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Content 7


The Doctor and the Pharmacist

Radio Show Articles:
August 8, 2016

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Gut Microbiome might play Important Role in Allergies and Autoimmune Diseases
Children's Oral Habits and Risk for Allergy and Asthma
A Single Treatment with a Novel Molecule Cured Type 2 Diabetes in Rodents
A Clinical Update on the Female Athlete Triad
The Weight Trainer's Choice: Brain or Brawn
Parent-Administered PT for Preterm Infants
Newer Diabetes Drugs could boost risk for Gallbladder and Bile Duct Disease
How might Farming Confer Asthma Protection?
Estrogen-Containing Contraceptive use tied to Higher Vitamin D Levels
Do Certain Postpartum Contraceptives cause Depression?
Are MRSA Antibiotics Overprescribed for Community-Acquired Pneumonia?
Racial Differences in End-of-Life Care among Patients with Metastatic Cancer
Predictors of Fecal Microbiota Transplant Failure
Increased Mortality in Patients with Peptic Ulcers

Cell 2016 May 5; 165:842
Gut Microbiome might play Important Role in Allergies and Autoimmune Diseases
Regional differences in infants' gut microbiomes might explain regional differences in incidence of immune disorders.
Finland is adjacent to the Karelia region in northwest Russia, and Estonia is nearby. Yet the incidence of type 1 diabetes is more than fivefold higher and the incidence of allergies is two- to sixfold higher in Finland and Estonia than in Karelia. Why?
An international team assessed gut microbiomes monthly in 74 infants from Finland or Estonia who were matched for sex and HLA type (because certain HLA types confer higher risk for allergy and autoimmunity) with 74 infants from Russia. Particularly in the first year of life, Finnish and Estonian gut microbiomes contained more Bacteroides species, whereas the Bifidobacterium genus was more prevalent in Russian children. Finnish and Estonian infants also developed insulin autoantibodies earlier in life than did Russian infants. When the researchers looked at mice, they found that lipopolysaccharide from Bacteroides species depresses immune responses and suppresses development of tolerance to self-antigens.
COMMENT: These results suggest that a greater number of Bacteroides species in the gut microbiome in early life can increase vulnerability to autoimmune diseases and allergies and show a possible explanatory molecular mechanism. An infant's gut microbiome is influenced strongly by the mother's gut microbiome (during vaginal birth); a mother's microbiome is influenced by diet and other lifestyle factors, which in turn might be related to a region's economic development and standard of living. This report also raises the tantalizing possibility that characterization and probiotic alteration of the infant gut microbiome someday might limit risks for autoimmune disease in genetically vulnerable babies.
CITATION(S): Vatanen T et al. Variation in microbiome LPS immunogenicity contributes to autoimmunity in humans.Cell 2016 May 5; 165:842. (http://dx.doi.org/10.1016/j.cell.2016.04.007)

