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Content 7


The Doctor and the Pharmacist

Radio Show Articles:
June 1, 2013

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Randomized Controlled Trial of Various Doses of Supplemental Vitamin D in Infancy
Update: Breast Cancer and Hormone Therapy in the WHI Observational Study
When Should CV Risk Be Remeasured in People at Low or Intermediate Risk?
Chest Pain: What Happens After the Emergency Department?
Penicillin-Susceptible S. aureus Bacteremia — Treat with Penicillin, if Possible!
Avoiding Chemotherapy in HER2-Positive Breast Cancer
Bald Twins
"Rule Out Ectopic": Can Any Single Test Clinch the Diagnosis?
Discovery of a Natural Heart-Rejuvenating Molecule in Mice
DSM-5 Debuts to a Scornful Review in Annals, Skepticism from NIMH
Fries with That? Immigrants' Health Found to Deteriorate After Life in U.S.
Do Sleeping Babies React to Parental Arguments?
Elevated Autism Risk with Prenatal Valproate Exposure
High-Dose NSAIDs Pose Increased Cardiovascular Risk
Gestational Hypertension Linked with Difficult Infant Temperament
Considering CRP Concentration Improves Diagnosis of Pneumonia

MM: This study demonstrates that the current recommended levels of Vitamin D for infants are too low. It also brings to light that a couple of other concerns. The level of 250 nmol/L(100ng/ml) as an upper range is still considered dangerousand that it would place the majority of infants at risk of hypercalcemia. I completely disagree with that train of thought. This is an archaic position and has not been demonstrated as accurate or as fact. Also, the premise that a minimum level of 50-75nmol/L (20-30ng/ml) is an acceptable endpoint is preposterous for any kind of good health. Although the research is headed in the right direction, I maintain that there is still too much misinformation and fear associated with Vitamin D and this is a situation that will hopefully continue to be corrected with time and additional supportive research and data.
JAMA 2013 May 1; 309:1785
Randomized Controlled Trial of Various Doses of Supplemental Vitamin D in Infancy
For now, 400 IU still seems to be the best daily dose.
The current recommended dose of supplemental vitamin D for infants — 400 IU/day — is enough to prevent rickets, but few studies have examined the ideal dose necessary to achieve other bone and nonbone health outcomes or to maintain adequate plasma 25-hydroxyvitamin D (25[OH]D) levels in infants (recommended as ≥75 nmol/L [30 ng/mL] by the Endocrine Society and ≥50 nmol/L [20 ng/mL] by the Institute of Medicine). To examine the effects of a range of doses on vitamin D status, researchers in Canada randomized 132 healthy, term, 1-month-old breast-fed singleton infants (mostly white) to receive daily vitamin D doses of 400, 800, 1200, or 1600 IU until age 12 months. Most infants were receiving vitamin D supplementation at baseline. The primary outcome was the dose necessary to achieve 25(OH)D levels ≥75 nmol/L in 97.5% of infants at age 3 months.
At age 3 months, 55%, 81%, 92%, and 100% of infants who received 400, 800, 1200, and 1600 IU, respectively, achieved the target 25(OH)D concentrations, and percentages tended to decline thereafter until age 12 months. Regardless of dose, almost all infants had levels >50 nmol/L at ages 3 through 12 months. The 1600-IU dose was discontinued halfway through the study because 15 of the first 16 infants who received this dose reached 25(OH)D levels >250 nmol/L (100 ng/mL), increasing risk for hypercalcemia; these infants were reassigned to the 400-IU group. Bone mineral concentration, growth, and blood and urine chemistries were similar in all four groups.
Comment: In this study, only the 1600 IU/day dose of vitamin D led to all 3-month-old infants achieving 25(OH)D levels of 75 nmol/L (30 ng/mL), but this high dose was considered potentially unsafe. In contrast, practically all infants reached 50 nmol/L (20 ng/mL), even at the currently recommended dose of 400 IU/day. Similar bone health markers at all four doses suggest that 50 nmol/L is adequate for infant bone development. Determining whether higher levels are optimal for nonbone health will require follow-up into childhood. This study population was relatively homogeneous, and as an editorialist implies, ideal vitamin D supplementation for infants might need to consider multiple factors such as weight, gestational age, latitude (sun exposure), and race.
Cornelius W. Van Niel, MD  Published in Journal Watch Pediatrics and Adolescent Medicine May 29, 2013
Citation(s): Gallo S et al. Effect of different dosages of oral vitamin D supplementation on vitamin D status in healthy, breastfed infants: A randomized trial. JAMA 2013 May 1; 309:1785.
