• Calorie Restriction in Nonobese Adults is associated with Improvements in Mood,
Sleep Quality, and Sexual Function
• Once PPIs Work for Esophageal Eosinophilia, then what?
• Histamine 1 Blockers for IBS Treatment
• Juice is best for Treating Mild Gastroenteritis with Minimal Dehydration
• Cardiac Toxicity among Breast Cancer Patients in Routine Practice
• Nutraceuticals as Adjunctive Treatments for Depression?
• Roughly a Third of Outpatient Antibiotic Prescriptions may be Inappropriate
• Medical Errors — Third-Leading Cause of U.S. Deaths?
• Infecting Mosquitoes with Bacteria could help fight Zika
• Fasting isn't Required before Lipid Levels are Measured
• Can Vitamin D Supplementation prevent Type 2 Diabetes?
JAMA Intern Med 2016 May 2
Calorie Restriction in Nonobese Adults is associated with Improvements in Mood, Sleep Quality, and Sexual Function
Two years of 25% calorie restriction resulted in significant weight loss, with no negative effects on health-related quality of life.
Calorie restriction (CR) extends lifespan in many animal species, including nonhuman primates, but whether it has adverse effects on mood and quality of life in humans remains a question. In this multisite U.S. study, investigators randomized 220 healthy nonobese adults (mean age, 38; mean body-mass index, 25 kg/m2) to 2 years of 25% CR or usual calorie intake on an ad libitum (AL) basis. CR participants received individual and group counseling throughout the study period.
At 24 months, mean weight loss was 7.6 kg in the CR group (10% of baseline weight) and 0.4 kg in the AL group. Compared with the AL group, the CR group showed significant improvements in mood, quality of life, sleep quality, and sexual drive and relationship satisfaction. Most measures of improvement in the CR group correlated with percent weight loss.
COMMENT: These findings are reassuring that CR in nonobese adults results not only in weight loss but also in improvements in mood and quality of life.
CITATION(S): Martin CK et al. Effect of calorie restriction on mood, quality of life, sleep, and sexual function in healthy nonobese adults: The CALERIE 2 randomized clinical trial. JAMA Intern Med 2016 May 2; [e-pub].
(http://dx.doi.org/10.1001/jamainternmed.2016.1189)
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Aliment Pharmacol Ther 2016 Feb; 43:534
Once PPIs Work for Esophageal Eosinophilia, Then What?
A step-down approach may work to determine appropriate dose and duration but requires longer-term study.
National guidelines recommend that clinicians rule out proton-pump inhibitor (PPI)–responsive esophageal eosinophilia (EE) before diagnosing eosinophilic esophagitis (EoE; NEJM JW Gastroenterol Aug 2013 and Am J Gastroenterol 2013; 108:679). But once a patient with suspected EoE responds to a PPI, what dose should we recommend, and for how long?
To answer this question, researchers prospectively evaluated outcomes of a step-down approach to PPI therapy in 40 patients identified with PPI-responsive EE. All participants had achieved complete symptomatic and endoscopic response to omeprazole 40 mg twice daily for ≥2 months. Endoscopy was performed after each PPI dose adjustment but not until at least 8 weeks after the adjustment.
Initially, 38 patients were tapered to 40 mg daily, of whom 31 (81%) maintained total remission (clinical and histologic) at 2 months. (Three patients who relapsed were given 60 mg and achieved total remission.) Subsequently, 13 of 31 patients left the study and 18 were tapered to 20 mg daily, of whom 15 (83%) continued to remain in remission. Subsequently, 12 patients left the study and 2 patients were tapered to 10 mg daily. Patients leaving the study were asymptomatic. No patient with histologic remission showed clinical relapse, but 50% with histologic relapse were in clinical remission.
COMMENT: Sustained remission and prevention of recurrent symptoms or strictures is key to management of PPI-responsive EE. Although PPIs continue to be the focus of long-term safety challenges, they constitute one of the safest drug classes we have for treating gastroenterology diseases. Key issues that remain unsettled are what dose and duration of PPI treatment are predictive of a need for lifetime therapy for prevention of relapse, and whether histologic relapse predicts a higher likelihood of fibrostenotic disease. My personal bias is to use histologic parameters to guide best practice at present and not rush to get to the lowest PPI dose. Larger studies with longer follow-up are needed to provide better direction on dose and interval dosing.