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Pediatrics 2016 Aug; 138:e20160443
Children's Oral Habits and Risk for Allergy and Asthma
Thumb-sucking or nail-biting was associated with reduced risk for atopic sensitization, but not allergic disease.
Does elevated exposure to environmental microorganisms in childhood result in lower risk for atopy later in life? To address this question, researchers assessed whether thumb-sucking or nail-biting habits in children were associated with reduced rates of atopic sensitization, asthma, or hay fever in a prospective birth-cohort study of New Zealand residents. Thumb-sucking and nail-biting were assessed via parental questionnaire at ages 5, 7, 9, and 11 years. Skin-prick testing for selected antigens was conducted in most participants at ages 13 and 32 years, at which time asthma and hay fever were self-reported.
Among 1013 participants, having one or both habits (prevalence, 31%) was associated with reduced risk for atopic sensitization at age 13 years, and having both habits conferred more risk protection than having one. In multivariate analyses, nail-biting or thumb-sucking were significantly associated with reduced risk (about 30%–40%) for atopic sensitization (≥1 positive response to any skin-prick test) at ages 13 and 32, and thumb-sucking specifically was also significantly associated with reduced risk at age 13. Neither thumb-sucking nor nail-biting was associated with later risk for asthma or hay fever.
COMMENT: In interpreting these results, we should bear in mind that atopic sensitization is not synonymous with allergic disease. Though the relationship between oral habits and sensitization is interesting, there was no association between oral habits and disease (i.e., asthma and hay fever) and thus no clear evidence of clinical benefit. That does not mean one does not exist, but for the primary care clinician, this study should be taken as a primarily negative result, with a curious positive finding on the side (not the other way around).
CITATION(S): Lynch SJ et al. Thumb-sucking, nail-biting, and atopic sensitization, asthma, and hay fever. Pediatrics2016 Aug; 138:e20160443.
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Nat Med 2016 Jul; 22:800
A Single Treatment with a Novel Molecule Cured Type 2 Diabetes in Rodents
Injection of fibroblast growth factor–1 into the cerebral ventricles conferred durable glucose control.
The brain can profoundly influence metabolic and inflammatory diseases of other organs. The latest example: A multi-institutional team injected a molecule, fibroblast growth factor–1 (FGF1), into the cerebral ventricles of a mouse model of type 2 diabetes, with remarkable results. FGF1 affects hypothalamic neurons that control metabolic rate and appetite.
Based on past research, the researchers expected to see a transient lowering of blood glucose. Instead, glucose levels normalized during the next 7 days and remained normal for the next 17 weeks (when the study was terminated). The same durable response was seen in three other mouse and rat models of type 2 diabetes. None of the animals developed hypoglycemia, and no other complications were detected. The treatment reduced food intake and body weight temporarily, but those changes did not explain the durable drop in blood sugar. The lower blood sugar levels appeared to be caused by increased glucose uptake by the liver and conversion of the glucose to glycogen. When the same treatment was given to normoglycemic healthy mice, no substantial effect on blood sugar levels was noted.
COMMENT: Investigators will likely test whether this treatment produces durable normoglycemia and fewer diabetic complications in humans with type 2 diabetes. These researchers already have shown that injecting FGF1 directly into the cerebral ventricles might not be necessary: In rodents, a nasal spray of FGF1 confers similar physiological effects. Is this result too good to be true? Stay tuned.
CITATION(S): Scarlett JM et al. Central injection of fibroblast growth factor 1 induces sustained remission of diabetic hyperglycemia in rodents. Nat Med 2016 Jul; 22:800. (http://dx.doi.org/10.1038/nm.4101)
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Pediatrics 2016 Aug; 138:e20160922
A Clinical Update on the Female Athlete Triad
Treatment should address increasing energy availability and decreasing training volume.
The components of the female athlete triad involve three physiologic processes: (abnormal) menstrual function, (decreased) bone mineral density (BMD), and (low) energy availability.
A clinical report from the American Academy of Pediatrics (AAP) reviews key features of this condition likely encountered by pediatricians:

COMMENT: The AAP recommends screening for this triad at all pre-participation physical examinations, using all but 4 of the 12 questions in the Female Athlete Triad Coalition's screening instrument (http://www.femaleathletetriad.org/~triad/wp-content/uploads/2008/11/ppe_for_website.pdf). Educate parents and teenagers that oligomenorrhea or amenorrhea should never be dismissed as secondary to training. Increasing EA and/or decreasing training volumes are the key components of treatment. Using oral contraceptives may produce regular menses but is unlikely to reverse the other factors at play.
CITATION(S): Weiss Kelly AK et al. The female athlete triad. Pediatrics 2016 Aug; 138:e20160922.