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MM: It's unfortunate and even tragic that information such as this is sensationalized and mis-reported or just as much of a problem is the absence of details. One such detail is that the 'progestin' being referred to is the synthetic progestin, in most cases, medroxyprogesterone (MPA), and not Bio-identical Progesterone; a completely different molecule and one that decreases the risk of breast cancer, whereas MPA may promote it. Additionally, the data fails to differentiate between the risk of oral estrogen vs transdermal estrogen. This is a subtlety that has extensive data indicating thet transdermal and transvaginal application has a very high statistical safety index whereas oral presentation of estrogen does not.Once again, it is important to have all the facts and not just some of them.
J Natl Cancer Inst 2013 Apr 17; 105:526
Update: Breast Cancer and Hormone Therapy in the WHI Observational Study
New findings about breast cancer risk reinforce older ones from the Women's Health Initiative.
In the randomized Women's Health Initiative (WHI) study, postmenopausal women treated with estrogen-progestin hormone therapy (HT) had higher incidence of breast cancer than did placebo recipients (JW Gen Med Jul 26 2002). An observational WHI study paralleled the randomized trial. In this report from the observational study, researchers present data on breast cancer incidence among 41,000 women who had negative mammograms within 2 years of study entry and who used either estrogen-progestin HT (16,000) or no HT (25,000).
During 11 years of follow-up, 2200 invasive breast cancers were diagnosed. With adjustments for numerous demographic and clinical variables, the annual incidence of breast cancer was significantly higher in the HT users than in nonusers (0.6% vs. 0.4%; hazard ratio, 1.55). Breast cancer risk was highest when HT was initiated at menopause (HR, 1.68). In women who commenced HT use within 5 years after menopause, breast cancer risk was significantly elevated, even with <5 years of use (HR, 1.45). Risk for breast cancer followed by death from any cause was higher in HT users than in nonusers (HR, 1.65). Findings were similar in women who adhered to regular mammographic screening.
Comment: These results mirror those of the randomized Women's Health Initiative study. Notably, use of estrogen-progestin hormone therapy close to the time of menopause was associated with highest breast cancer risk. Some clinicians have been advising patients that short-term use is safe in the early postmenopausal period; these findings are at odds with that message. Women should understand that even short-term use just after menopause appears to raise breast cancer risk, although absolute risks are quite small ({approx}2 cases per 1000 patients annually). Lastly, these findings do not apply to women who use estrogen-only HT.
Allan S. Brett, MD  Published in Journal Watch General Medicine May 21, 2013
Citation(s): Chlebowski RT et al. Estrogen plus progestin and breast cancer incidence and mortality in the Women's Health Initiative observational study. J Natl Cancer Inst 2013 Apr 17; 105:526.
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MM: Good news for those who have watched their weight, exercised regularly, maintained optimal blood pressure, blood sugar, HbA1c and cholesterol levels! It seems that if you have lived a healthy lifestyle for the majority of your life to date and at are at low risk for CV disease, then there is a reduced risk of that turning on a dime and becoming at increased risk for cardiovascular disease. I think that the only ones who are benefitted from this study may be those who are hypochondriacs in the first place. The really good news is that those who are being coerced to take lipid lowering drugs just "for the sake of it" now have data to support the response of "just saying NO!"
BMJ 2013 Apr 3; 346:f1895
When Should CV Risk Be Remeasured in People at Low or Intermediate Risk?
Few people whose baseline cardiovascular risk was very low or low became high risk after 8 years.
The Framingham risk assessment tool employs age, sex, cholesterol levels, smoking status, and blood pressure to estimate 10-year risk for an adverse cardiovascular (CV) event. According to NIH guidelines, the threshold LDL cholesterol level at which to start lipid-lowering drug therapy depends on one's 10-year risk; nearly all people at high risk (i.e., those with 10-year risk >20%) are candidates for drug therapy. To determine the probability of progressing to high risk for CV disease among people at low and intermediate risk, investigators analyzed data from a total of 18,000 participants in two separate cohorts (Tokyo and Framingham). At baseline, all participants (age range, 30–74) had CV risk <20%, and none were using agents to lower blood pressure or lipid levels.
