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Content 7


The Doctor and the Pharmacist

Radio Show Articles:
July 9, 2011

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Probiotic Therapy for UTIs: Are We Ready for Vaginal Supplements?
Salt Restriction: Updated Analysis Finds No Definite Proof of Benefit
Children: Stay Asleep and Stay Lean
Most Inpatients Do Not Require Acid Suppression
Sharps Injuries
Spinach and Seafood Excel as Eye Sun-Shields
OMG! Texting Doubles Smokers' Confirmed Quit Rates at 6 Months
Check the Pulse: Elevated Resting Heart Rate Is a Risk Factor for Elevated BP in Boys
Does the HbA1c Criterion for Prediabetes Predict Incident Diabetes?
Adding Exercise to Diet in Early Type 2 Diabetes
Most Online Pharmacies Illegal According to NABP
Ethics Left Behind as Drug Trials Soar in Developing Countries
Drug R&D Spending Fell 3% to $68 Billion in 2010 from $70 Billion in 2009 and
   2008 and May be Heading Lower
New Report Shows Dangerous Gap in Drug Safety Efforts; Senator Asks FDA
   to Tighten Oversight on PHARMA Outsourcing
Preterm Birth: When an Ounce of Prevention Is Too Expensive
Beta-Blockers as Breast Cancer Therapy?
Secondhand Smoke in the Brain
An Endorsement for Nitrofurantoin in UTI
Chantix Linked to Cardiovascular Events in Patients Free of CVD
Functional Dyspepsia Linked to Disordered Sleep
Developmental Pathway to Depression in Children of Mothers with Postpartum Depression
Is OCD an Anxiety Disorder?
Addicted to Compulsions
ASCEND-HF: Nesiritide (Natrecor®) Does Not Benefit Patients with Acute Heart Failure
Photoprotection for Infants and Children
Primary Care Physicians and the Quality and Cost of Medical Care
On the Horizon: Test to Predict Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis
Ulcerative Colitis: Should Mucosal Healing Be the Goal?
Predicting 30-Day Mortality After Colorectal Cancer Surgery

Clin Infect Dis 2011 May 15; 52:1212
Probiotic Therapy for UTIs: Are We Ready for Vaginal Supplements?
Lactobacillus-containing vaginal capsules lowered risk for recurrent urinary tract infections.
     More than half of U.S. women will experience at least one urinary tract infection (UTI) during their lives. Because traditional antibiotic therapy for UTIs might add to the burgeoning problem of resistance, interest in probiotics has grown. Normal vaginal flora is dominated by hydrogen peroxide (H2O2+)-producing lactobacilli that displace competitive pathogenic bacteria (particularly Escherichia coli). Can an H2O2+-producing vaginal probiotic prevent recurrent UTIs?
     In a trial that involved 100 women (median age, 21) with recurrent UTIs who were seen at the University of Washington student health center, investigators evaluated the efficacy of vaginal Lactobacillus crispatus (Lactin-V). Seven to 10 days after participants received standard antimicrobial therapy for acute treatment, they were randomized to L. crispatus vaginal suppositories (108 CFUs/mL) or placebo (self-administered once daily for 5 days, then once weekly for 10 weeks). At 1 and 10 weeks, participants were followed for UTIs; levels of L. crispatus colonization also were evaluated with quantitative polymerase chain reaction assay of vaginal swabs. High-level colonization was defined as ≥106 16S RNA gene copies per swab.
     Women in both groups had UTI-associated depletions in Lactobacillus colonization. At week 10, at least one UTI had occurred in 15% of L. crispatus recipients versus 27% of placebo recipients (relative risk, 0.5; 95% confidence interval, 0.2–1.2). High-level L. crispatus colonization was attained in 93% of L. crispatus recipients versus 68% of placebo recipients (P=0.004). Among women with high-level colonization, risk for recurrent UTI was lower in L. crispatus recipients (RR, 0.07) than in placebo recipients (RR, 1.1; P<0.01).
     Comment: The finding that a vaginal probiotic can lower risk for recurrent UTI is intriguing; however, one wonders why the high-level endogenous Lactobacillus crispatus repopulation in some placebo recipients was ineffective. The authors hypothesize that the L. crispatus isolate in Lactin-V might be better able to inhibit growth of pathogenic Escherichia coli. Given that adherence to therapy in the face of active infection often is difficult, I am skeptical that women will embrace this preventive strategy, even to avoid recurrent UTI.
Anne A. Moore, WHNP/ANP-BC, FAANP Published in Journal Watch Women's Health
June 30, 2011
     Citation(s):Stapleton AE et al. Randomized, placebo-controlled phase 2 trial of a Lactobacillus crispatus probiotic given intravaginally for prevention of recurrent urinary tract infection. Clin Infect Dis 2011 May 15; 52:1212.
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Salt Restriction: Updated Analysis Finds No Definite Proof of Benefit
     Reductions in dietary salt are not followed by reductions in all-cause mortality or cardiovascular events, according to an updated Cochrane meta-analysis in the American Journal of Hypertension.
     Researchers examined seven randomized, controlled trials encompassing some 6300 participants who either restricted salt intake or acted as controls. Studies included normotensives, hypertensives, mixed populations, and patients with heart failure.
     Salt reduction was associated with a mean decrease in systolic blood pressure between 1 and 4 mm Hg. Rates of mortality and cardiovascular events were not significantly lowered among normotensives or hypertensives. Patients with heart failure showed an increased risk for all-cause mortality after salt restriction.
     Although the authors say their findings are not inconsistent with "the belief that salt reduction is beneficial in normotensive and hypertensive people," they admit that their conclusions are hampered by the small amount of evidence. They call for rigorous research "capable of definitively demonstrating the [cardiovascular] benefit of dietary salt reduction."
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BMJ 2011 May 26; 342:d2712
Children: Stay Asleep and Stay Lean
In the first longitudinal study to measure sleep objectively, reduced sleep duration during early childhood increased risk for becoming overweight.
     Short sleep duration has been linked with increased risk for obesity in children. In a longitudinal study, researchers in New Zealand used objective measures of sleep and body composition to examine this association in 244 children (83% white) recruited from a birth cohort and followed from age 3 to 7 years.
     Sleep duration and physical activity were determined by accelerometer at ages 3, 4, and 5 years. Body-mass index (BMI), anthropometry, and body composition (fat mass and free fat mass measured by bioelectrical impedance and dual energy x-ray absorptiometry) were assessed annually. Children's dietary intake and maternal BMI, education, and smoking during pregnancy were assessed by questionnaire.
     In analysis adjusted for multiple confounders, each additional hour of sleep per night between ages 3 and 5 years was associated with a reduction in BMI of 0.48 and a 61% reduced risk for being overweight (BMI ≥85th percentile) at age 7 years. Weight gain resulted from increased fat deposition rather than accumulation of fat-free mass. Maternal factors and gestational smoking did not affect the results.
     Comment: This was the first longitudinal study to use objective measurements and demonstrate that young children who sleep less are at increased risk for becoming overweight. An editorialist cites sleep deprivation experiments suggesting that short sleep duration causes increased energy intake and reduced energy expenditure by activating leptin and ghrelin — leading to increased appetite, glucose intolerance, and insulin resistance. We should actively encourage parents to develop healthy sleep patterns in young children by educating them about factors associated with sleep latency (JW Pediatr Adolesc Med Aug 19 2009 and JW Pediatr Adolesc Med Apr 6 2011) and nighttime behaviors that promote sustained sleep (e.g., avoiding caffeine, creating a quiet home environment 1 hour before sleep, eliminating the television in a child's bedroom, taking a lukewarm bath, reading to the child in bed with only a reading light).
