and the oldest known surgical treatise (no true surgery) no magic[5]
    • 1300 BC – Brugsch Papyrus and London Medical Papyrus
    • 1250 BC – Asklepios[5]
    • 9th century – Hesiod reports an ontological conception of disease via the Pandora myth. Disease has a "life" of its own but is of divine origin.[7]
    • 8th century – Homer tells that Polydamna supplied the Greek forces besieging Troy with healing drugs Homer also tells about battlefield surgery Idomeneus tells Nestor after Machaon had fallen: A surgeon who can cut out an arrow and heal the wound with his ointments is worth a regiment.[5]
    • 700 BC – Cnidos medical school; also one at Cos
    • 500 BC – Darius I orders the restoration of the House of Life (First record of a (much older) medical school)[5]:47
    • 500 BC – Bian Que becomes the earliest physician known to use acupuncture and pulse diagnosis
    • 500 BC – the Sushruta Samhita is published, laying the framework for Ayurvedic medicine
    • c. 490 – c. 430 – Empedocles four elements[8]
    • 510–430 BC – Alcmaeon of Croton scientific anatomic dissections. He studied the optic nerves and the brain, arguing that the brain was the seat of the senses and intelligence. He distinguished veins from the arteries and had at least vague understanding of the circulation of the blood.[5] Variously described by modern scholars as Father of Anatomy; Father of Physiology; Father of Embryology; Father of Psychology; Creator of Psychiatry; Founder of Gynecology; and as the Father of Medicine itself.[9] There is little evidence to support the claims but he is, nonetheless, important.[8][10]
    • fl. 425 BC – Diogenes of Apollonia[8]
    • c. 484 – 425 BC – Herodotus tells us Egyptian doctors were specialists: Medicine is practiced among them on a plan of separation; each physician treats a single disorder, and no more. Thus the country swarms with medical practitioners, some undertaking to cure diseases of the eye, others of the head, others again of the teeth, others of the intestines,and some those which are not local.[5]
    • 496–405 BC – Sophocles "It is not a learned physician who sings incantations over pains which should be cured by cutting."[11]
    • 420 BC – Hippocrates of Cos maintains that diseases have natural causes and puts forth the Hippocratic Oath. Origin of rational medicine.

    Medicine after Hippocrates[edit]

    After Galen 200 AD[edit]

    Main article: Medieval medicine

    1200–1499[edit]

    1500–1799[edit]

     

    Hieronymus Fabricius, Operationes chirurgicae, 1685

    1800–1899[edit]

    1900–1999[edit]

    2000 – present[edit]

    Further information: 21st century § Medicine

    See also: Medicine in the 2010s

    See also[edit]

    Notes[edit]