Participants were stratified by CV risk (very low risk [<5%], low risk [5%–10%], intermediate risk [10%–15%], and high-intermediate risk [15%–20%]). At baseline, most participants were at very low or low risk. In the Tokyo cohort, the probability of crossing the 20% threshold at 3 years was <1% for those at very low or low risk, 6% for those at intermediate risk, and 16% for those at high-intermediate risk. In the Framingham cohort, the probability of crossing the high-risk threshold at 8 years was <1% for those at very low risk, 9% for those at low risk, 32% for those at intermediate risk, and 74% for those at high-intermediate risk.
Comment: In this study, few participants at very low or low baseline cardiovascular risk became high risk after 8 years, whereas many patients at intermediate and high-intermediate risk became high risk — the point at which lipid-lowering drug therapy nearly always is recommended. Clinicians can use these results to reassure patients at very low or low risk and to decide how often to remeasure lipid levels.
Paul S. Mueller, MD, MPH, FACP  Published in Journal Watch General Medicine May 21, 2013
Citation(s): Bell KJL et al. When to remeasure cardiovascular risk in untreated people at low and intermediate risk: Observational study. BMJ 2013 Apr 3; 346:f1895.
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MM: Well, here is a good reason to be pro-active following a CV event and not simply going into denial. Testing is worthwhile when there is a reason to do so and testing following a chest pain incident may save your life.
Circulation 2013 Apr 2; 127:1386.
Chest Pain: What Happens After the Emergency Department?
Patients who follow up with cardiologists do best.
Researchers examined patterns of follow-up care and outcomes in high-risk patients with chest pain who presented to Ontario emergency departments (EDs) from 2004 to 2010. High risk was defined as having a prior diagnosis of cardiovascular disease, diabetes, or both. The primary outcome was a composite of all-cause death and hospitalization for myocardial infarction within 1 year after the index visit.
Of nearly 57,000 patients, 17% followed up with a cardiologist (with or without a visit to primary care) within 30 days after ED discharge, 57% followed up with a primary care practitioner only, and 25% did not have a visit to a physician recorded. After adjustment for clinical, demographic, and hospital characteristics, the cardiologist group had a significantly lower hazard ratio for the composite outcome (HR, 0.79; P<0.001) than the no–follow-up group and the PCP-only group (HR, 0.85; P<0.001). PCP-only follow-up was significantly beneficial compared to no follow-up (HR, 0.93; P<0.023). Patients seen by cardiologists underwent more testing and received more evidence-based therapies within 100 days after discharge.
Comment: These robust results demonstrate that what happens after the emergency department visit is as important as what happens during the ED visit, and that postdischarge care for patients with high-risk chest pain should include timely assessment by a cardiologist.
J. Stephen Bohan, MD, MS, FACP, FACEP Published in Journal Watch Emergency Medicine April 19, 2013
Citation(s): Czarnecki A et al. Association between physician follow-up and outcomes of care after chest pain assessment in high-risk patients. Circulation 2013 Apr 2; 127:1386.
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MM:This classic example of "less is more" demonstrates that the judicious use of pre-testing for sensitivity to an antibiotic prior to administration may save more lives than giving "shotgun therapy" broad spectrum antibiotic use. This use of stewardship will serve long term to save lives based on sensitivity and indication as well as serve to maintain the integrity of the potential life saving benefits of more potent antibiotics when they are truly indicated and needed.
J Antimicrob Chemother 2013 Apr 18
Penicillin-Susceptible S. aureus Bacteremia — Treat with Penicillin, if Possible!
In patients with penicillin-susceptible Staphylococcus aureus bacteremia, risk for 30-day mortality was 2.5-fold higher with cefuroxime treatment than with penicillin treatment.
Some strains of Staphylococcus aureus remain susceptible to classic penicillin, with the proportion varying by geographic region. Is penicillin the best treatment for infections caused by such pathogens, as is suggested by ex vitro data indicating a superior potency of penicillin over penicillinase-resistant β-lactams?
To answer this question, researchers conducted a retrospective analysis involving adult patients with penicillin-susceptible S. aureus bacteremia at six hospitals in Denmark over a 5-year period. Of these 588 patients, 92% received empirical antibiotic treatment within 1 day of blood culture. By days 3 and 4, 77% and 93% of patients, respectively, were on definitive antimicrobial treatment: penicillin in 28%, dicloxacillin in 19%, cefuroxime in 14%, and another agent or combination therapy in 39%. Penicillin, dicloxacillin, and cefuroxime were optimally dosed in 96%, 55%, and 94% of recipients.