Martin T. Stein, MD Published in Journal Watch Pediatrics and Adolescent Medicine
July 6, 2011
     Citation(s):Carter PJ et al. Longitudinal analysis of sleep in relation to BMI and body fat in children: The FLAME study. BMJ 2011 May 26; 342:d2712. (http://dx.doi.org/10.1136/bmj.d2712)
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Arch Intern Med 2011 Jun 13; 171:991
Most Inpatients Do Not Require Acid Suppression
Although effective, such drugs are needed only for critically ill patients at risk for
upper GI bleeding.

     Severe physiological stress (multiorgan injury or failure, mechanical ventilation) is associated with stress-related mucosal disease and gastrointestinal bleeding (GIB). Acid suppression medication is often prescribed to prevent GIB in such patients; however, its use is sometimes expanded to lower-risk hospitalized patients but with unknown frequency and efficacy.
     To assess the frequency of nosocomial GIB outside the intensive care unit (ICU) and the use of acid suppression in hospitalized patients, investigators examined records of 78,394 patients admitted for at least 3 days to determine whether they had received acid suppression — defined as either a proton-pump inhibitor or histamine-2-receptor antagonist — or experienced gastrointestinal bleeding. Admissions with primary diagnoses of GIB or bleeding events in an ICU were excluded.
     Acid-reduction medication was dispensed during 59% of admissions, and 224 nosocomial bleeding episodes occurred (0.29%). Bleeding incidence was higher in patients receiving acid-reduction drugs than in those not receiving the drugs (0.33% vs. 0.22%; odds ratio, 1.53). However, after adjustment for comorbidities and prior history, patients who received acid suppressants were less likely to experience nosocomial bleeding (OR, 0.63). The number needed to treat (NNT) to prevent one episode of bleeding was 770.
     Comment: The authors suggest that nosocomial bleeding is rare outside ICUs and that the high NNT should dissuade clinicians from treating non–critically ill patients with acid-reduction drugs. Documented frequency of nosocomial GIB was low in non–critically ill patients and higher among patients given acid-reducing medications. Although the authors adjusted for confounders of preexisting indications using a propensity score (which reversed the association between exposure and outcome from positive to negative), residual confounding might still exist. The very large NNT is driven by the small number of patients who bled, not the magnitude of the effect of treatment. It is common sense to avoid unnecessary medications for any patient. Therefore, the conclusion that acid-reduction medication should not be given to patients without a clinical indication (more than the extremely small risk of nosocomial bleeding) is valid regardless of the relative risk reduction from treatment.
David J. Bjorkman, MD, MSPH (HSA), SM (Epid.) Published in Journal Watch Gastroenterology July 8, 2011
     Citation(s):Herzig SJ et al. Acid-suppressive medication use and the risk for nosocomial gastrointestinal tract bleeding. Arch Intern Med 2011 Jun 13; 171:991.
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Infect Control Hosp Epidemiol 2011 Jun; 32:538
Sharps Injuries
Prevention efforts have led to consistent decline in some — but not all — sharps injuries.
     Among healthcare workers, the greatest risk for bloodborne pathogen exposure comes from percutaneous injury by "sharp" devices such as hollow needles, suture needles, and scalpels. In 2001, the Occupational Health and Safety Administration mandated that healthcare institutions minimize these injuries through such measures as use of sharp devices with engineered sharps-injury (SI) protection, reduced use of sharp devices overall, and improved education; the efficacy of these measures has not been well studied. Now, using data from the Massachusetts Sharps Injury Surveillance System, researchers have examined SI incidence among workers at 76 acute care hospitals in Massachusetts from 2002 through 2007.
     During the study period, 16,158 SIs were reported (41% in nurses, 29% in physicians, 21% in technicians, 9% in other workers). The injuries occurred most frequently in operating and procedure rooms (41%), followed by inpatient units (23%); they happened most often during injection procedures (23%), blood procedures (19%), and suturing (19%). Fifty percent of the injuries occurred after device use (36% before disposal; 14% during or after disposal).
     The annual rate of SIs was 22% lower in 2007 than in 2002. Significant decreases in SI rate were seen for nurses but not physicians — and with the use of winged steel needles and hypodermic needles and syringes but not intravenous stylets or suture needles.
     Comment: These data show a clear benefit from SI-reduction efforts, although success has not been uniform in all areas. Further work is needed, particularly in preventing injury from suture needles and intravenous stylets.
Richard T. Ellison III, MD Published in Journal Watch Infectious Diseases June 8, 2011
     Citation(s):Laramie AK et al. Sharps injuries among employees of acute care hospitals in Massachusetts, 2002–2007. Infect Control Hosp Epidemiol 2011 Jun; 32:538.
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June 30, 2011
Spinach and Seafood Excel as Eye Sun-Shields
Two studies show that people who love the sun should favor diets rich in cooking greens, egg yolks, and fish  
by Craig Weatherby
     By now, it’s pretty clear that the omega-3 DHA in fish fat is very good for human vision ... for prior research, see “Omega-3s & Eye Health” in our news archive. This is in part because DHA is an essential component of the retina ... see our sidebar “Why your eyes need omega-3 DHA”, below. And the carotene-class “antioxidants” in egg yolks and dark, leafy greens – beta carotene, lutein (loo-teen), and zeaxanthin (zee-ah-zan-thin) – are also vital to both basic and optimal eye health.
      Recently, a study in Dutch people susceptible to macular degeneration found that those who ate higher levels of zinc, dark, leafy greens, or fish-type omega-3s – were one-third less likely to develop the disease (Ho L et al. 2011). Age-related macular degeneration accounts for half of all cases of blindness, and this vision-sapping erosion of the retina occurs in more than six out of every 100 American adults over 40. And as the Dutch research team wrote, “To achieve this benefit, it does not appear necessary to consume excessive amounts of these nutrients; the recommended dietary allowance will suffice.” (Ho L et al. 2011)
     (The U.S. recommended dietary allowance for zinc is 11mg for men and 8mg for women. Men and women alike are advised to consume at least 500 mg of omega-3 fatty acids (EPA + DHA) daily.)
     Good sources of zinc include oysters, red meat, nuts, and beans. Oily fish like salmon, tuna, and sardines are the best food sources of omega-3s, while beta carotene abounds in peppers (chili and bell), carrots, and sweet potatoes. Lutein and zeaxanthin are concentrated in egg yolks, dark green leafy vegetables (e.g., spinach, collard greens, kale, chard, turnip greens, broccoli, zucchini, and Brussels sprouts), and in whole yellow corn or cornmeal. Supplemental lutein is usually made from marigolds … which are also fed to many commercial chickens, to make their skin look more yellow and appealing in the meat case.

Lutein shines in summer eye protection study
      To judge by a Japanese study in mice, the apparent eye health benefits of lutein – a carotene-class compound concentrated in green leafy vegetables and egg yolk – may extend to protection against the damaging effects of strong light (Sasaki M et al. 2011). Findings published recently in the Journal of Nutritional Biochemistry showed that lutein may protect the DNA of “photoreceptor” cells in the retina from the harmful effects of strong light. Now, Japanese researchers report that visual impairment produced by strong light exposure was greatly reduced in mice fed supplemental lutein.