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Biol Psychiatry 2016 Jun 30
The Weight Trainer's Choice: Brain or Brawn
Long-term use of anabolic androgenic steroids is linked to decreases in brain volumes on magnetic resonance imaging.
The cardiovascular and psychiatric complications of anabolic androgenic steroid (AAS) use are well known. To determine whether they are associated with changes in brain structure, Norwegian investigators used high-resolution magnetic resonance imaging in 82 weightlifters who had used AASs for more than a year with 68 weightlifters who never used AASs or other doping substances.
Compared with nonusers, AAS users had less overall gray matter, lower cortical and putamen volumes, and thinner cortex throughout the brain. More prolonged and greater use of AASs was associated with more loss of cortical thickness and volume. The results were not explained by comorbid abuse of non-AAS substances, but comorbid substance abuse amplified the effects of AAS on brain structure.
COMMENT: AASs readily enter the brain and bind to androgen receptors. The possible mechanisms of AAS-induced neurotoxicity include formation of amyloid-β, oxidative stress, and cardiovascular effects on brain circulation. Regardless of the cause, the consequences include accelerated brain aging, cognitive decline, and dementia, as well as decreased resilience associated with psychiatric syndromes. Clinicians should warn all AAS users about these risks and follow cognitive function in patients who continue to use these substances.
CITATION(S): Bjørnebekk A et al. Structural brain imaging of long term anabolic-androgenic steroid users and non-using weightlifters. Biol Psychiatry 2016 Jun 30; [e-pub].
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Pediatrics 2016 Aug; 138:e20160271
Parent-Administered PT for Preterm Infants
Parents improved motor performance in preterm infants with physical therapy focused on postural control, head control, and midline orientation.
Early physical therapy to improve motor function in preterm infants has had limited success. However, small studies have shown modest effectiveness when parents are included in the therapy.
Now, investigators have conducted a multicenter, randomized, controlled trial involving 153 infants (gestational age ≤32 weeks) who received either parent-administered physical therapy (74 infants) or usual care (79 controls). Parents performed therapeutic maneuvers on infants under the supervision of a physical therapist for 10 minutes twice daily from 34 through 36 weeks postmenstrual age. The therapy focused on postural control, head control, and midline orientation.
Motor performance assessed with standardized tests at 34 and 37 weeks showed that infants who received parent-directed therapy had significant improvement in motor performance compared with those who received conventional care; the effect size (0.40) was modest.
COMMENT: I was impressed with this study, which demonstrated the effectiveness of parents performing a procedure that is typically done by a professional. Early physical therapy is predicated on our knowledge that motor development of premature infants is dependent on experience and active engagement with animate and inanimate objects, a process that promotes synaptogenesis and organization of neuronal patterns. The authors plan a 2-year follow-up assessment to determine if the benefits of this brief intervention are lasting.
CITATION(S): Ustad T et al. Early parent-administered physical therapy for preterm infants: A randomized controlled trial. Pediatrics 2016 Aug; 138:e20160271. (http://dx.doi.org/10.1542/peds.2016-0271)