Overall 30-day mortality was 21%. In a multivariate, propensity-score–adjusted analysis that corrected for several confounders, risk for such mortality was higher with cefuroxime than with penicillin (hazard ratio, 2.7; 95% confidence interval, 1.5–4.8) or with dicloxacillin (HR, 3.4; 95% CI, 1.7–7.1). Other variables significantly associated with 30-day mortality included older age, greater disease severity, and a primary respiratory focus. Risk for death was not significantly higher with dicloxacillin — or with other antibiotics, including combinations — than with penicillin.
Propensity-score–matched case-control studies confirmed greater risk for 30-day mortality with cefuroxime than with penicillin (odds ratio, 2.7; 95% CI, 1.1–6.2), and with cefuroxime than with dicloxacillin (OR, 3.3; 95% CI, 1.2–9.0).
Comment: In contrast to another recent investigation (JW Infect Dis Dec 7 2011), this study suggests a clear survival advantage for a penicillin over a cephalosporin in treating penicillin-susceptible S. aureus bacteremia. Besides the presumably better efficacy, a narrower spectrum and a lower risk for Clostridium difficile colitis further favor the use of penicillins.
Thomas Glück, MD  Published in Journal Watch Infectious Diseases May 22, 2013
Citation(s): Nissen JL et al. Effectiveness of penicillin, dicloxacillin and cefuroxime for penicillinsusceptible Staphylococcus aureus bacteraemia: A retrospective, propensity-score-adjusted case–control and cohort analysis. J Antimicrob Chemother 2013 Apr 18; [e-pub ahead of print].
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MM: When a celebrity like Angelina Jolie makes a demonstrative pro-active action like a double mastectomy, people sit up and take notice. The threat of breast or ovarian cancer and death become more real and take on super-sized proportions. This article discusses treatment options for the HER2-Positive condition.
J Clin Oncol 2013 May 10; 31:1726
Avoiding Chemotherapy in HER2-Positive Breast Cancer
Dual targeting of human epidermal growth factor receptor 2 produced in-breast pathologic complete remission in 27% of patients.
The goal of avoiding chemotherapy and its attendant adverse effects is attractive to breast cancer patients and clinicians. In appropriate patients with estrogen receptor (ER)-positive breast cancer, the strategy of exhausting endocrine therapy options has been used to delay time to chemotherapy and help maintain quality of life. A similar strategy has been considered in select patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Previous reports have shown that combining anti-HER2 agents with endocrine agents in ER-positive and HER2-positive metastatic breast cancer is more effective than endocrine therapy alone.
More recently, a clinical trial involving women with HER2-positive disease compared various combinations of chemotherapy and anti-HER2 treatment administered preoperatively, including one that combined pertuzumab and trastuzumab without chemotherapy (Lancet Oncol 2012 Jan; 13:25). Although the pathologic complete remission (pCR) rate was higher with chemotherapy, patients who received only the antibodies still attained a pCR rate of nearly 20%, suggesting that chemotherapy may be avoided in certain patients.
To test such a no-chemotherapy approach further, investigators conducted a multicenter, phase II trial involving 66 patients with stage II–III HER2-positive disease (62% were ER-positive) who received standard trastuzumab plus lapatinib (1000 mg daily) for 12 weeks. Women with ER-positive tumors also received letrozole (plus a luteinizing hormone–releasing hormone agonist, if premenopausal). Sequential biopsies were obtained at diagnosis, at weeks 2 and 8, and at surgery. The median tumor size was 6 cm (range, 1–30 cm).
Overall, the in-breast pCR was 27% (21% for ER-positive disease; 36% for ER-negative disease). The most common adverse effects were those largely expected with lapatinib: diarrhea (grades 1–2, 63%; grades 3–4, 3%), rash (grades 1–2, 55%; grades 3–4, 1%), fatigue (32%), nausea (31%), and elevated liver function tests (grades 1–2, 18%; grade 3, 5%; grade 4, 2%).
Comment: Dual targeting of HER2 has proven to be an effective strategy for increasing tumor shrinkage, compared with single-agent HER2 therapy, with or without chemotherapy. To realize the full potential of this strategy, clinicians must be able to identify which patients can avoid chemotherapy. (The serial tumor samples obtained in this trial might possibly be used to identify a biomarker that could identify such patients.) Until then, combining chemotherapy with anti-HER2 therapy remains a standard approach for HER2-positive breast cancer.
