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Content 7


The Doctor and the Pharmacist

Radio Show Articles:
April 22, 2017

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A Changing Understanding of GERD-Related Cough
Late-Life Mentally Stimulating Activities and Incident Mild Cognitive Impairment
Does Vitamin D Supplementation Prevent Adverse Cardiovascular Events?
Celiac Disease and Anorexia Nervosa: Are They Connected?
Comparison of Two Guidelines on Statins for Primary Cardiovascular Disease Prevention
In Vitro Fertilization Contributes Substantially to U.S. Births
Keep a Close Eye on Women Who Become Pregnant Too Soon After Gastric Bypass Surgery
Gastric Acid Suppression and Risk for Recurrent Clostridium difficile Infection

Gut 2017 Mar 15
A Changing Understanding of GERD-Related Cough
Acid doesn't seem to be a determinant of cough.
Although cough is a well-recognized “extraesophageal manifestation” of gastroesophageal reflux disease (GERD), it does not respond well to acid suppression with proton-pump inhibitors (PPIs), especially in patients who do not have typical GERD symptoms of heartburn or regurgitation.
To identify determinants of cough in GERD, researchers in Europe evaluated 24-hour esophageal pH impedance pressure monitoring results (off PPIs) in 49 patients identified with reflux-induced cough. They compared characteristics of reflux episodes with and without an accompanying cough burst (≥2 rapid simultaneous pressure peaks within 3 seconds). A reflux episode was defined as an orally progressing sequential drop in impedance to <50% of baseline value and was considered acidic if pH was <4 for at least 4 seconds.
Of 2270 reflux episodes identified, 395 included cough bursts. Factors significantly associated with cough burst were a higher proximal extent of the refluxate and longer volume clearance time, but not pH drop or acid clearance time. The percentage of reflux episodes that were acidic was similar with or without cough. Among the 49 patients, 19 had no typical GERD symptoms (heartburn, regurgitation, or both).
COMMENT: Although acid is an extremely important contributing factor in GERD, this study indicates its lack of causal importance in GERD-related cough. The fact that some reflux episodes reaching only the distal esophagus included cough events suggests a neurogenic esophagobronchial reflex in some, rather than frank aspiration. Clearly, impedance pH monitoring in patients with GERD-related cough is helpful to guide therapies and expectations for successful response.
CITATION(S): Herregods TVK et al. Determinants of reflux-induced chronic cough. Gut 2017 Mar 15; [e-pub].
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JAMA Neurol 2017 Mar1; 74:332
Late-Life Mentally Stimulating Activities and Incident Mild Cognitive Impairment
Mentally stimulating activities may decrease the risk for mild cognitive impairment in late life.
To evaluate the effect of late-life mentally stimulating activities on the incidence of mild cognitive impairment (MCI), researchers conducted a longitudinal, population-based study. The 1929 participants (median age, 77) completed a questionnaire about mentally stimulating activities within 1 year of enrollment. Neuropsychological testing was performed at baseline and every 15 months. Cognitive status was determined by an expert consensus panel. Apolipoprotein E ℇ4 status was also obtained.
Of the participants, 512 were apolipoprotein E ℇ4 carriers, and 456 developed MCI during about 4 years of follow-up. After adjustment for age, sex, and education, mentally stimulating activities performed at least 1 to 2 times a week were associated with a decrease in MCI risk of 22% for playing games, 28% for craft activities, 30% for computer uses, and 23% for social activities. Reading books did not significantly affect MCI risk. Craft activities, computer use, and social activities were associated with an approximate 25% risk reduction for amnestic MCI. Only computer use was associated with a decreased risk for nonamnestic MCI. The lowest MCI risk was seen in apolipoprotein E ℇ4 noncarriers who performed mentally stimulating exercises (except for craft activities), and the highest MCI risk was seen in apolipoprotein E ℇ4 carriers who did not perform mentally stimulating activities.
COMMENT: Consistent engagement in mentally stimulating activities may reduce the risk for MCI in late life. Effects may be modified by apolipoprotein E ℇ4 status. Although these results are promising, other lifestyle factors such as physical exercise and diet may affect cognitive status and should be considered in the overall assessment of patients. Controlling other risk factors for cognitive decline, including hypertension, diabetes, and obesity, also remain important.