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Newer Diabetes Drugs could boost risk for Gallbladder and Bile Duct Disease
By Kelly Young, Edited by David G. Fairchild, MD, MPH, and Jaye Elizabeth Hefner, MD
Use of glucagon-like peptide 1 (GLP-1) receptor agonists is associated with increased risk for gallbladder and bile duct diseases, according to new research published in JAMA Internal Medicine. These agents are recommended as second-line treatment for type 2 diabetes management.
Using U.K. databases, researchers assessed information on 71,000 adults with type 2 diabetes who were starting a new antidiabetic drug class. During a mean follow-up of 3.2 years, 850 patients were admitted to the hospital for bile duct or gallbladder disease. Patients who used GLP-1 analogues had an increased risk for bile duct and gallbladder disease relative to those using at least two oral antidiabetes drugs (6.1 vs. 3.3 per 1000 person-years). Use of dipeptidyl peptidase-4 (DPP-4) inhibitors did not pose increased risk.
The authors note that GLP-1 boosts the activity of cholangiocytes, which has raised concerns about possible adverse effects.
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N Engl J Med 2016 Aug 4; 375:411
How Might Farming Confer Asthma Protection?
Low levels of asthma in Amish children were linked with their exposure to a rich, distinct microbial environment.
Children who grow up on farms, have older siblings, or have furry pets in their homes all seem to have lower risk for atopic diseases. Two U.S. farming communities, the Amish of Indiana and the Hutterites of South Dakota, have similar genetic backgrounds but different farming practices; the Amish still live on traditional single-family dairy farms, whereas the Hutterites practice large-scale mechanized farming. In previous studies, Amish schoolchildren had lower prevalence of asthma (5% vs. 21%) and allergic sensitization (7% vs. 33%) compared with Hutterite schoolchildren. In the current study, researchers explored what immunological mechanisms might account for this difference.
Immunological and genetic testing was performed in 30 randomly selected children from each community, and dust samples were collected from homes. None of the Amish children had asthma, whereas six Hutterite children did, and the rate of allergic sensitization was higher among Hutterite children. Endotoxin levels were seven times higher in Amish homes, and innate immunity–related cytokine levels were higher in the blood of Amish children. When Amish, but not Hutterite, house dust was administered to mice intranasally, it inhibited airway inflammation, and this effect was blunted in mice who were deficient in toll-like receptor signaling.
COMMENT: These findings lend further support to the hygiene hypothesis and suggest that bacterial endotoxin inhibits allergic inflammation by stimulating the innate immune system. The ideal amount and timing of endotoxin exposure is not known, and it remains to be seen if some day these benefits can be achieved using purified samples in children not living on traditional farms.
CITATION(S): Stein MM et al. Innate immunity and asthma risk in Amish and Hutterite farm children. N Engl J Med2016 Aug 4; 375:411.
Chatila TA.Innate immunity in asthma. N Engl J Med 2016 Aug 4; 375:477.
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Estrogen-Containing Contraceptive Use Tied to Higher Vitamin D Levels
By Kelly Young, Edited by André Sofair, MD, MPH, and William E. Chavey, MD, MS
Hormonal contraception use is associated with higher serum levels of 25-hydroxyvitamin D (25[OH]D), according to a large, observational study in the Journal of Clinical Endocrinology & Metabolism.
Nearly 1700 black women aged 23 to 34 years in the Detroit area had their vitamin D levels checked and provided information on their contraceptive histories. Overall, vitamin D levels were low — a median of 15.7 ng/mL, below the Institute of Medicine’s recommendation of 20.0 ng/mL.
After multivariable adjustment, women who currently used contraceptives with estrogen had a 20% higher level of 25(OH)D than those not taking estrogen-containing contraceptives. One proposed mechanism of action is that exogenous estrogen has been tied to increases in vitamin D binding protein, which could potentially increase the half-life of 25(OH)D, although the exact mechanism remains unclear.
The authors conclude: "This finding has clinical implications when counseling women who are planning to conceive and identifying women who may be at risk of deficiency.”

J Fam Plann Reprod Health Care 2016 Jul; 42:171
Do Certain Postpartum Contraceptives Cause Depression?
Injectable contraception may raise risk for postpartum depression.
In many settings, depot medroxyprogesterone acetate (DMPA) is commonly offered postpartum for contraception. To evaluate the effects of DMPA on risk for postpartum depression, South African researchers randomized 242 women (87% of whom had previously used DMPA) to receive DMPA or a copper intrauterine device within 48 hours of delivery. At 1 and 3 months postpartum, participants completed the Beck Depression Inventory (BDI-II) and the Edinburgh Postnatal Depression Scale (EPDS).
At 1 month postpartum, median EPDS scores — but not BDI-II scores — were significantly higher among women who received DMPA. At 3 months postpartum, median BDI-II scores — but not EPDS scores — were significantly higher among women who received DMPA. At 1 and 3 months, no significant between-group differences in number of women with EPDS scores ≥12 were observed (scores ≥10 indicate possible depression). In addition, no significant differences occurred in the number of women with BDI-II ≥14, although at 3 months, 8 of 113 women who received DMPA versus 2 of 117 who received a copper IUD (P=0.05) had BDI-II scores ≥29 (indicating severe depression).
COMMENT: The authors note that the BDI-II and the EPDS have different foci as screening tools, which may explain the apparent inconsistencies in outcomes. As they conservatively conclude, they cannot rule out the possibility that immediate postnatal DMPA use is associated with depression. Until further evidence becomes available, subdermal contraception (which can be promptly removed if depressive symptoms appear) offers a highly effective alternative.
CITATION(S): Singata-Madliki M et al. The effect of depot medroxyprogesterone acetate on postnatal depression: A randomised controlled trial. J Fam Plann Reprod Health Care 2016 Jul; 42:171.