William J. Gradishar, MD  Published in Journal Watch Oncology and Hematology May 21, 2013
Citation(s): Rimawi M et al. Multicenter phase II study of neoadjuvant lapatinib and trastuzumab with hormonal therapy and without chemotherapy in patients with human epidermal growth factor receptor 2–overexpressing breast cancer: TBCRC 006 J Clin Oncol 2013 May 10; 31:1726.
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Plast Reconstr Surg 2013 May; 131:794e
Bald Twins
Wear a hat, de-stress, and don't smoke if you want to be the more lushly haired brother.
Genetics may contribute to male (androgenic) alopecia (AA), but even within families, the expression and penetrance is variable. To address more directly the influence of other factors on AA, investigators studied 92 identical male twins (mean age, 51; range, 23–84), comparing completed questionnaires, four-view standardized photographs, and sputum samples analyzed for testosterone levels. Degree of hair thinning was assessed from photographs by two independent, blinded observers using the Likert scale. Linear regression modeling identified independent predicators of hair loss measures.
Independent factors that contributed to hair loss included genetics, older age, smoking, dandruff, having more children, higher caffeine ingestion, lower BMI, and history of skin disease. Not all of these factors affected hair loss at all anatomic sites (frontal, temporal, vertex). Increased testosterone levels were significantly associated with increased vertex hair loss and decreased temporal hair loss, but a difference between twins was not a predictor.
In intertwin analysis, twins who reported longer duration of stress had significantly greater hair loss than their identical counterpart. Twins with relatively increased durations of exercise had more vertex hair loss (P=0.05). A twin who drank more than four alcoholic drinks per week had more vertex hair loss than his more abstinent twin brother (P=0.004), but vertex hair loss was also found more commonly in twins who didn't drink at all (P=0.03)
Comment: Intertwin analysis found daily hat use associated with decreased temporal hair loss — information that could further motivate men to wear them. The testosterone story is complicated. Saliva testosterone serves as an indirect measure of free testosterone, as sex hormone–binding globulin is not secreted in saliva, but levels do not reflect the critically important ability of follicles to convert free testosterone to dihydrotestosterone. Dandruff was associated with greater temporal and frontal hair loss, suggesting that looking for and treating dandruff might benefit balding men over the long term.
Mark V. Dahl, MD  Published in Journal Watch Dermatology May 24, 2013
Citation(s): Gatherwright J et al. The contribution of endogenous and exogenous factors to a male alopecia: A study of identical twins. Plast Reconstr Surg 2013 May; 131:794e. (http://dx.doi.org/10.1097/PRS.0b013e3182865ca9)
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JAMA 2013 Apr 24; 309:1722
"Rule Out Ectopic": Can Any Single Test Clinch the Diagnosis?
Transvaginal ultrasound is the best diagnostic test for ectopic pregnancy.
Early detection of ectopic pregnancy lowers morbidity and mortality associated with tubal rupture or spontaneous abortion; however, current diagnostic tools fail to achieve a single-visit diagnosis in as many as 40% of women with ectopic gestations. Investigators reviewed 14 studies to evaluate clinical tools for assessing hemodynamically stable women with suspected ectopic pregnancy.
Ectopic pregnancy was diagnosed in 15% of pregnant women who presented with pelvic pain or vaginal bleeding. Patient history was not diagnostically useful (positive likelihood ratio [+LR] <1.5). Cervical motion tenderness and abdominal tenderness on physical exam were associated with moderately elevated risk for ectopic gestation (+LR, 4–5). Importantly, normal findings on physical examination did not lower the likelihood of ectopic pregnancy. The predictive value of a single serum human chorionic gonadotropin (hCG) measurement was inconsistent among studies. In contrast, the finding of an adnexal mass without an intrauterine pregnancy on transvaginal ultrasound was associated with a high likelihood of ectopic pregnancy (+LR, 111).
Comment: Timely diagnosis of ectopic pregnancy in a hemodynamically stable patient with pelvic pain or vaginal bleeding remains a challenge. This review demonstrates that, for establishing a diagnosis, patient history is not reliable and physical examination is only modestly so. A single measurement of serum hCG cannot confirm an ectopic gestation, although serial measurements in combination with ultrasound are clinically valuable (JW Womens Health Feb 16 2012). Because transvaginal ultrasound continues to be the single most useful test in the diagnosis of ectopic pregnancy, access to this technology and to clinicians skilled in its interpretation must be ensured for all women.