     For the new study the researchers divided mice into two groups and fed them different diets for 10 days before being exposed to strong light. Both were fed normal chow, but one group had chow supplemented with 0.1 percent lutein.
     The lutein group showed a smaller range of detrimental effects associated with light exposure, including less visual impairment, and less thinning of the layer of photoreceptor cells. In addition, the researchers note that a marker of DNA damage was up-regulated in the normal chow-fed animals, but not in the lutein-fed animals. Finally, DNA repair was increased in the lutein group, which also had less light-induced oxidative stress in the retina, and less light-induced visual impairment.
     So if you spend time in strong sun, be sure to get plenty of dark, leafy greens, egg yolks, and fish … it’s a wonderfully tasty “prescription” for eye health that brings many other health benefits.
     Sources: Ho L, van Leeuwen R, Witteman JC, van Duijn CM, Uitterlinden AG, Hofman A, de Jong PT, Vingerling JR, Klaver CC. Reducing the Genetic Risk of Age-Related Macular Degeneration With Dietary Antioxidants, Zinc, and {omega}-3 Fatty Acids: The Rotterdam Study. Arch Ophthalmol. 2011 Jun;129(6):758-66.
Sasaki M, Yuki K, Kurihara T, Miyake S, Noda K, Kobayashi S, Ishida S, Tsubota K, Ozawa Y. Biological role of lutein in the light-induced retinal degeneration. J Nutr Biochem. 2011 Jun 8. [Epub ahead of print]
Thomson LR, Toyoda Y, Delori FC, Garnett KM, Wong ZY, Nichols CR, Cheng KM, Craft NE, Dorey CK. Long term dietary supplementation with zeaxanthin reduces photoreceptor death in light-damaged Japanese quail. Exp Eye Res. 2002 Nov;75(5):529-42.
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OMG! Texting Doubles Smokers' Confirmed Quit Rates at 6 Months
     Texting motivational messages to people trying to quit smoking doubles their biochemically confirmed quit rates, compared with a control intervention of messages unrelated to smoking, according to a Lancet study.
     Some 5800 patients seeking to quit smoking were randomized to receive either motivational text messages (the txt2stop group) or messages simply thanking them for participating in the trial (the controls). Motivational messages reminded participants of the benefits of quitting, and participants could text "crave" to the system to receive support in overcoming temptations to smoke.
     At 6 months, the txt2stop group had a 10.7% rate of biochemically confirmed abstinence, versus 4.9% in controls.
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J Pediatr 2011 Apr; 158:634.
Check the Pulse: Elevated Resting Heart Rate Is a Risk Factor
for Elevated BP in Boys

In an observational study, elevated resting heart rate was significantly associated with high blood pressure — independent of obesity — in male children and adolescents.
     Elevated resting heart rate is an independent risk factor for cardiovascular disease in healthy adults, but what is the association in children? Researchers in Brazil conducted a cross-sectional study of 358 healthy male children and adolescents (age range, 8–18 years; 65% white) who were not taking any medications. Resting heart rate (2 measurements after 5 minutes of rest in a sitting position), blood pressure (BP; 2 electronic measurements), and body fat (dual-energy x-ray absorptiometry % body fat) were measured using a strict protocol. Elevated BP was defined as the 95th percentile of the 2004 National High Blood Pressure Education Program cutoffs, adjusted for age and height.
     Among participants with resting heart rates ≥86 beats/minute, 42% exhibited elevated BP. Among participants with resting heart rates <70 beats/minute, only 15% had elevated BP. As expected, body fat was significantly associated with systolic and diastolic BP. The association between heart rate and BP was independent of obesity, age, and ethnicity.
     Comment: This study confirms an association between elevated resting heart rate and high blood pressure in a pediatric population. Surprisingly, the association was independent of obesity, ethnicity, and age. Therefore, the results suggest that measurement of resting heart rate in children and adolescents can provide insight into a child's future cardiovascular health, regardless of body fat. Clinicians should offer anticipatory guidance about the positive effects of ongoing exercise in lowering cardiovascular risk over time.
— Louis M. Bell, MD Dr. Bell is a Professor of Pediatrics at the University of Pennsylvania School of Medicine; Chief, Division of General Pediatrics; and Associate Chair for Clinical Activities at The Children's Hospital of Philadelphia.
Published in Journal Watch Pediatrics and Adolescent Medicine June 8, 2011
     Citation(s): Fernandes RA et al. Resting heart rate is associated with blood pressure in male children and adolescents. J Pediatr 2011 Apr; 158:634.
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Lancet 2011 Jun 25
Does the HbA1c Criterion for Prediabetes Predict Incident Diabetes?
Measuring both fasting glucose and glycosylated hemoglobin levels might be the best method.
     The American Diabetes Association recently added a new criterion for diagnosis of prediabetes — glycosylated hemoglobin (HbA1c) level of 5.7% to 6.4%. To evaluate this new criterion, Japanese investigators studied 6241 people who had five or six consecutive annual health examinations that included measurements of fasting glucose and HbA1c levels.
     At their baseline examinations, 2092 patients were identified as prediabetic: 60% by impaired fasting glucose (IFG; 100–125 mg/dL) alone, 20% by HbA1c alone, and 20% by both tests. During a mean 4.7-year follow-up, 338 patients progressed to diabetes, of whom 292 (86%) had been identified as prediabetic at baseline: 32% by IFG alone, 9% by HbA1c alone, and 46% by both tests. Both IFG alone and HbA1c alone predicted incident diabetes equally strongly, with multivariate-adjusted hazard ratios of about 6, compared with that for baseline normoglycemia. Patients who were prediabetic by both criteria at baseline were 32 times more likely to progress to diabetes than those who were normoglycemic.
     Comment: These results are similar to those from a U.S. data set (Diabetes Care 2010; 33:2190). Impaired fasting glucose and HbA1c measure different aspects of dysglycemia and, together, provide more sensitive and specific prediction of excess risk for diabetes than does either one alone. However, whether this accuracy improves clinically meaningful long-term outcomes remains unclear.
Bruce Soloway, MD Published in Journal Watch General Medicine July 7, 2011
     Citation(s):Heianza Y et al. HbA1c 5·7–6·4% and impaired fasting plasma glucose for diagnosis of prediabetes and risk of progression to diabetes in Japan (TOPICS 3): A longitudinal cohort study. Lancet 2011 Jun 25; [e-pub ahead of print]. (http://dx.doi.org/10.1016/S0140-6736(11)60472-8)
Misra A and Garg S. HbA1c and blood glucose for the diagnosis of diabetes. Lancet 2011 Jun 25; [e-pub ahead of print]. (http://dx.doi.org/10.1016/S0140-6736(11)60789-7)
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Lancet 2011 Jun 25
Adding Exercise to Diet in Early Type 2 Diabetes
Brisk walking, added to intensive dietary intervention, did not result in additional lowering of glycosylated hemoglobin.
     International consensus guidelines recommend that initial treatment of patients with diabetes include dietary management and increased exercise, but few studies have addressed long-term benefits of these interventions in early type 2 diabetes.