CITATION(S): Gómez-Torrijos E et al. The efficacy of step-down therapy in adult patients with proton pump inhibitor-responsive oesophageal eosinophilia. Aliment Pharmacol Ther 2016 Feb; 43:534.
(http://dx.doi.org/10.1111/apt.13496)
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Gastroenterology 2016 Apr; 150:875
Histamine 1 Blockers for IBS Treatment
Preliminary data indicate that ebastine reduces abdominal pain and other IBS symptoms.
Visceral hypersensitivity is an important mechanism of irritable bowel syndrome (IBS). Transient reporter potential channel V1 (TRPV1) is a nociceptor that responds to capsaicin and other noxious stimuli. Sensitization of the TRPV1 receptor has been documented in some pain syndromes and could be induced by mast cell mediators including histamine. Researchers examined this hypothesis and tested a histamine receptor H1blocker in patients with IBS in a multiphase study.
In phase one of the study, rectal biopsy specimens from 9 patients with IBS and 12 healthy control patients were studied. In vitro analyses showed that TRPV1 was sensitized in the patients with IBS, the sensitization was mediated by the effects of histamine on its receptor, and a histamine metabolite called imidazole acetaldehyde could also sensitize the TRPV1 receptor via its effects on the histamine H1 receptor.
In the second phase, investigators randomized 55 patients with IBS to receive the second-generation histamine receptor H1 blocker ebastine (20 mg daily) or placebo. During the 12-week treatment period, patients recorded symptoms, and their rectal sensitivity was evaluated before and after treatment using a barostat study. Compared with the placebo group, the ebastine group experienced significant reductions in abdominal pain scores, reduced flatulence and bloating, and improved sleep, diet, and emotional role scores on quality-of-life questionnaires. In the barostat studies, ebastine use was associated with greater reduced sensitivity to distention at lower pressures compared with placebo. Additional analyses demonstrated no effect of ebastine on measures of immune response.
COMMENT: Given their excellent side-effect profiles, low cost, and their availability (for some) over the counter, the incorporation of second-generation H1 blockers into the armamentarium of IBS treatments seems a major advance.
CITATION(S):Wouters MM et al. Histamine receptor H1–mediated sensitization of TRPV1 mediates visceral hypersensitivity and symptoms in patients with irritable bowel syndrome. Gastroenterology 2016 Apr; 150:875.
(http://dx.doi.org/10.1053/j.gastro.2015.12.034)
http://www.ncbi.nlm.nih.gov/pubmed/26752109?access_num=26752109&link_
type=MED&dopt=Abstract
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JAMA 2016 Apr 30
Juice is best for Treating Mild Gastroenteritis with Minimal Dehydration
Dilute apple juice for initial hydration followed by fluids of the child's choice was superior to electrolyte maintenance solution for treating children with mild gastroenteritis and minimal dehydration.
Oral rehydration with electrolyte maintenance solutions has become a mainstay in treating moderate to severe dehydration, but could less-expensive, better-tasting fluids such as diluted juice be just as effective in milder cases?
In a single-blind noninferiority trial, researchers randomized 647 children (aged 6−60 months) presenting to a Canadian pediatric emergency department with gastroenteritis and minimal dehydration to receive either 1) half-strength apple juice for initial hydration followed by fluids of the child's choice or 2) apple-flavored electrolyte maintenance solution. The primary outcome was treatment failure, defined as occurrence of any of the following within 7 days: intravenous rehydration, hospitalization, unscheduled visit to a physician, treating physician's request to cross over to other study arm, weight loss ≥3% or Clinical Dehydration Scale score ≥5 at follow-up.
Treatment failure was significantly lower in the juice/preferred fluids group (16.7% vs. 25.0%); the difference met the study's criteria for noninferiority and superiority. Significantly fewer children in the juice/preferred fluids group received intravenous rehydration at the index visit (0.9% vs. 6.8%) and within 7 days (2.5% vs. 9.0%). Juice/preferred fluids was most beneficial in children ≥24 months of age (treatment failure rate, 9.8% vs. 25.9%).