    1. Jump up ^ The dates given for these medical works are uncertain. A Tribute to Hinduism suggests that Sushruta lived in the 5th century BC.
    1. Jump up ^ Wilford, John Noble (1998-12-08). "Lessons in Iceman's Prehistoric Medicine Kit". The New York Times. ISSN 0362-4331. Retrieved 2015-12-07. 
    2. Jump up ^ Issues in Pharmaceuticals by Disease, Disorder, or Organ System: 2011 Edition (2011 ed.). pp. P. ISBN 9781464967566
    3. ^ Jump up to: a b Magill, Frank Northen; Aves, Alison (1998). Dictionary of World Biography. Taylor & Francis. ISBN 9781579580407. Retrieved 1 September 2013. 
    4. Jump up ^ "Imhotep". Collins Dictionary. n.d. Retrieved December 30, 2015. 
    5. ^ Jump up to: a b c d e f g h Silverberg, Robert (1967). The dawn of medicine. Putnam. Retrieved 18 August 2012. 
    6. ^ Jump up to: a b c d e f g h i j Colón, A. R.; Colón, P. A. (January 1999). Nurturing children: a history of pediatrics. Greenwood Press. p. 61. ISBN 9780313310805. Retrieved 19 October 2012. 
    7. ^ Jump up to: a b c d e Loudon, Irvine (2001). Western Medicine: An Illustrated History. Oxford University Press. ISBN 9780199248131. Retrieved 16 December 2013. 
    8. ^ Jump up to: a b c d e f g h Longrigg, James (1993-07-28). Greek Rational Medicine: Philosophy and Medicine from Alcmaeon to the Alexandrians. Psychology Press. ISBN 9780415025942. Retrieved 19 August 2012. 
    9. ^ Jump up to: a b Harris, Charles Reginald Schiller (1973). The heart and the vascular system in ancient Greek medicine, from Alcmaeon to Galen. Clarendon Press. Retrieved 19 August 2012. 
    10. ^ Jump up to: a b c Magill, Frank N. (2003-01-23). Dictionary of World Biography: The Ancient World. Taylor & Francis. ISBN 9781579580407. Retrieved 23 August 2012. 
    11. Jump up ^ Carrick, Paul (2001). Medical Ethics in the Ancient World. Georgetown University Press. ISBN 9780878408498. Retrieved 19 August 2012. 
    12. Jump up ^ Traver, Andrew G. (2002). From Polis to Empire, the Ancient World, C. 800 B.C.-A.D. 500: A Biographical Dictionary. Greenwood Publishing Group. ISBN 9780313309427. Retrieved 19 October 2012. 
    13. ^ Jump up to: a b c d e f g Nutton, Dr Vivia (2005-07-19). Ancient Medicine. Taylor & Francis US. ISBN 9780415368483. Retrieved 19 August 2012. 
    14. Jump up ^ Philip II of Macedonia: Greater Than Alexander by Richard A. Gabriel, 2010, pg. 10
    15. Jump up ^ Adler, Robert E. (2004-03-29). Medical Firsts: From Hippocrates to the Human Genome. Wiley. ISBN 9780471401759. Retrieved 16 May 2014. 
    16. Jump up ^ Celsus, Aulus Cornelius (1837). The first four books of Aur. Corn. Celsus de re medica, with an ordo verborum and tr. by J. Steggall. Retrieved 10 October 2014. 
    17. ^ Jump up to: a b c d e f g h Durant, Will (March 1993). The Age of Faith: A History of Medieval Civilization-Christian, Islamic, and Judaic-From Constantine to Dante: A.D. 325-1300. Fine Communications. ISBN 9781567310153. Retrieved 9 September 2012. 
    18. ^ Jump up to: a b c d e f g h i j Loudon, Irvine (2002-03-07). Western Medicine: An Illustrated History. Oxford University Press. ISBN 9780199248131. Retrieved 29 August 2012. 
    19. ^ Jump up to: a b c d e f g h Prioreschi, Plinio (2001). A History of Medicine: Byzantine and Islamic medicine. Horatius Press. ISBN 9781888456042. Retrieved 10 September 2012. 
    20. Jump up ^ Prioreschi, Plinio (1996). A History of Medicine: Medieval Medicine. Edwin Mellen Press. ISBN 9781888456059. Retrieved 28 December 2012. 
    21. Jump up ^ Getz, Faye (1998-11-02). Medicine in the English Middle Ages. Princeton University Press. ISBN 9781400822676. Retrieved 2 April 2015. 
    22. Jump up ^ Albala, Ken (2002). Eating Right in the Renaissance. University of California Press. ISBN 9780520927285. Retrieved 18 December 2013. 
    23. ^ Jump up to: a b Russell, Gül. "GREECE x. GREEK MEDICINE IN PERSIA – Encyclopaedia Iranica". Retrieved 19 May 2013. 
    24. Jump up ^ Athens.), Stephanus (of; Dickson, Keith M. (1998). Stephanus the Philosopher and Physician: Commentary on Galen's Therapeutics to Glaucon. BRILL. ISBN 9789004109353. Retrieved 9 December 2012. 
    25. Jump up ^ Riggs, Christina (2012-06-21). The Oxford Handbook of Roman Egypt. Oxford University Press. pp. 311–312. ISBN 9780191626333. Retrieved 10 October 2014. 
    26. Jump up ^ Pormann, P. E. (2004). The Oriental Tradition of Paul of Aegina's "Pragmateia". BRILL. ISBN 9789004137578. Retrieved 19 May 2013. 
    27. Jump up ^ Selin, Helaine, ed. (1997). Encyclopaedia of the history of science, technology and medicine in non-western cultures. Kluwer. p. 930. ISBN 0-7923-4066-3
    28. Jump up ^ David W. Tschanz, PhD (2003), "Arab Roots of European Medicine", Heart Views 4 (2).
    29. Jump up ^ Graetz, Heinrich; Bloch, Philipp (1894). History of the Jews. Jewish Publication Society of America. Retrieved 30 October 2012. 
    30. Jump up ^ "Islamic Culture and the Medical Arts: Ophthalmology and Surgery". www.nlm.nih.gov. Retrieved 2015-12-07. 
    31. Jump up ^ Schulman, Jana K. (2002). The Rise of the Medieval World, 500-1300: A Biographical Dictionary. Greenwood Publishing Group. ISBN 9780313308178. Retrieved 19 October 2012. 
    32. Jump up ^ Howells, John G.; Osborn, M. Livia (1984). A Reference Companion to the History of Abnormal Psychology. Greenwood Press. ISBN 9780313221835. Retrieved 30 October 2012. 
    33. Jump up ^ O'Leary, De Lacy (1939). Arabic Thought and Its Place in History. Forgotten Books. ISBN 9781605066943. Retrieved 5 September 2012. 
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    References[edit]