Allison Bryant, MD, MP
Published in Journal Watch Women's Health May 23, 2013
Citation(s): Crochet JR et al. Does this woman have an ectopic pregnancy? The Rational Clinical Examination systematic review. JAMA 2013 Apr 24; 309:1722.
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Cell 2013 May 9; 153:828
Discovery of a Natural Heart-Rejuvenating Molecule in Mice
Raising the serum concentration of GDF11 in old mice rescued the myocardium.
Age-related diastolic dysfunction is a common cause of congestive heart failure: No specific treatments repair the stiff and thickened myocardium. Investigators from Harvard have discovered a molecule that reverses a similar age-related process in mice.
The research team joined the circulation of an old mouse to that of a young mouse. After 4 weeks of shared circulation, the thickened and stiff heart muscle of the old mouse became dramatically less thick and stiff. The investigators postulated that some substance was present in the blood of the young mouse that rejuvenated the heart muscle of the old mouse. They identified a molecule called GDF11 that was present in higher concentrations in the blood of young mice than in old mice. To prove that GDF11, and not something else related to the conjoined circulation, really was the cause of the rejuvenated heart muscle, old mice were treated with enough GDF11 to raise their blood levels to those normally present in young mice. Again, the thickened and stiff heart muscles became rejuvenated.
Comment: The discovery of a molecule in mice that rescues myocardium from age-related thickening and stiffening could eventually lead to a treatment that prevents or reverses age-related diastolic dysfunction in humans. Presently, the mechanism for this effect is unknown, but this is just the latest evidence that aging is a biological process that can be slowed.
Anthony L. Komaroff, MD Published in Journal Watch General Medicine May 23, 2013
Citation(s): Loffredo FS et al. Growth differentiation factor 11 is a circulating factor that reverses age-related cardiac hypertrophy. Cell 2013 May 9; 153:828.
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DSM-5 Debuts to a Scornful Review in Annals, Skepticism from NIMH
The new, fifth edition of the Diagnostic and Statistical Manual of Mental Disorders has been panned in an Annals of Internal Medicine commentary. The author, chair of the DSM-4 task force, advises that clinicians use it "cautiously, if at all."
Separately, the director of the National Institute of Mental Health says that "patients with mental disorders deserve better." Late last month he wrote that the institute will be "re-orienting its research away from DSM categories" to focus on biomarkers of mental disease rather than clusters of symptoms.
The Annals commentator seems especially disappointed with the proliferation of diagnoses "at the fuzzy boundary with normality." He says the result "will probably lead to substantial false-positive rates and unnecessary treatment." Perhaps most damning is his charge that the American Psychiatric Association has a financial conflict of interest driven by DSM revenues (the new edition costs about $200), which led to "premature publication of an incompletely tested and poorly edited product."
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Fries with That? Immigrants' Health Found to Deteriorate After Life in U.S.
By Joe Elia
For immigrants, the effects of life in the U.S. include greater income along with higher cardiovascular risks, researchers are concluding.
In a survey of the problem in the New York Times, it's reported that American-born children of immigrants tend to have shorter lifespans than their parents. American-style behaviors, such as eating high-calorie diets and not getting enough exercise, seem to be to blame.
One researcher has found that Hispanic immigrants live almost 3 years longer than American-born Hispanics.
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Psychol Sci 2013 May 1; 24:782
Do Sleeping Babies React to Parental Arguments?
Sleeping infants whose mothers report greater interparental conflict show larger focal brain activations in response to angry voices.
Parental behaviors are known to affect neurophysiological development in young children, but the origins of these effects have been unclear. These investigators examined whether interparental conflict might affect specific neurophysiological processes in young infants, who are known to be sensitive to environmental signals (JW Psychiatry May 13 2013).
Mothers of 20 infants aged 6 to 12 months rated the extent of nonphysical interparental conflict in their marital relationships. During periods of natural sleep, the infants underwent functional magnetic resonance imaging (fMRI) while being exposed to recorded voices reciting nonsense-word sentences in very or mildly angry, happy, or neutral vocal tones. In response to "very angry" speech compared with neutral voices, greater fMRI activation in the infants' rostral anterior cingulate cortex and hypothalamus/caudate areas was significantly associated with mothers' higher interparental conflict scores.