     U.K. researchers randomized 593 adults with recently diagnosed diabetes to usual care (standard advice on diet and exercise every 6 months), an intensive diet intervention (goal-oriented motivational dietary consultation every 3 months with monthly nurse support), or an intensive diet intervention plus an exercise intervention (30 minutes of brisk pedometer-monitored walking 5 times weekly). Medications were adjusted by doctors who were blinded to study allocation.
     After 12 months, mean glycosylated hemoglobin (HbA1c) levels rose by 0.06% in the usual-care group and fell by 0.26% in the diet-only group and by 0.21% in the diet-plus-exercise group. HbA1c changes in both intervention groups differed significantly from that in the usual-care group but not from each other. The interventions had no effect on blood pressure. The two intervention groups had similar and significant mean improvements in weight, waist and hip circumferences, and insulin resistance, compared with the usual-care group.
     Comment: The authors conclude that limited resources would be better applied to intensified dietary interventions than to added exercise interventions in patients with early type 2 diabetes. But these researchers did not examine the effects of an exercise intervention alone, and this exercise intervention might not have been sufficiently intense or optimally designed or timed for maximal effectiveness.
Bruce Soloway, MD Published in Journal Watch General Medicine July 7, 2011
     Citation(s):Andrews RC et al. Diet or diet plus physical activity versus usual care in patients with newly diagnosed type 2 diabetes: The Early ACTID randomised controlled trial. Lancet 2011 Jun 25; [e-pub ahead of print].
Hu FB. Diet and exercise for new-onset type 2 diabetes? Lancet 2011 Jun 25; [e-pub ahead of print]. (http://dx.doi.org/10.1016/S0140-6736(11)60692-2)
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Most Online Pharmacies Illegal According to NABP
     Over 96% of online pharmacies operate illegally, according to data presented by NABP at a June briefing in the Senate Visitor Center at the U.S. Capitol in Washington, DC.  The NABP Internet Drug Outlet Identification Program had reviewed 8,207 online pharmacy websites, and of these websites, they identified 7,890 sites as acting in conflict with pharmacy laws and practice standards.
     An FDA spokesperson said “These are not pharmacists.  These people who are selling the drugs over the Internet from these sites don’t know anything about pharmacy.  They just want to make a buck.  They don’t care about the patient that is going to be receiving these products.”
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Ethics Left Behind as Drug Trials Soar in Developing Countries
     By 2008, the number of clinical trials conducted in developing countries had tripled.  However, the legal and ethical framework to make them fair is often not in place, the 7th World Conference of Science Journalists, in Qatar, heard recently.
     For PHARMA, the attractions are the lower costs and the availability of “treatment-naive” patients, who are much less likely to have been previously exposed to drugs or trials.
     Incentives for the developing countries include the promise of advanced medical science and access to the latest medications.  Problems include a less stringent ethical review, anticipated under-reporting of side effects, and the lower risk of litigation, all of which make carrying out research in the developing world less demanding.
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Drug R&D Spending Fell 3% to $68 Billion in 2010 from $70 Billion in 2009 and 2008 and May be Heading Lower
     Pharmaceutical research and development has experienced the first-ever decline.  It may become a trend that continues as Pfizer, and others, do more downsizing.  The overall expenditure on discovering and developing new medicines amounted to an estimated $68 billion last year, down nearly 3 percent on the $70 billion spent in both 2008 and 2009.
     The fall reflects a growing disillusionment with poor returns on pharmaceutical R&D.  Disappointing research productivity is arguably the biggest single factor behind the declining valuations of the sector over the past decade.  In the past, R&D laboratories have been largely immune to cost cutting; however, that has changed, and in recent months the pace of cutbacks has increased.  Pfizer has taken the most dramatic steps with plans to slash around a quarter of its R&D budget over the next two years; other companies have also made smaller cuts.  Decreasing research budgets represents a major change for an industry that has invested billions of dollars into the hunt for new drugs, often with little to show for it.
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New Report Shows Dangerous Gap in Drug Safety Efforts; Senator Asks FDA to Tighten Oversight on PHARMA Outsourcing
     For several years, Senator Sherrod Brown has been raising the flag on potential quality problems posed by outsourced manufacturing.  He is now calling on the FDA to look more closely at outsourcing APIs for drugs made at home.
     A new report has found that more than 80% of APIs are made abroad, mostly in plants rarely inspected by the FDA.  Outsourcing pharmaceutical ingredients results in outsourcing drug safety standards.  Brown said “It’s simply unacceptable to allow drug companies to skirt existing regulations by importing ingredients from countries with lax safety standards."
     Brown sent a letter to FDA Commissioner Margaret Hamburg citing all these things and posing some additional questions, including, “Have FDA inspectors ever denied access to foreign API plants and if so, could FDA bar the products from those plants?”
     The letter also hints at potential new rules, including the feasibility of charging fees when PHARMA companies move operations overseas to help pay for FDA inspections of those plants.  Senator Brown has previously introduced legislation to mandate a country-of-origin labeling requirement for pharmaceuticals.
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Obstet Gynecol 2011 Jun; 117:1408
Preterm Birth: When an Ounce of Prevention Is Too Expensive
The price of FDA-approved injectable 17-OHP has met with justifiable resistance.
     The search for preventive measures to lower risk for preterm birth has centered on progestins ever since, in 2003, injectable 17α-hydroxyprogesterone caproate (17-OHP) was shown to improve delivery outcomes in women with histories of preterm birth (JW Womens Health Aug 19 2003). Soon thereafter, use of supplemental progesterone became widespread — and, in the absence of an FDA-approved, commercially available product, most healthcare providers relied on compounding pharmacies to provide 17-OHP. The most widely used dose is 250 mg (intramuscular) weekly, which was the dose in the 2003 trial.
     The recent FDA approval of KV Pharmaceutical's 17-OHP (Makena) precipitated an even greater potential problem with access when KV announced its intention to price Makena at least 75 times higher than compounded 17-OHP. As a result, individuals, as well as professional societies and the academic community, called on the FDA to clarify its position on allowing compounding pharmacies to continue to produce 17-OHP; they also asked KV to rethink its pricing and have encouraged investigation of other progesterone formulations (some of which are already FDA-approved). These calls for action have elicited or coincided with several events:

     Comment: Providers of obstetric care to women at excess risk for spontaneous preterm birth remain in an unenviable position, at least for now. Rather than prescribe what many still consider to be an overpriced agent, options include using injectable progestin made by compounding pharmacies or using vaginal progestin. Although neither strategy is ideal, both approaches are supported by existing evidence and provide stop-gap measures until a more reasonably priced FDA-approved injectable formulation becomes available.
Allison Bryant, MD, MPH Published in Journal Watch Women's Health June 30, 2011
     Citation(s):Cohen AW et al. Unjustified increase in cost of care resulting from U.S. Food and Drug Administration approval of Makena (17α-hydroxyprogesterone caproate). Obstet Gynecol 2011 Jun; 117:1408.
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J Clin Oncol 2011 May 31
Beta-Blockers as Breast Cancer Therapy?
Two studies suggest beneficial effects on breast cancer recurrence and survival, but many questions remain.