    • Bynum, W. F. and Roy Porter, eds. Companion Encyclopedia of the History of Medicine (2 vol. 1997); 1840pp; 72 long essays by scholars excerpt and text search
    • Conrad, Lawrence I. et al. The Western Medical Tradition: 800 BC to AD 1800 (1995); excerpt and text search
    • Loudon, Irvine, ed. Western Medicine: An Illustrated History (1997) online
    • McGrew, Roderick. Encyclopedia of Medical History (1985)
    • Porter, Roy (1997). The Greatest Benefit to Mankind: A Medical History of Humanity from Antiquity to the Present. Harper Collins. ISBN 0-00-215173-1
    • Porter, Roy, ed. The Cambridge History of Medicine (2006); 416pp; excerpt and text search
    • Singer, Charles, and E. Ashworth Underwood. A Short History of Medicine (2nd ed. 1962)
    • Watts, Sheldon. Disease and Medicine in World History (2003), 166pp online

    Top 10 Greatest Medical Discoveries of All Times

    Drotumdi O

    By Adam Sinicki | Medicine | Rating:

    Science has never moved at such a rapid rate as it is now and as each discovery brings with it countless more developments, it stands to reason that our scientific understanding has ‘snowballed’ with time. So great are many of these developments in fact, and so much have they impacted our daily lifestyles, that it’s sometimes almost impossible to imagine a world before many of these breakthroughs. This is particularly true of medical discoveries, and while we might complain of long hospital waiting lists or the poor bedside manner of some of the nurses, we shouldn’t forget that only a few generations ago the same condition that is now an ‘irritation’ could have led to the loss of a limb... without anaesthetic.

    To celebrate these developments then, and to put things back in perspective somewhat, let’s look at ten of the most important medical discoveries of all time, and at how they have changed the world for the better. It leaves you wondering – what will the world be like in another hundred years?

    10) Vitamins – The discovery of vitamins by Frederick Hopkins and contemporaries, accomplished through feeding studies using animals at the start of the 1900s, led to a far better understanding of nutrient and helped to prevent many illnesses and conditions that resulted from deficiencies.

    9) HIV – HIV was discovered in the 1980s by Robert Gallo and Luc Montagnier and following an influx of patients around the time. This discovery of course led to a greater awareness of the dangers of unprotected sex as well as to the various treatments that exist today to make the condition manageable.

    8) The Circulatory System – The concept of the circulatory system was first described in 1242 by the physician Ibn al-Nafis, and first brought to prominence in 1628 by William Harvey. This led to a far better understanding of the human body in general and to many of the treatments and techniques we now take for granted.

    7) X-Ray – Before x-rays repairing broken bones and identifying the cause of many other problems would have been hugely more difficult and has played a role in colouring our understanding of the human body even further. When Conrad Rontgen first discovered the technique in 1895 he used it to create an image of his wife’s hand.

    6) DNA – DNA was discovered by the Swiss physician Friedrich Miescher and was at first known as ‘nuclein’ (what was wrong with that name?). This has led to a much better understanding of a range of diseases and illnesses, but is likely to lead to many more discoveries in the future as gene therapy becomes more widely used. Of course the discovery of DNA has also lead to many important discussions on the nature of humanity and our role in our own evolution.