Clin Infect Dis 2016 Aug 1; 63:300
Are MRSA Antibiotics Overprescribed for Community-Acquired Pneumonia?
Nearly 30% of hospitalized CAP patients received antibiotics for MRSA, even though fewer than 1% had MRSA-associated CAP.
Recent reports suggest that Staphylococcus aureus and, particularly, methicillin-resistant S. aureus(MRSA) seldom cause community-acquired pneumonia (CAP). However, many clinicians empirically treat CAP with the anti-MRSA antibiotics vancomycin and linezolid because of concerns about MRSA.
To better define the incidence and clinical presentation of MRSA-associated CAP, investigators conducted a CDC-funded, multicenter, prospective, active-surveillance study of patients hospitalized with CAP in Illinois and Tennessee between 2010 and 2012. Diagnoses were based on bacterial tests of blood and high-quality sputum samples, urinary antigen tests, and nucleic acid amplification tests of oropharyngeal swabs. S. aureus CAP was defined as detection of S. aureus from a respiratory or blood specimen.
Of 2259 CAP patients who underwent etiologic testing, 1.6% had S. aureus CAP and 0.7% had MRSA CAP. Compared with pneumococcal pneumonia patients, MRSA CAP patients presented with similar signs and symptoms but were more likely to be on hemodialysis, to have diabetes, and to have more severe disease. Vancomycin or linezolid was prescribed during the first 3 days of admission for 29.8% of all CAP patients.
COMMENT: This study shows that despite the relative infrequency of CAP due to S. aureus and, especially, MRSA, empirical therapy for MRSA was given in nearly a third of all cases. For now, this is a ripe issue for antimicrobial stewardship. In the future, rapid and specific tests for pulmonary pathogens, including Staphylococcus, would be helpful.
CITATION(S):Self WH et al. Staphylococcus aureus community-acquired pneumonia: Prevalence, clinical characteristics, and outcomes. Clin Infect Dis 2016 Aug 1; 63:300. (http://dx.doi.org/10.1093/cid/ciw300)


J Clin Oncol 2016 Jul 1; 34:2265
Racial Differences in End-of-Life Care Among Patients with Metastatic Cancer
Compared with white patients, black patients were more likely to receive intensive medical intervention and to overestimate their life expectancy.
Two studies provide complementary insights on racial differences in end-of-life medical care in the U.S.
Researchers linked national cancer-registry and Medicare data to examine end-of-life interventions in 883 women (age, ≥65; 85% white, 15% black) who had stage IV disease at initial presentation with breast cancer and who died between 2007 and 2012. Black women, compared with white women, were less likely to use hospice (60% vs. 71%), less likely to receive antidepressants or medications for insomnia, more likely to die in the hospital (36% vs. 22%), and more likely to either be admitted to an intensive care unit or have more than one hospitalization or emergency department visit during the last 30 days of life (40% vs. 29%).
Another study involved 229 patients (86% white, 14% black) with metastatic cancer and physician-estimated life expectancy of <6 months. Patients were asked to estimate their life expectancies and to indicate the source of their estimates. All patients died during the study's observation period. White patients were significantly more likely than black patients (43% vs. 13%) to give estimates that fell within 12 months of actual survival. Fully 65% of black patients (vs. 22% of white patients) overestimated their survival by at least 5 years. Black patients' estimates came from personal beliefs (65%) or religious beliefs (35%), whereas white patients' estimates came mostly from personal beliefs (72%) or information from physicians (21%).
COMMENT: The higher intensity of medical care near the end of life among black cancer patients seems to fit with their overestimates of life expectancy (compared with white patients' estimates). These studies weren't designed to determine specific reasons for their findings, but black patients' mistrust of the medical establishment — an outgrowth of a history of discrimination — is a plausible factor mentioned by the authors of the life-expectancy study.
CITATION(S): Check DK et al. Investigation of racial disparities in early supportive medication use and end-of-life care among Medicare beneficiaries with stage IV breast cancer. J Clin Oncol 2016 Jul 1; 34:2265.