     The search for novel cancer therapies extends to medications for unrelated illnesses when preclinical data suggest a biological rationale and epidemiologic observations suggest an anticancer effect. The therapeutic potential of beta-blockers (BBs) in this setting is supported by experiments showing that activation of β-adrenergic receptors on primary tumor and stromal cells can induce growth and metastatic dissemination of malignant cells. Moreover, BBs can hinder cell growth that arises from stress-associated activation of β-adrenergic receptors. Now, two research groups have asked whether BBs affect breast cancer recurrence and survival.
     In the first study, investigators retrospectively reviewed medical records of 1400 patients with triple-negative breast cancer (negative for estrogen receptors [ERs], progesterone receptors [PRs], and human epidermal growth factor receptor 2 [HER2]) who received neoadjuvant therapy. Outcomes of 102 patients who were also taking BBs (usually β1 antagonists) were compared with those of 1311 patients not taking BBs. Pathologic complete response rates did not differ between groups; however, analysis adjusted for confounders showed that BB use was associated with significantly better relapse-free survival (RFS; hazard ratio, 0.52; P=0.015) but not overall survival (OS). Among 377 patients with triple-negative breast cancer, BB use also was associated with improved RFS (HR, 0.30; P=0.027) but not OS.
     The second group analyzed Irish cancer registry and pharmacy data from women with stage I to IV breast cancer to evaluate outcomes in 70 patients who took propranolol (a β1/β2 antagonist) and 525 who took atenolol (a β1 antagonist) during the preceding year, compared with 4738 patients who did not take BBs. Women who took propranolol were much less likely to receive advanced breast cancer diagnoses (T4 tumors, N2/3 nodal disease, or metastatic involvement) than were nonusers. Long-term outcomes in propranolol users also were better: Five years after diagnosis, 9% of users had died of breast cancer, compared with 27% of nonusers. These beneficial effects were not seen in atenolol users.
     Comment: If these findings hold true, they imply that the course of breast cancer could be altered by taking a BB for only a few dollars per month. Intriguing as these observations are, however, our knowledge has too many gaps to suggest that BBs be prescribed to treat or prevent breast cancer. The two sets of results are discordant regarding subtype specificity of adrenergic receptor antagonists (β1 or β1/β2) that mediate anticancer effects. In addition, the second study was not sufficiently powered to determine whether the beneficial effects of BBs were restricted to certain biological subtypes of breast cancer. Also, an influence of other factors or concurrent medications cannot be ruled out. For now, BBs should be prescribed only for their noncancer indications.
William J. Gradishar, MD Published in Journal Watch Oncology and Hematology June 28, 2011
     Citation(s):Melhem-Bertrandt A et al. Beta-blocker use is associated with improved relapse-free survival in patients with triple-negative breast cancer. J Clin Oncol 2011 May 31; [e-pub ahead of print]. (http://dx.doi.org/10.1200/JCO.2010.33.4441)
Barron TI et al. Beta blockers and breast cancer mortality: A population-based study. J Clin Oncol 2011 May 31; [e-pub ahead of print]. (http://dx.doi.org/10.1200/JCO.2010.33.5422)
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Arch Gen Psychiatry 2011 May 2
Secondhand Smoke in the Brain
Secondhand smoke has measurable and detrimental behavioral and neurobiological effects.
     Imaging studies of cigarette smoking show 50% occupancy of the nicotinic acetylcholine receptor subtype α4β2* nAChR (plasma nicotine levels, 0.87 ng/mL). But what are the effects of exposure to secondhand smoke (SHS)? These researchers exposed 13 nonsmokers and 11 dependent smokers (mean age, 32) abstinent for 2 days (verified via exhaled carbon monoxide) to 1 hour of SHS inside a closed car. Pre- and postexposure, participants underwent positron emission tomography with a α4β2* nAChR ligand and provided plasma for testing of nicotine levels. Participants rated their SHS-related symptoms (e.g., running nose) and tobacco urges on analog scales.
     Postexposure occupancy of α4β2* nAChRs across thalamus, brainstem, and cerebellum was statistically similar in smokers and nonsmokers (19% and 18%). Postexposure nicotine levels were 0.37 ng/mL in smokers (increased from a baseline of 0.16 ng/mL) and 0.17 ng/mL in nonsmokers (undetectable at baseline). Symptoms after SHS exposure did not differ between groups; in smokers, however, cravings increased, and lower thalamic occupancy correlated with greater relief after smoking, which was permitted after scanning.
     Comment: Exposure to SHS has been linked to increased risk for smoking among teenagers. These findings delineate the biological basis for this phenomenon, including its effect on the urge to smoke, and underscore the need for intensified public health campaigns to reduce SHS exposure, especially in venues that families may not recognize (e.g., parks, street fairs). Hospital wards that use enclosed smoking areas to lessen in-patient smoking, including wards for patients with schizophrenia, which is associated with high smoking rates, may inadvertently enhance SHS exposure.
Barbara Geller, MD Published in Journal Watch Psychiatry June 6, 2011
     Citation(s):Brody AL et al. Effect of secondhand smoke on occupancy of nicotinic acetylcholine receptors in brain. Arch Gen Psychiatry 2011 May 2; [e-pub ahead of print]. (http://dx.doi.org/10.1001/archgenpsychiatry.2011.51)
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Mayo Clin Proc 2011 Jun; 86:480
An Endorsement for Nitrofurantoin in UTI
Prevalent resistance to other drugs makes this old standby a cost-effective alternative for urinary tract infections.
     Uncomplicated urinary tract infection (UTI) has become surprisingly complicated to treat in recent years because of growing prevalence of microbial resistance to trimethoprim-sulfamethoxazole (TMP-SMX) and quinolones. Many experts now propose resurrection of the venerable antibiotic nitrofurantoin as a first-line treatment for uncomplicated cystitis.
     Mayo Clinic researchers constructed a decision tree to analyze the costs of common empirical antibiotic choices for uncomplicated UTI at different community levels of drug resistance. The model included costs of the drugs and of complications such as requisite retreatment, development of pyelonephritis, and development of vaginal candidiasis.
     When 3-day courses of TMP-SMX or a fluoroquinolone were compared with a standard 5-day course of nitrofurantoin, the model indicated that nitrofurantoin became the most cost-effective option when the community's level of TMP-SMX resistance exceeded 17% and its quinolone resistance exceeded 12%. (Below these levels, the 3-day drug with the least resistance was favored.) Recent surveys indicate that TMP-SMX resistance exceeds 15% everywhere in the U.S. and exceeds 40% in some areas; fluoroquinolone resistance is as high as 20% in some regions.
     Comment: This is the second major shout-out for nitrofurantoin this year. Earlier, the Infectious Diseases Society of America endorsed it as a first-line treatment for cystitis (JW Infect Dis Feb 23 2011) not because of cost (pill for pill, the drug actually is more expensive than double-strength TMP-SMX) but for efficacy and ecology: Minimal resistance to this drug has developed among Enterobacteriaceae, and, because ingested drug largely stays in the urine, little resistance is likely to evolve. Clinicians should keep this old standby in mind. However, they also should remind themselves of its potential toxicity, which includes idiosyncratic pneumonitis and hemolysis in glucose-6-phosphate dehydrogenase–deficient patients; in addition, the drug is contraindicated when creatinine clearance is <60 mL/minute.