    5) Insulin – Before the discovery of the hormone insulin in 1920 by Frederick Banting, diabetes was a condition that would lead to a slow and unpleasant death. Today, thanks to this finding, most diabetic patients manage to live normal and full lives which has affected the lives of millions of people around the world.

    4) Anaesthetic – If you ever had to have an operation without any form of anaesthetic then you would likely have a whole new appreciation for just how important this discovery was. Before anaesthetic you had a rope to bite into and a shot of vodka...

    3) Germ Theory – While we’ll get to penicillin soon enough, it wouldn’t have been possible with Louis Pasteur’s initial ‘germ theory’ which shed light on the causes of diseases and lead to many of the hygiene practices we now take for granted.

    2) Vaccination – Originally in the Western World the concept of vaccination – using small doses of disease to teach the body to protect itself from certain viruses – was a controversial one. However it is only thanks to vaccinations that we have managed to stop the spread of many epidemics and even completely eradicate some of the world’s most deadly diseases.

    1) Penicillin – Discovered by Alexander Fleming in 1928, this is the one that everyone learns about in school, and was the big ‘game changer’ for modern medicine. Essentially the discovery of penicillin is responsible for the development of all the antibiotics that we use today to combat bacteria. Before that, if you got a cut on your leg and it became infected you would have had to choose between death or amputation...

    10 Health Advances That Changed The World

    Drotumdi O

     

    • By Dan Childs

    • SUSAN KANSAGRA

    • M.D.

    • ABC NEWS MEDICAL UNIT

    Sept. 20, 2007

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    Whether it's the technology that allows us to peer deep into the body or medicines that extend the lives of those with chronic diseases, it's easy to see how advances in health and medicine have touched the lives of nearly every person on the planet.

    Yet considering the ubiquitous nature of these developments, it is easy to see how many people take for granted the technologies and practices that, at one point or another, almost certainly saved their own lives or the lives of people they've loved.

    The list below encompasses 10 advances in health and medical practices that have changed -- and in many ways continue to change -- the world today.

     

    Vaccines

    Throughout history, communicable diseases have had a tremendous impact on human history. So too, then, has the development of one of the most effective ways to defend against rampant viral infection -- vaccination.

    Dr. Edward Jenner first introduced the idea of vaccinations in 1796, when he successfully prevented a young English boy from getting smallpox.

    The concept of vaccination was propelled further by scientists such as Louis Pasteur, and in the modern era, when large groups of soldiers were successfully vaccinated in World War I and II against such diseases as tetanus, diphtheria and typhus.

    "Polio vaccine is one that people think of because it had such an impact," said Dr. Jeffrey Baker, director of the history of medicine program at the Duke University School of Medicine.

    But from the global health standpoint, Baker said Jenner's introduction of the smallpox vaccine may have had an even more significant impact in terms of lives saved.

     

    Surgical Anesthetic and Antisepsis

    Without a doubt, surgery used to be a much graver proposition than it is today. One of the chief reasons for this is that before the middle of the 19th century, anesthetic simply wasn't an option.

    That changed Oct. 16, 1846, when William T.G. Morton demonstrated the mysterious wonder of ether -- a substance powerful enough to dull the pain and agony that had long been associated with surgery.

    But while anesthetic was a great advance in and of itself, another advance that occurred at roughly the same time may have been even more beneficial -- antisepsis, or the creation of a sterile surgical environment.

    "Anesthetic made it possible to operate on a patient without pain," Baker notes, "but without antisepsis they'd die anyway."

     

    Clean Water and Improved Sanitation

    Put them beside surgical advances and other cutting-edge technologies, and public health measures don't look so sexy. But the fact is that clean water and sanitation have likely saved millions -- perhaps billions -- of lives since they were widely implemented in the 19th and 20th centuries.

    "It's something that's so important around the world and in America," Baker said. "It used to be that 15 percent of infants would die, and the biggest reason for this was diarrhea brought about by unclean water and milk."

    Clean water and public health measures dramatically cut down the incidence of such deadly water-borne diseases as cholera and improved sanitation, drastically lowering the health impacts of parasitic infections and other health conditions related to the environment.