Comment: Although the possible co-occurrence of physical conflict wasn't controlled for — and researchers should develop more direct and specific measures of interparental conflict — the current findings suggest that even the relatively moderate stressor of angry tones heard during sleep influences and perhaps sensitizes developing infant brains. The affected anterior cingulate cortex and hypothalamic/caudate areas are key to emotional processing and stress reactivity. These findings are consistent with emerging research showing exposure to higher interparental conflict to be associated with infants' behavioral responses, physiological stress reactivity, and shifts in parasympathetic tone. Eventually, researchers might uncover even earlier, perhaps intrauterine, impacts of prominent voice tones on fetal brain development. Clinicians and parents should know that far from being oblivious, infants, even when sleeping, can be sensitive to the emotional tones of their surroundings.
Joel Yager, MD  Published in Journal Watch Psychiatry May 24, 2013
Citation(s): Graham AM et al. What sleeping babies hear: A functional MRI study of interparental conflict and infants' emotion processing. Psychol Sci 2013 May 1; 24:782.
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JAMA 2013 Apr 24; 309:1696
Elevated Autism Risk with Prenatal Valproate Exposure
A case-control study associates prenatal valproate exposure with autism and autism spectrum disorders in offspring.
Valproate is a drug commonly prescribed for the treatment of epilepsy, bipolar disease, migraine, and other conditions. Evidence shows that prenatal exposure to valproate is associated with a high rate of congenital malformations (10.4%; JW Neurol Jul 13 2010) and lower IQ scores at 6 years of age (JW Neurol Mar 5 2013). Despite these data, a significant percentage of women of childbearing age continue to receive treatment with the drug. To assess the risk for autism with prenatal valproate exposure, researchers surveyed data from Danish national registries over a 10-year period. The study cohort consisted of 655,615 children followed for up to 14 years; 508 were exposed to valproate in utero.
The absolute risks for autism spectrum disorder and autism were 4.42% and 2.50%, respectively. After adjusting for several risk factors for autism, the authors found the adjusted hazard ratios to be 2.9 (95% CI, 1.7–4.9) for autism spectrum disorders and 5.2 (95% CI, 2.7–10.0) for childhood autism. The authors did not find any effect of timing of exposure on risk for autism or any effect of disease (epilepsy vs. no epilepsy). Other findings from the study included the absence of increased risk in women exposed to other antiseizure medications (carbamazepine, oxcarbazepine, lamotrigine, and clonazepam monotherapy) and in women who had stopped taking valproate prior to pregnancy.
Comment: This study provides convincing evidence linking prenatal valproate exposure to development of autism in childhood. The large sample size allowed the authors to control for several potential confounding factors, further strengthening their conclusions. The reliance on registries and prescription refills for data extraction is one limitation the authors acknowledge. In particular, the effect of valproate dosage and blood level could not be addressed. Despite this, the findings of this study add to the current body of evidence indicating increased risk to the fetus with use of prenatal valproate, and its use in women of childbearing age should be minimized whenever possible.
— Rani A. Sarkis, MD, and Ellen J. Bubrick, MD
Dr. Sarkis is an Epilepsy Fellow, Department of Neurology, Brigham and Women's Hospital, Boston. Dr. Bubrick is an Associate Neurologist, Brigham and Women's Hospital, and an Instructor in Neurology, Harvard Medical School, Boston.
Published in Journal Watch Neurology May 28, 2013  Citation(s): Christensen J et al. Prenatal valproate exposure and risk of autism spectrum disorders and childhood autism. JAMA 2013 Apr 24; 309:1696.
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High-Dose NSAIDs Pose Increased Cardiovascular Risk
By Kelly Young
High-dose diclofenac and coxibs, non-steroidal anti-inflammatory drugs (NSAIDs), carry similarly elevated cardiovascular risks, a Lancet meta-analysis finds.
Researchers examined over 600 randomized trials — comprising over 300,000 patients — comparing NSAIDs with placebo or another NSAID. Relative to placebo, the risk for major vascular events was about a third higher in patients taking coxibs or diclofenac, mostly attributable to higher rates of major coronary events. The authors estimate that coxibs or diclofenac would cause roughly three extra major vascular events per 1000 patients annually.
Ibuprofen had double the risk for major coronary events, but no increase in vascular events, while naproxen was not associated with increased cardiovascular risk.
A commentator concludes: "Long-term use of high-dose NSAIDs should be reserved for those who receive considerable symptomatic benefit from the treatment and understand the risks." Others should receive nonpharmacological regimens, topical therapy, and lower-risk NSAID treatments.