Abigail Zuger, MD Published in Journal Watch General Medicine July 5, 2011
     Citation(s): McKinnell JA et al. Nitrofurantoin compares favorably to recommended agents as empirical treatment of uncomplicated urinary tract infections in a decision and cost analysis. Mayo Clin Proc 2011 Jun; 86:480. (http://dx.doi.org/10.4065/mcp.2010.0800) http://www.ncbi.nlm.nih.gov/pubmed/21576512?dopt=Abstract
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Chantix Linked to Cardiovascular Events in Patients Free of CVD
     The smoking-cessation drug varenicline (Chantix) is associated with an increased risk for adverse cardiovascular events among smokers free of cardiovascular disease at baseline, according to a meta-analysis in the Canadian Medical Association Journal.
     Researchers analyzed data from 14 clinical trials comparing varenicline with placebo among some 8200 tobacco users. Varenicline users had a 72% increased risk for any ischemic or arrhythmic adverse cardiovascular event, compared with placebo users (absolute risk: 1.06% vs. 0.82%). The authors cite a published finding that 10 people would need to be treated with varenicline for one additional person to quit smoking, and they estimate that 28 would need to be treated for one person to experience a cardiovascular event.
     The article's senior author told the New York Times that varenicline should be pulled from the shelves: "I don't see how the FDA can leave Chantix on the market." The FDA had recently warned about increased cardiovascular risk among patients with existing cardiovascular disease.
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Clin Gastroenterol Hepatol 2011 May; 9:410
Functional Dyspepsia Linked to Disordered Sleep
But, the nature of the association remains unclear.
     Although gastroesophageal reflux disease (GERD) and irritable bowel syndrome have been associated with sleep disorders, a link between functional dyspepsia (FD) and sleep disorders has not been established.
     Now, investigators have examined the magnitude and extent of sleep disorders in 121 adults who met Rome III criteria for FD and 50 healthy controls without dyspepsia or potentially confounding comorbid conditions. Participants completed validated questionnaires about general health, depression, and sleep disorders.
     Mean scores for anxiety and depression were significantly higher for FD patients than controls. FD patients with moderate or severe symptoms had poorer sleep quality and insomnia index scores than did FD patients with mild symptoms or controls. Multivariate analysis showed that FD (odds ratio, 3.25; 95% confidence interval, 1.47–7.20) and female sex (OR, 2.36; 95% CI, 0.99–5.7) were independently associated with sleep disorders.
     Comment: The authors concluded that FD is associated with disordered sleep, particularly in patients with more-severe symptoms and higher levels of anxiety. However, it is difficult to determine whether a cause-and-effect relationship exists between FD and disordered sleep — or whether both are part of a broader symptom complex.
David J. Bjorkman, MD, MSPH (HSA), SM (Epid.)
Published in Journal Watch Gastroenterology June 17, 2011
     Citation(s): Lacy BE et al. Functional dyspepsia is associated with sleep disorders. Clin Gastroenterol Hepatol 2011 May; 9:410.
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MM: This brings up an interesting question. Since women who are supplemented with bio-identical progesterone during pregnancy seem to have smarter offspring and fewer problemps with post partum depression, is it possible that this could be a strategy to improve post-partum offspring insecurity as well?
J Am Acad Child Adolesc Psychiatry 2011 May; 50:460
Developmental Pathway to Depression in Children of Mothers with
Postpartum Depression

Insecure attachment in infancy and low ego resilience predict adolescent depression.
     Exposure to postnatal maternal depression is associated with increased risk for adolescent depression in offspring. Researchers in the U.K. prospectively examined the developmental risk pathway to adolescent depression in children of mothers with postnatal depression. They screened a community sample of 702 mothers with healthy full-term infants for depression at 6 weeks postpartum and conducted psychiatric interviews in probable cases and in a random sample of nondepressed mothers. Fifty-eight depressed mothers and 42 nondepressed mothers were recruited. Children were assessed for infant attachment at age 18 months, ego resilience at ages 5 and 8 years, and psychiatric diagnoses at ages 13 and 16 years (93% were assessed at age 16 years).
     Children of depressed mothers were significantly more likely to exhibit insecure (vs. secure) early attachment behavior and lower ego resilience than children of nondepressed mothers. At age 16 years, children of depressed mothers were significantly more likely than children of nondepressed mothers to have major depressive disorder or dysthymia (42% vs. 13%) or anxiety disorders (32% vs. 15%). Both insecure attachment at age 18 months and low resilience at age 8 years predicted adolescent depression. Using a complex statistical methodology of structural equation modeling, the authors determined that insecure infant attachment lowered childhood ego resilience, leading to adolescent depression.
     Comment: Pediatricians know about the early effects of postpartum maternal depression in young children. Infants who are not engaged with their mothers in normal contingent responsiveness (i.e., social play) are fussier, more withdrawn, less responsive, and smile less. The association between postnatal depression and subsequent insecure attachment behavior, diminished resilience, and adolescent depression demonstrated in this study highlights the importance of screening for postnatal maternal depression using either the Edinburgh Postnatal Depression Scale or by asking a few questions about mood, stress, and enjoyment of life (JW Pediatr Adolesc Med May 16 2007).
Martin T. Stein, MD Published in Journal Watch Pediatrics and Adolescent Medicine
June 15, 2011
     Citation(s): Murray L et al. Maternal postnatal depression and the development of depression in offspring up to 16 years of age. J Am Acad Child Adolesc Psychiatry 2011 May; 50:460.
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Psychol Med 2011 May 13;
Is OCD an Anxiety Disorder?
This analysis of family study data both indicates that the answer is affirmative and highlights common comorbidities.
     Experts have suggested removing obsessive-compulsive disorder (OCD) from the category of anxiety disorders in the next DSM edition (DSM-V), instead grouping it with other supposedly OCD-related conditions. These researchers analyzed large datasets from two OCD comorbidity and family studies to examine the evidence for this proposal.
     The researchers analyzed structured diagnostic interview data from the OCD Collaborative Genetics Study on 382 probands with OCD and 974 of their first-degree relatives and from the Johns Hopkins OCD Family Study on 73 non-OCD controls and 233 of their first-degree relatives. OCD probands with Tourette disorder were excluded.
     Compared with non-OCD controls, probands with OCD had significantly higher rates of all anxiety disorders, especially generalized anxiety disorder, panic disorder, and agoraphobia. Also strongly associated with OCD were obsessive-compulsive personality disorder, avoidant personality disorder, tic disorders, hypochondriasis, body dysmorphic disorder, trichotillomania, pathological skin picking, and unipolar depression (but not eating disorders, substance-use disorders, pathological gambling, kleptomania, and pyromania). In analyses comparing prevalence of these diagnoses in first-degree relatives of probands versus those of controls, the results were similar. The significance of the findings persisted when adjusted for demographic variables and probands' diagnoses. In relatives of OCD probands, the presence of OCD increased the prevalence of comorbid diagnoses.
     Comment: Because OCD is familial, primarily because of genetic factors, these data provide some support for a genetic relationship between OCD and other disorders. The findings support retaining OCD in the same category as the anxiety disorders in DSM-V, as well as including several other highly comorbid OCD-related disorders. In addition to its implications for diagnostic nosology, this study confirms that OCD often co-occurs with several conditions, which clinicians should look for in OCD patients.