     

    Antibiotics and Antivirals

    As with vaccination, the advent of antibiotics hailed a new era in the treatment of communicable disease.

    Interesting, then, that the concept of antibiotics may have been uncovered accidentally. In 1928, Sir Alexander Fleming left a petri dish of Staphylococci bacteria uncovered and later noted that the bacteria had been killed by a mold.

    Upon further studying the mold, he discovered it was from a family called Penicillium notatum. Others soon saw the potential uses of what later came to be known as penicillin.

    Today, antibiotics are used to treat a plethora of bacterial illnesses. And today, researchers are developing antivirals -- most notably, the AIDS-fighting antiviral AZT -- to deal with a host of viral illnesses as well.

     

    The Birth Control Pill

    Arguably, few developments have had as profound a social impact as the introduction of the birth control pill -- though its path to widespread use has been a rocky one.

    Although the Federal Drug Administration approved contraception as safe in the early 1960s, it only became legal for married couples in 1965 and for unmarried couples in 1972.

    But because of the Pill, countless women have been given control over their own fertility -- a concept that created a social revolution.

    "Thinking about how it has transformed women's lives, in terms of family planning and the entry of women into the work force, its impact has been significant indeed," Baker said. "It was the first-ever lifestyle drug. It's not treating a disease, but it was making life better for women."

     

    Improvements in Heart Surgery and Cardiac Care

    Heart disease remains at the top of the list of the country's killers. Despite this, numerous important advances in its treatment have made a considerable impact, extending and improving the lives of its sufferers.

    Not the least of these advancements is surgeons' ability to operate on and repair the heart -- without putting the patient at an unreasonable amount of risk.

    "Maybe the breakthrough moment was the rise of the heart-lung bypass, which made it possible to operate on the heart for more than just a few minutes at a time," Baker said. "This was followed by coronary artery bypass grafting, which is, I believe, a most important procedure."

     

    Randomized Controlled Trials

    Another development largely unnoticed by the public at large, the advent of the randomized controlled trial -- what many refer to as the gold standard of medical research -- gave medical researchers an important tool in determining which treatments work, and which do not.

    Randomized trials are conducted by dividing patient populations into two groups, where one group receives the intervention to be studied while the other does not. Examining the differences between groups in these types of trials has ushered in an era of evidence-based medicine that continues to guide clinical practice on a daily basis.

    "I think this is huge," Baker said. "This is really what's changed how we deal with cancer and lots of other disease, too. In the future we'll look back at this as a huge step forward."

     

    Radiologic Imaging

    Before the development of radiologic imaging technologies, beginning with the use of the X-ray, doctors were usually relegated to looking only for external signs of injury or damage.

    Today, the ability to peer inside the body and determine the cause, extent, or presence of disease has revolutionized the very way medicine operates and has saved countless lives in the process.

    Much of the initial work surrounding the discovery of X-rays was done by Roentgen, a German physicist in the late 1800s. Initially, they were viewed as an invasion of privacy rather than a life-saving tool.

    Its utility was soon realized, however, and many additional imaging technologies eventually followed.

    "CT scans didn't come into the picture until the 1970s," Baker said, adding that this technology was brought to us by the company BMI -- the same BMI which had previously made a fortune off the British band known as the Beatles.

     

    Advancements in Childbirth

    Up until the middle of the 20th century in the United States, childbirth was considered to be the most feared part of a woman's life.

    "Go into any old graveyard, and you always see a number of women who died in their 20s," Baker said. "That was in a large part due to childbirth."

    With the advent of techniques in anesthesia, cesarean section, and forceps delivery, the chances of a successful have pregnancy improved, at least in developed countries. Unfortunately, many resource-poor societies around the world still lag behind in this arena.

     

    Organ Transplantation

    Few surgical interventions today carry as much complexity -- or as much ethical significance -- as organ transplantation.

    "It's such a technically complex intervention that it's an amazing thing that it can even be done," Baker said. "It ties together both surgery and immunology."

    The first successful transplant operation, which took place in 1954, removed a kidney from one donor and installed it in the body of his identical twin. Other organ transplants followed, including the first liver transplant in 1967 and the first heart transplant in 1968.

    Today, there are more than 90,000 people awaiting a transplant in the United States alone -- a situation that also reveals the moral considerations that come entwined with such techniques.