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MM: I have always wondered why some infants seem to always be happy, to coo and smile while others seem to be constantly upset and distraught. Intrauterine conditions may have something to do with this. Imagine if more exercise and higher progesterone levels during pregnancy would help with infant temperament. Both Dr. John R. Lee and Dr Katharina Dalton stated during their lifetimes that higher gestational progesterone levels in the mom led to smarter babies at 3,6 and 10 years of age. Perhaps improved temperament at an earlier age leeds to a more receptive infant and toddler student. Just something to ponder.
J Dev Behav Pediatr 2013 Apr; 34:174
Gestational Hypertension Linked with Difficult Infant Temperament
Mothers with gestational hypertension or preeclampsia reported significantly more infants with difficult temperaments at age 12 months.
Hypertension during pregnancy has been associated with psychological problems and low verbal abilities in school-age children. Researchers in Australia prospectively assessed the association between gestational hypertension and "difficult" infant temperament in 2384 mothers enrolled in a prospective pregnancy cohort study. The women were assessed twice between 18 and 34 weeks' gestation and then completed a standardized infant temperament scale when their children were aged 12 months. Infant temperaments were classified as easy, difficult, or slow to warm up.
Gestational hypertension was defined as pregnancy-induced increase in systolic pressure ≥140 mm Hg, diastolic pressure ≥90 mm Hg, or both, in woman with normal blood pressure before 24 weeks' gestation. In multivariate regression analysis (adjusted for pre- and postnatal medical, sociodemographic, and psychological factors), mothers with gestational hypertension or preeclampsia were significantly more likely to report infants with difficult temperaments during the first year than mothers without gestational hypertension or preeclampsia.
Comment: Temperament refers to stable, individual ways of responding to the environment based on differences in emotional reactivity, attention, activity level, and self-regulation. A child's temperament is relatively stable over time and plays a significant role in early development by regulating parent–child interactions. Psychological factors also play a role in gestational hypertension. If the association between maternal gestational blood pressure and child temperament is confirmed and more effective ways to prevent and control gestational hypertension are developed, we might see more infants with greater adaptability, less intense behaviors, and a more persistent attention span consistent with an "easy" temperament.
Martin T. Stein, MD  Published in Journal Watch Pediatrics and Adolescent Medicine May 29, 2013
Citation(s): Robinson M et al. Hypertensive diseases of pregnancy predict parent-reported difficult temperament in infancy. J Dev Behav Pediatr 2013 Apr; 34:174.
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BMJ 2013 Apr 30; 346:f2450
Considering CRP Concentration Improves Diagnosis of Pneumonia
Low C-reactive protein levels helped rule out pneumonia.
Acute bronchitis is managed expectantly, and pneumonia is managed with antibiotics. However, accurately distinguishing these conditions, based on history and physical examination alone, is difficult. Although chest x-ray can distinguish acute bronchitis from pneumonia, it is expensive, exposes patients to radiation (often unnecessarily), and is unavailable in some settings. In this European study, investigators determined whether measuring blood C-reactive protein (CRP) and procalcitonin concentrations, in addition to history and physical examination, improved diagnostic accuracy.
Among 2820 adults (mean age, 50) who presented with cough to primary care practices, chest x-ray confirmed pneumonia in 140 patients (5%). The optimum combination of history and examination findings for pneumonia was absence of runny nose and presence of breathlessness, crackles and diminished breath sounds on auscultation, tachycardia, and fever. Adding CRP level as a continuous variable resulted in significantly improved ability to predict pneumonia (multivariate odds ratio, 1.2 per 10 mg/L rise in CRP concentration). Adding CRP as a dichotomized variable (>30 mg/L as high-risk for pneumonia) yielded similar results. Of 665 patients with low probability (<2.5%) for pneumonia based on history and examination findings only, 11 (2%) actually had pneumonia. Adding CRP level reclassified 891 additional patients into the low-risk group (total, 1556); of these, 31 (2%) actually had pneumonia. Procalcitonin added no diagnostic information.
Comment: In this study, adding blood CRP concentration to history and examination findings improved diagnostic accuracy for pneumonia — mainly by ruling out the infection. Of course, this approach depends on the availability of timely point-of-care CRP testing.
Paul S. Mueller, MD, MPH, FACP  Published in Journal Watch General Medicine May 30, 2013
Citation(s): van Vugt SF et al. Use of serum C reactive protein and procalcitonin concentrations in addition to symptoms and signs to predict pneumonia in patients presenting to primary care with acute cough: Diagnostic study. BMJ 2013 Apr 30; 346:f2450.

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