CITATION(S): Krell-Roesch J et al. Association between mentally stimulating activities in late life and the outcome of incident mild cognitive impairment, with an analysis of the APOE ℇ4 genotype. JAMA Neurol 2017 Mar1; 74:332.
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MM: I see fault with this study in that it persists in failing to recognize that an optimal blood level of Vitamin D is significantly greater than what is being considered in this study. I maintain that optimal levels of Vitamin D are 60-80ng/ml and not the paltry 25ng/ml that is touted in this study. It is my belief that as long as these lower levels are considered optimal, these studies will continue to be skewed. Additionally, many studies have demonstrated that a daily or weekly dose of Vitamin D more closely approximates what we would normally obtain from diet and sun exposure and that receiving a monthly high dose in not as beneficial.
JAMA Cardiol 2017 Apr 5
Does Vitamin D Supplementation Prevent Adverse Cardiovascular Events?
In a randomized trial, the answer was “no.”
Some observational studies suggest excess cardiovascular (CV) risk in people with low vitamin D levels. To determine whether vitamin D supplementation prevents adverse CV events, about 5000 New Zealand adults (age range, 50–84) were randomized to receive either vitamin D3 (100,000 units once monthly) or placebo. At baseline, the mean 25-hydroxyvitamin D (25[OH]D) level was 25 ng/mL. About half the participants had no known cardiovascular (CV) disease. The other half were labeled as having CV disease, but hypertension was the most common diagnosis (only 6% had previous myocardial infarction).
Mean 25(OH)D levels doubled in the supplemented group and didn't change in the placebo group. However, during average follow-up of 3.3 years, the incidence of adverse CV events was 12% in both groups. Supplementation did not lower adverse CV event rates in the subgroup with 25(OH)D levels <20 ng/mL at baseline (about 30% of participants) and did not lower event rates regardless of previous history of CV disease.
COMMENT: Vitamin D supplementation did not prevent adverse CV events in this trial. The inverse relation between vitamin D levels and CV disease, noted in observational studies, might well reflect confounding by comorbidities associated with both low vitamin D status and CV risk. Some critics will question the vitamin D dosing in this study (monthly rather than daily) or the low proportion of participants with established CV disease other than hypertension. In any case, we still have no evidence that vitamin D supplementation confers CV benefit.
CITATION(S): Scragg R et al. Effect of monthly high-dose vitamin D supplementation on cardiovascular disease in the vitamin D assessment study: A randomized clinical trial. JAMA Cardiol 2017 Apr 5; [e-pub].
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MM: This is not a particularly surprising result when we consider the inflammatory effect of gluten and the subsequent increase in insulin resistance and belly fat associated with this. The frustration experienced with chronic weight and belly fat gain coupled with the general pressure towards having a "trim and fit" body could lead to a body dysmorphic condition that would then lead to an increased risk of anorexia nervosa.
Pediatrics 2017 Apr 3
Celiac Disease and Anorexia Nervosa: Are They Connected?
A bidirectional association was observed in Swedish girls and women.
Anorexia nervosa (AN) has been linked to celiac disease (CD) in case reports. To test this possible association further, investigators conducted a retrospective, case-control, cohort study involving 17,959 women with CD (median age at diagnosis, 28 years; range, 6–52 years) and 89,379 age- and sex-matched, population-based controls identified in the Swedish national health registry.
From 1987 through 2009, during more than 1 million person-years of follow-up, patients with a biopsy-proven diagnosis of CD were more likely than controls to have later AN (27 vs. 18/100,000 person-years; hazard ratio, 1.46). Also, patients with AN were more likely than controls to have later CD (odds ratio, 2.18). In subgroups of patients with mucosal inflammation on bowel biopsy or abnormal CD serology but a normal CD biopsy, an association with AN before and after biopsy was also found. In a small group of men with AN, no association with CD was identified.
COMMENT: These results demonstrate that an association exists between AN and CD in Swedish girls and women. We should watch for the development of either diagnosis once one condition is identified. These data are noteworthy in light of the widespread public concern about dietary gluten. Editorialists raise the intriguing question of whether the voluntary avoidance of gluten for personal preference might lead to later AN.
CITATION(S): Marild K et al. Celiac disease and anorexia nervosa: A nationwide study. Pediatrics 2017 Apr 3; [e-pub].