    "It represented an important turning point in the field of medical ethics," Baker said. "It really challenged physicians' ethic of 'first, do no harm.'"

     

    What's Next?

    Considering the progress that has been made in years past, it is tempting to view the state of health and medicine today as an endpoint.

    "Medicine has made it possible to deal with many conditions," Baker said. "Our lives are longer. Still, we have to say in all honesty that our control over chronic diseases is somewhat mixed."

    Additional research into how best to stave off these conditions -- even by delving into the secrets of the human genome -- could represent the next hopeful steps toward healthier, longer lives.

    "In the future, I think we will begin to see more and more applications from genomic medicine, which will help us identify individuals at risk for chronic diseases and allow us to intervene earlier," Baker said.

    Trial of Solanezumab for Mild Dementia Due to Alzheimer’s Disease

    Drotumdi O

    Teaching Topic

    Solanezumab for Alzheimer’s Disease

    ORIGINAL ARTICLE

    Trial of Solanezumab for Mild Dementia Due to Alzheimer’s Disease

    L.S. Honig and Others

        

     

    Honig et al. conducted a randomized, double-blind, phase 3 trial (EXPEDITION 3), which enrolled only patients who had mild Alzheimer’s disease, defined as a Mini–Mental State Examination score of 20 to 26 (on a scale from 0 to 30, with higher scores indicating better cognition), and had biomarker evidence of cerebral beta-amyloid deposition. Patients were randomly assigned to receive intravenous infusions of either solanezumab at a dose of 400 mg or placebo every 4 weeks for 76 weeks. This trial was intended to further investigate the secondary efficacy analyses from two earlier trials.

     

    Clinical Pearls

      What is the amyloid beta (Aβ) hypothesis regarding the pathogenesis of Alzheimer’s disease?

    The neuropathological hallmarks of Alzheimer’s disease include extracellular plaques containing amyloid beta (Aβ) and intracellular neurofibrillary tangles containing hyperphosphorylated tau protein, along with synaptic and neuronal losses. The Aβ hypothesis of the mechanism of Alzheimer’s disease proposes that early pathogenesis of the disease results from the overproduction of or reduced clearance of Aβ, leading to the formation of oligomers, fibrils, and neuritic Aβ plaques. Treatments that slow the production of Aβ or that increase the clearance of Aβ may slow the progression of Alzheimer’s disease.

      What is solanezumab?

    Solanezumab, a humanized immunoglobulin G1 monoclonal antibody that binds to the mid-domain of the Aβ peptide, was designed to increase clearance from the brain of soluble Aβ, peptides that may lead to toxic effects in the synapses at a stage before the deposition of the fibrillary form of the protein.

    Morning Report Questions

    Q. Is solanezumab effective in the treatment of mild Alzheimer’s disease?

    A. In the trial by Honig et al., the primary efficacy measure was the change from baseline to 80 weeks in the score on the 14-item cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-cog14; scores range from 0 to 90, with higher scores indicating greater cognitive impairment). The trial showed no significant between-group difference at week 80 in the change in score from baseline (change, 6.65 in the solanezumab group and 7.44 in the placebo group; difference, −0.80; P=0.10).

    Q. What are some possible explanations for the lack of benefit associated with solanezumab in the trial by Honig et al.?

    A. According to the authors, the solanezumab dose that was administered in this trial was associated with a high level of peripheral target engagement, sufficient to reduce free plasma Aβ concentrations by more than 90%. However, this effect did not produce clinical efficacy. Thus, a reduction in peripheral free Aβ alone is unlikely to lead to clinically meaningful cognitive benefits. Second, the dose of solanezumab (400 mg, administered every 4 weeks) may have been insufficient to produce a meaningful effect. Third, the pathological changes in the mild stage of Alzheimer’s disease–related dementia may not be amenable to treatment with a drug targeting soluble Aβ. Fourth, solanezumab was designed to increase the clearance of soluble Aβ from the brain, predicated on the Aβ hypothesis of Alzheimer’s disease — that the disease results from the overproduction of or reduced clearance of Aβ (or both). Although the amyloid hypothesis is based on considerable genetic and biomarker data, if amyloid is not the cause of the disease, solanezumab would not be expected to slow disease progression.