Trevino KM et al. Accuracy of advanced cancer patients' life expectancy estimates: The role of race and source of life expectancy information. Cancer 2016 Jun 15; 122:1905. (http://dx.doi.org/10.1002/cncr.30001)

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Am J Gastroenterol 2016 Jul; 111:1024
Predictors of Fecal Microbiota Transplant Failure
Disease severity, in-patient status, and additional C. difficile hospitalization were risk factors for failure.
Ten- to 20% of patients treated with fecal microbiota transplant (FMT) for recurrent or refractoryClostridium difficile infection (CDI) fail to experience a cure. Investigators sought to identify risk factors associated with such failure.
Data on 328 patients from two referral centers was used to determine predictors of FMT failure. Patients from a third center provided a validation cohort. Predictors of FMT failure were severe or severe-complicated disease, inpatient status at the time of FMT, and previous hospitalization for C. difficile.
A risk score of 0–13 indicated low, moderate, or high risk for early treatment failure. (Early failure was defined as nonresponse or recurrent diarrhea with positive C. difficile tests within 1 month of FMT.) Severe or severe-complicated disease contributed 5 points to the score and inpatient FMT 4 points, with 1 point for each CDI-related hospitalization. In the developmental cohort, the risk for early failure within the first month was 5.6% for low-risk, 12.7% for moderate -risk, and 41.0% for high-risk patients. Rates were similar in the validation cohort.
COMMENT: These results should help clinicians predict which patients will have high risk for FMT failure or recurrent CDIs.
CITATION(S): Fischer M et al. Predictors of early failure after fecal microbiota transplantation for the therapy ofClostridium difficile infection: A multicenter study. Am J Gastroenterol 2016 Jul; 111:1024.

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Aliment Pharmacol Ther 2016 Aug; 44:234
Increased Mortality in Patients with Peptic Ulcers
Cause of death in these patients is usually attributable to comorbid disease.
Despite advances in the care of peptic ulcer disease (PUD), mortality in hospitalized PUD patients has not changed significantly, and details of long-term mortality in these patients remain unclear. Investigators used Finnish health databases to identify 8146 patients hospitalized with PUD between 2000 and 2008 and evaluated mortality and cause of death in these patients during a mean 4.9 years of follow-up (40,200 patient-years).
Overall mortality was higher in patients with PUD than in the standard population (standardized mortality ratio, 2.53; 95% confidence interval, 2.44–2.63). Almost 12% of the patients died within 1 year; there was no change in the death rate over the study period. Patients with complicated (bleeding, perforated) ulcers had higher mortality than those with uncomplicated ulcers: Hazard ratios at 6 months were 2.06 (95% CI, 1.68–2.54) for perforated and 1.32 (95% CI, 1.11–1.58) for bleeding ulcers compared with patients with uncomplicated PUD. PUD was the cause of 30-day mortality in 31% to 43% of patients, but more than 50% died from cardiovascular or malignant or benign gastrointestinal diseases. PUD caused less than 15% of 1-year mortality; malignancy and cardiovascular disease were the two leading causes of death at this time point. Prior use of statins was associated with a decrease in all-cause mortality.
The authors conclude that patients hospitalized with PUD have decreased long-term survival, noting that most of the deaths were from comorbid illnesses. They suggest that focusing treatment on comorbid illnesses, such as cardiovascular disease, could improve the survival of patients with PUD.
COMMENT: The results of this study are consistent with other studies of short-term mortality, showing that most patients with PUD die from comorbid illness. The interaction of PUD with underlying disease appears to increase short-term and long-term mortality compared with the standard population.
CITATION(S): Malmi H et al. Increased short- and long-term mortality in 8146 hospitalised peptic ulcer patients. Aliment Pharmacol Ther 2016 Aug; 44:234.

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