Golden NH and Park KT.Celiac disease and anorexia nervosa — an association well worth considering.Pediatrics 2017 Apr 3; [e-pub].
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MM; Be very careful of what you listen to in the future when recommendations will be made about taking statins for raised cholesterol. I fear that the results from this study will be touted in the media and by drug manufacturers to increase the number of people taking statins when there are lifestyle choices that should be exercised first.
JAMA 2017 Apr18; 317:1563
Comparison of Two Guidelines on Statins for Primary Cardiovascular Disease Prevention
One U.S. guideline recommends statins for substantially more patients than does the other.
Two U.S. guidelines — one from the U.S. Preventive Services Task Force (USPSTF; NEJM JW Gen Med Dec 15 2016 and JAMA 2016; 316:1997) and the other from the American College of Cardiology/American Heart Association (ACC/AHA; NEJM JW Gen Med Dec 15 2103 and J Am Coll Cardiol 2014; 63:2889) — differ in their recommendations on eligibility for statins to prevent cardiovascular disease (CVD). To illustrate these differences, researchers applied both guidelines to 3416 adults (median age, 53) without CVD in a U.S. national health database; 22% already were taking lipid-lowering medications.
Applying the USPSTF recommendations would have resulted in an additional 16% of patients receiving statins, whereas applying the ACC/AHA guideline would have resulted in an additional 24% receiving statins. About 9% more patients would be eligible under ACC/AHA guidelines than under USPSTF guidelines. Among patients who were eligible only by ACC/AHA criteria, more than half had relatively low 10-year risk for CVD (<10%) but had higher long-term risk due to traditional CVD risk factors, especially diabetes.
COMMENT: If these results were extrapolated to all U.S. adults, an estimated 9.3 million more adults would be eligible for primary preventive therapy with statins under ACC/AHA than under USPSTF recommendations. Most of the additional people included by ACC/AHA guidelines are younger (age range, 40–59), and many of them might prefer detailed guidance on other approaches to CVD risk reduction before resorting to drug therapy.
CITATION(S): Pagidipati NJ et al. Comparison of recommended eligibility for primary prevention statin therapy based on the US Preventive Services Task Force recommendations vs the ACC/AHA guidelines. JAMA 2017 Apr18; 317:1563.
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JAMA 2017 Mar 28; 317:1272
In Vitro Fertilization Contributes Substantially to U.S. Births
Older women are more likely use IVF, and live birth is more likely with insurance coverage.
In vitro fertilization (IVF) is now responsible for 1.6% of U.S. births. Two analyses provide additional insight into the societal impact of assisted reproductive technology. Using national data from 2012 through 2014, CDC investigators estimated that the proportion of births resulting from IVF increases with maternal age: IVF was used in 76% of the 2020 births to women 50 or older versus 4% of some 1.5 million births among those aged 35 to 39. Moreover, frozen oocytes or embryos were used in >70% of IVF births in which women older than 45 provided their own eggs — and in >95% of such births in women 50 or older. Use of gestational carriers also increased with maternal age, accounting for 20% of such births to women 50 or older.
In the second study, investigators at a single academic fertility center compared cumulative probabilities of live birth from 2001 through 2010 among women with IVF insurance versus those without such insurance. Patients with insurance coverage were younger, but likelihood of live birth in any single cycle did not differ with or without coverage. The proportion of women returning for a second cycle if the first cycle failed was significantly higher in those with IVF insurance, as was mean cumulative live birth probability after four cycles.
COMMENT: Together these two studies expand our knowledge of IVF's impact on U.S. society. Because IVF pregnancies carry higher risk than naturally occurring pregnancies, these findings point to the need for clinicians to learn the circumstances of their patients' pregnancies. The data further suggest that more high-risk pregnancies may occur in states with IVF insurance mandates.
CITATION(S): Levine AD et al. Contribution of assisted reproductive technology to overall births by maternal age in the United States, 2012-2014. JAMA 2017 Mar 28; 317:1272.
Jungheim ES et al. In vitro fertilization insurance coverage and chances of a live birth. JAMA 2017 Mar28; 317:1273.