Deborah Cowley, MD Published in Journal Watch Psychiatry June 13, 2011
     Citation(s):Bienvenu OJ et al. Is obsessive-compulsive disorder an anxiety disorder, and what, if any, are spectrum conditions? A family study perspective. Psychol Med 2011 May 13; [e-pub ahead of print]. (http://dx.doi.org/10.1017/S0033291711000742)
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Biol Psychiatry 2011 May 1
Addicted to Compulsions
An imaging study pinpoints differences in response speed and brain activations in reaction to reward stimuli in patients with obsessive-compulsive disorder.
     Obsessive-compulsive disorder (OCD) is frequently conceptualized as a failure of executive control over behavior-generating systems, resulting in anxiety generated by obsessions. This Dutch functional magnetic resonance imaging (fMRI) study of 18 OCD patients (11 with high-risk assessment obsessions; 7 with contamination obsessions) and 19 healthy controls illustrates an additional dimension — dependence on compulsive behavior because of defective reward processing.
     Study participants were given a task that involved responding to a cue that signaled either a monetary reward or no reward. All subjects reacted more rapidly to reward cues than to nonreward cues, but OCD patients were significantly slower than controls to respond to reward cues. At the same time, on fMRI, the OCD patients had substantially less activation of the bilateral nucleus accumbens and the left insula in anticipation of reward, especially in the patients with prominent contamination fears. No fMRI differences were found after receipt of the reward.
     Comment: The nucleus accumbens is part of the reward-processing system in the ventral striatum. These results suggest that in OCD, this system is less activated by normally rewarding stimuli, at least in patients with contamination fears. The investigators theorize that because normal rewards are less reinforcing to these patients, their reward systems may become more responsive to the relief of reduced anxiety afforded by acting on compulsions, and patients come to depend on this reward. In this sense, compulsions may become addicting. A treatment model that takes into consideration the preference for frequently repeated behaviors that make patients feel good temporarily might be added to traditional therapies for OCD.
Steven Dubovsky, MD Published in Journal Watch Psychiatry June 6, 2011
     Citation(s):Figee M et al. Dysfunctional reward circuitry in obsessive-compulsive disorder. Biol Psychiatry 2011 May 1; 69:867.
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N Engl J Med 2011 Jul 7; 365:32.
ASCEND-HF: Nesiritide (Natrecor®) Does Not Benefit Patients with
Acute Heart Failure

Rapid approval of the drug for early symptom relief has proven to be unjustified.
     Many drugs are introduced into practice with scant information about their effects on patient outcomes. Nesiritide (Natrecor® by J&J), a recombinant B-type natiuretic peptide, was approved by the FDA in 2001 for acute heart failure (HF) based on studies showing that it reduced pulmonary-capillary wedge pressure and symptoms after a few hours of treatment. In 2005, after pooled-study analyses, questions were raised about risks associated with the drug. In response, ASCEND-HF, an industry-sponsored trial, was launched to determine the effects of nesiritide on dyspnea, HF readmission, death, and renal function. Investigators randomized 7141 patients hospitalized with acute HF to receive nesiritide or placebo for 24 to 168 hours. The co-primary endpoints were change in dyspnea at 6 and 24 hours and the composite of rehospitalization for HF and death at 30 days.
     Neither primary endpoint differed significantly between the two groups. Thirty-day incidences of clinical outcomes with nesiritide compared with placebo were:

     Comment: The authors of this trial state unequivocally that nesiritide cannot be recommended in the broad population of patients with heart failure. The findings indicate that nesiritide has provided no clear benefit — and may have increased the risk for hypotension — in many of the patients who received it. This study clearly demonstrates the importance of testing the effects of new drugs on patient outcomes before approving them for clinical use.
Harlan M. Krumholz, MD, SM Published in Journal Watch Cardiology July 6, 2011
     Citation(s):O'Connor CM et al. Effect of nesiritide in patients with acute decompensated heart failure. N Engl J Med 2011 Jul 7; 365:32.
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Pediatrics 2011 Jun 6
Photoprotection for Infants and Children
The skin's barrier protection is not fully developed in the first years of life, and UV-induced skin changes begin early.
     Recommendations for photoprotection are part of clinical practice. This is particularly important for infants and young children, and special issues pertaining to this age group are the subject of a recent review. Infants (<1 year of age) and toddlers (1–3 years of age) have less endogenous protection against ultraviolet (UV) radiation than adults; their skin contains less melanin; and the stratum corneum of the epidermis is thinner. Studies in infants who have been carefully protected from recreational sun exposure but not from incidental UV exposure (e.g., inside a car, in the shade, or on a cloudy day) demonstrate seasonal differences in the pigmentation of the outer, but not the inner, aspect of the arms, indicating that even incidental sun exposure can affect the skin. The importance of early sun protection can also be construed from genetic changes in nevi. Sun exposure early in life is associated with increased numbers of pigmented nevi, which contain genetic mutations different from those found in congenital nevi.
     Although meticulous sun-protective practices have been endorsed by the American Academy of Pediatrics (AAP) and the American Academy of Dermatology, implementation by parents is less than ideal. Between 29% and 83% of children develop sunburn each summer. Because of their higher surface-area-to-body-mass ratio, greater susceptibility to percutaneous absorption, and differences in metabolism of sunscreen products, sun avoidance is the preferred method of photoprotection in this age group. However, the AAP has suggested that small amounts of sunscreen with an SPF of 15 or higher can be applied to small areas of skin (e.g., face, back of hands) of children younger than 1 year, when adequate clothing and shade are unavailable. Care must be taken to use sunscreens that are nonirritating to the skin and eyes. Inorganic filters such as zinc oxide and titanium dioxide do not penetrate beyond the first two layers of the stratum corneum, and tend to be less irritating, and therefore may be the preferred form of sunscreen for infants.
     Comment: The incidence of skin cancer continues to increase, occurring in ever younger age groups. UV radiation exposure during the first year of life can have especially damaging long-term effects. Pediatricians and dermatologists have the opportunity to reinforce sun-protective behaviors to children and their parents during periodic check-ups, and this should begin during the first year of life.
Craig A. Elmets, MD Published in Journal Watch Dermatology July 8, 2011
     Citation(s):Paller AS et al. New insights about infant and toddler skin: Implications for sun protection. Pediatrics 2011 Jun 6; [e-pub ahead of print]. (http://dx.doi.org/10.1542/peds.2010-1079). http://pediatrics.aappublications.org/content/128/1/92.abstract#aff-1
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JAMA 2011 May 25; 305:2096
Primary Care Physicians and the Quality and Cost of Medical Care
When PCPs are plentiful, quality is better.
     The role of primary care physicians has become central to the healthcare reform debate. In most previous studies, greater availability of primary care physicians has resulted in better care and lower cost, but the methodological issues are complex.
     Researchers evaluated health outcomes for 5 million fee-for-service Medicare beneficiaries according to two methods of measuring primary care access: One method was based on the number of family physicians and general internists per total population in 6542 primary care service areas (PCSAs); the other method used productivity data to calculate primary care physician full-time equivalents (FTEs) per 100,000 Medicare beneficiaries by PCSA. Quality outcomes were overall mortality and hospitalizations for ambulatory care–sensitive conditions (ACSCs; e.g., pneumonia, congestive heart failure, angina, urinary infection).