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MM; I couldn't agree more with the findings of this study. People seem to frequently be in a hurry to move forward with their life plans without fully acknowledging the risks initiated by severe changes to their lives. Al though gastric bypass frequently shows a rapid weight loss, it is not without risks. On the other hand, we have seen numerous women utilize the HCG weight loss and Metabolic Management program and successfully get pregnant soon afterwards and have no noticeable increased risk of any of the problems associated with gastric bypass surgery or other similar bariatric approaches.
Obstet Gynecol 2017 Apr 4
Keep a Close Eye on Women Who Become Pregnant Too Soon After Gastric Bypass Surgery
Such women are at excess risk for internal herniation and intestinal obstruction during the first postsurgical year.
To study the effect of bariatric surgery on risk for intestinal obstruction in pregnancies conceived postprocedure, investigators analyzed data from a national cohort of Swedish women who had undergone bariatric surgery (primarily gastric bypass operations) from 1987 to 2011 and subsequently became pregnant. A control group consisted of women with first-trimester body-mass index >35 kg/m2 who had not had bariatric surgery.
Among 2543 women who became pregnant after bariatric surgery, rates of intestinal obstruction during pregnancy stratified by time since surgery were 3.3% (<1 year), 1.9% (1–2 years), 1.1% (3 years), 0.5% (4 years), and 0.0% (5–12 years). The overall rate of intestinal obstruction requiring surgical treatment was 1.5% for the first pregnancy after bariatric surgery compared with 0.02% in obese women who had not undergone bariatric surgery (adjusted odds ratio, 34.3).
COMMENT: These findings reinforce the recommendation to delay pregnancy at least 1 to 2 years after gastric bypass surgery to reduce risk for various complications including internal herniation (NEJM JW Womens Health Mar 2017 and multiple citations). Most cases of intestinal obstruction following gastric bypass present with abdominal pain, nausea, and vomiting — but during pregnancy, it may be difficult to differentiate between pain caused by intestinal obstruction versus uterine contractions. Hence, diagnostic imaging should be considered for all pregnant women who present with severe abdominal pain and histories of bariatric surgery. Serial serum lactate measurements can also help identify women with progressing intestinal obstruction, bowel ischemia, and sepsis. During this study period, surgeons in Sweden were generally performing gastric bypass procedures; more recently, however, sleeve gastrectomy has become more common for reproductive-aged obese women considering pregnancy, a trend that may help reduce risk for postprocedure internal herniation and intestinal obstruction.
CITATION(S): Stuart A and Källen K.Risk of abdominal surgery in pregnancy among women who have undergone bariatric surgery. Obstet Gynecol 2017 Apr 4; [e-pub].
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JAMA Intern Med 2017 Mar 27
Gastric Acid Suppression and Risk for Recurrent Clostridium difficile Infection
Risk was particularly elevated in studies that involved proton-pump inhibitors.
Evidence of a relation between proton-pump inhibitors (PPIs) and risk for an initial episode of Clostridium difficile infection (CDI) is somewhat mixed but sufficient for the FDA to issue a warning. In this meta-analysis of 16 observational studies, researchers examined whether risk for recurrent CDI was higher in patients who took gastric acid suppressants (PPIs, histamine-2–receptor antagonists [H2RAs], or both) between initial and recurrent CDI episodes. Recurrent CDI was defined variably across studies as occurring within 30, 60, or 90 days after resolution of initial infection.
A remarkable 52% of 7700 patients with initial CDI were taking acid suppressants. Risk for recurrent CDI was significantly higher among those who used acid suppressants than among those who did not (22% vs. 17%; adjusted odds ratio, 1.52). In subgroup analyses, the association between acid suppressants and recurrent CDI was significant in studies in which only PPIs were used (OR, 1.66) but not in those that involved both PPIs and H2RAs (OR, 1.37).
COMMENT: Because some identified studies were not adjusted for clinical and demographic factors associated with CDI, risks attributed to PPIs could be overestimated due to confounding. Even so, the association between PPIs and recurrent CDI is strong enough that clinicians should avoid prescribing these drugs to patients with CDI (unless the patient has a strong indication for PPI therapy). Preferential use of H2RAs also might be considered for C. difficile–infected patients who have a strong indication for acid-suppressive therapy.
CITATION(S): Tariq R et al. Association of gastric acid suppression with recurrent Clostridium difficile infection: A systematic review and meta-analysis. JAMA Intern Med 2017 Mar 27; [e-pub].

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