     The primary care physician workforce varied considerably by PCSA, with a fivefold variation from highest to lowest quintile of physicians per 100,000 population (medians, 81.3 in the highest quintile vs. 17.4 in the lowest) and a twofold variation in physician FTEs per 100,000 beneficiaries (medians, 103.2 vs. 64.7). Adjusted analyses showed that mortality and ACSC hospitalizations were slightly, but significantly, lower in areas with more primary care physicians, and that costs were similar across quintiles. Mortality and ACSC hospitalizations were substantially lower (by 5% and 9%, respectively) in the highest than in the lowest quintile of primary care physicians per 100,000 beneficiaries; however, costs were slightly (1%) higher.
     Comment: Complex methods were used to assess both primary care physician availability and quality of care in this retrospective study. However, the results suggest that healthcare quality is better with a stronger primary care workforce, especially when measured according to actual beneficiaries rather than to overall population.
Thomas L. Schwenk, MD Published in Journal Watch General Medicine June 9, 2011
     Citation(s):Chang C-H et al. Primary care physician workforce and Medicare beneficiaries' health outcomes. JAMA 2011 May 25; 305:2096. (http://dx.doi.org/10.1001/jama.2011.665)
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J Am Acad Dermatol 2011 Apr 18
On the Horizon: Test to Predict Stevens-Johnson Syndrome/Toxic
Epidermal Necrolysis

A rapid immunochromatographic test for serum granulysin shows promise in a small study.
     Drug reactions that manifest early in the course of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) may resemble non–life-threatening drug eruptions before rapidly progressing to a life-threatening state. Because intervention may alter the course of SJS/TEN, it would be useful to predict which patients' conditions might worsen. The membrane-disrupting protein granulysin is found in the blisters of SJS/TEN patients and, along with Fas ligand, is elevated in the serum of such patients. Because the results of enzyme-linked immunosorbent assays (ELISA) are not immediately available, an immunochromatographic test that correlates well with ELISA was developed.
     Investigators in Japan compared serum granulysin in patients with SJS/TEN, patients with "ordinary" drug eruptions, and healthy controls. Immunochromatographic testing found elevated levels in 4 of 5 SJS/TEN patients, 1 of 24 simple-drug-eruption patients, and 0 of 31 controls. In the one SJS/TEN patient who had normal results, disease was limited to the mucosal surfaces. However, granulysin levels did not correlate with the severity of skin blistering.
     Comment: This is a relatively small study, and results have to be repeated and validated. Because this test is not currently available in the U.S., a research or large commercial lab would have to develop the assay for clinical practice. An assay that proved to have the 80% positive predictive value and a 95% negative predictive value seen in the trial would be clinically useful and would likely lower costs as intravenous immunoglobulin (IVIG), commonly used for SJS/TEN, could be avoided in the many patients with simple drug reactions.
Jeffrey P. Callen, MD Published in Journal Watch Dermatology June 3, 2011
     Citation(s):Fujita Y et al. Rapid immunochromatographic test for serum granulysin is useful for the prediction of Stevens-Johnson syndrome and toxic epidermal necrolysis. J Am Acad Dermatol 2011 Apr 18; [e-pub ahead of print].
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Clin Gastroenterol Hepatol 2011 Jun; 9:483
Ulcerative Colitis: Should Mucosal Healing Be the Goal?
Additional therapy should be considered for patients with moderate-to-severe disease who do not show endoscopic remission after the first course of systemic steroids.
     Patients with ulcerative colitis have traditionally been treated to the point of clinical remission. Increasingly, however, they are receiving treatment to the point of healing, which seems to improve the likelihood of long-term remission. In a 25-year prospective observational study performed in Italy, researchers compared outcomes between patients with clinical remission who did or did not achieve endoscopic remission. The analysis involved 157 patients with a first diagnosis of moderate-to-severe ulcerative colitis who received systemic steroid therapy within 12 months of diagnosis.
     Information collected at baseline included sex, family history of inflammatory bowel disease, smoking habits, previous appendectomy, age at disease onset, disease extent, clinical and endoscopic activity, and extraintestinal manifestations. Systemic steroids were prescribed at a starting dose of 40 to 60 mg per day, tapered over 3 months. Endoscopy and clinical evaluation were performed at 3 and 6 months and then every 6 months for 60 months or until colectomy.
     Forty-one percent of the patients had been treated with oral salicylates before receiving corticosteroids; none had taken immunosuppressive agents. The median time between diagnosis and initiation of systemic steroids was 1 month. After starting such therapy, 20% were using topical steroids concomitantly.
     At 5-year follow-up, significant differences were seen between the 60 patients who showed both clinical and endoscopic remission at 3 months and the 39 patients who showed clinical but not endoscopic remission: Those with both clinical and endoscopic remission had lower rates of hospitalization (25% vs. 49%), immunosuppressive therapy (5% vs. 26%), and colectomy (3% vs. 18%).
     Comment: None of the study patients received antitumor necrosis factor agents at any time, and the use of immunosuppressive agents seemed relatively conservative. However, the data suggest that when patients with moderate-to-severe ulcerative colitis are treated with systemic corticosteroids, they should undergo endoscopic evaluation at the end of the course of treatment, and additional therapy should be considered for those who are in clinical but not endoscopic remission.
Douglas K. Rex, MD Published in Journal Watch Gastroenterology July 1, 2011
     Citation(s):Ardizzone S et al. Mucosal healing predicts late outcomes after the first course of corticosteroids for newly diagnosed ulcerative colitis.
Clin Gastroenterol Hepatol 2011 Jun; 9:483.
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Gut 2011 Jun; 60:806.
Predicting 30-Day Mortality After Colorectal Cancer Surgery
Predictors include male sex, advanced age, low socioeconomic status, advanced tumor stage, and greater comorbidity.
     For some conditions, the likelihood of death within 30 days after surgery can be predicted by patient age, comorbidity, disease stage, and factors such as hospital volume or surgeon volume. Now, researchers in the U.K. have used the National Cancer Data Repository to examine predictors of 30-day mortality after surgery for colorectal cancer. The study included 160,290 patients who underwent major resection for a primary colorectal cancer diagnosed in the English National Health System between 1998 and 2006.
     Postoperative mortality declined slightly during the study period, from 6.9% to 5.9%. Numerous significant predictors of death were identified, including male sex (6.8%, vs. 6.5% for females), increasing age (15.0% for patients aged >80 vs. 1.2% for those aged <50), advanced tumor stage (9.9% for Dukes D vs. 4.2% for Dukes A tumors), lower socioeconomic status (5.7% in the most affluent group vs. 7.8% for the most deprived), and greater comorbidity (24.2% for Charlson score ≥3 vs. 5.4% for Charlson score 0). Mortality rates were also significantly higher for patients with colonic tumors than for those with rectal tumors (7.7% vs. 4.6%) and for emergency surgery than for elective surgery (14.9% vs. 5.8%). Throughout the study period, outcomes were significantly better than expected in three hospital systems and significantly worse than expected in one.
     Comment: Most of the predictors of colorectal cancer surgical mortality described here have been identified previously. The strengths of this study are its large size and its population-based approach. The underlying reason for better or worse mortality rates in a few specific centers was unclear.
Douglas K. Rex, MD Published in Journal Watch Gastroenterology July 1, 2011
     Citation(s):Morris EJA et al. Thirty-day postoperative mortality after colorectal cancer surgery in England. Gut 2011 Jun; 60:806.

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