COMMENT: Use of special oral rehydration solution in cases of mild gastroenteritis may not only be unnecessary but also could lead to worse outcomes than use of more readily available and cheaper fluids, such as apple juice. Juices and energy drinks with high glucose content have not been shown to harm children, and their palatability may lead to higher overall fluid intake. Evidence supporting a less-restrictive approach to rehydrating mildly dehydrated children should be welcomed by clinicians and parents alike.
CITATION(S): Freedman SB et al. Effect of dilute apple juice and preferred fluids vs electrolyte maintenance solution on treatment failure among children with mild gastroenteritis: A randomized clinical trial. JAMA 2016 Apr 30; [e-pub]. (http://dx.doi.org/10.1001/jama.2016.5352)
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J Clin Oncol 2016 Apr 18
Cardiac Toxicity among Breast Cancer Patients in Routine Practice
Patients had a threefold higher cumulative incidence of major cardiac events than did a control population without cancer.
Medical oncologists are attuned to the risk for cardiac toxicity from drugs such as anthracyclines and HER2-directed therapy in combination with chemotherapy. Most of the caution regarding these agents is derived from data obtained in carefully regimented clinical trials. To get a better sense of cardiac dysfunction associated with breast cancer therapy in routine clinical practice, investigators conducted a retrospective, population-based, cohort study involving 18,540 women (age, 47–62 years) with stage I–III breast cancer at 14 cancer centers in Ontario, Canada, between 2007 and 2012.
During a median follow-up of 3 years, patients had a higher cumulative incidence of major cardiac events — hospital admission or emergency room visit for congestive heart failure (CHF), outpatient diagnosis of CHF, or cardiovascular death — than did a control population without cancer (3.08% vs. 0.96%). Among study patients, the incidence of major cardiac events at 3 years was greater in those older versus younger than age 65 (5.35% vs. 2.51%). The estimated cumulative incidences of major cardiac events for the four categories of cancer treatment studied were as follows:
- Anthracycline-based chemotherapy without trastuzumab, 2.0%
- Nonanthracycline-based chemotherapy with trastuzumab, 5.1%
- Anthracycline-based chemotherapy followed by trastuzumab, 6.6%
- Chemotherapy without an anthracycline or trastuzumab, 3.2%
COMMENT: In two large pivotal trials that led to the approval of trastuzumab as a component of adjuvant therapy for patients with early-stage, HER2-positive breast cancer, at 5-year and 7-years of follow-up, the risks for major cardiac toxicity were 2.0% and 3.9%, respectively, with anthracycline-based chemotherapy followed by trastuzumab versus 0.7% and 1.5% for anthracycline-based chemotherapy without trastuzumab (NEJM JW Oncol Hematol Dec 2011 and N Engl J Med 2011; 365:1273, and NEJM JW Oncol Hematol Jan 2013 and J Clin Oncol 2012; 30:3792). In the current report, with shorter follow-up, these incidences were higher, which may reflect a higher rate of comorbidities found among patients in routine clinical practice. For example, the incidence of diabetes was 10.2% among one treatment group in the current study versus 3.4% and 3.8% among patients in the pivotal trials. These findings emphasize the need for ongoing vigilance in identifying cardiac risk factors and ongoing clinical monitoring.
CITATION(S): Thavendiranathan P et al. Breast cancer therapy–related cardiac dysfunction in adult women treated in routine clinical practice: A population-based cohort study. J Clin Oncol 2016 Apr 18; [e-pub].
(http://dx.doi.org/10.1200/JCO.2015.65.1505)
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Am J Psychiatry 2016 Apr 26
Nutraceuticals as Adjunctive Treatments for Depression?
Omega-3 fatty acids might merit routine adjunctive use for major depression, but data on other nutraceuticals are either less impressive or insufficient.
Investigators performed a systematic review and meta-analysis to determine the usefulness of nutraceuticals (pharmaceutical-grade nutrients) added to conventional antidepressants for treating depressive disorders.
Of 571 screened studies, 40 controlled clinical trials met inclusion criteria. Main categories were one-carbon–cycle agents (folic acid and related substances, S-adenosylmethionine [SAMe], and vitamins B6 and B12), various forms of tryptophan, omega-3 fatty acids, and others.
Despite considerable heterogeneity in 8 studies, positive results with moderate effect sizes were replicated for adjunctive omega-3 fatty acids, but apparently only for eicosapentaenoic acid (EPA) or ethyl-EPA preparations (common EPA dose, 1–2 mg/day) and not docosahexaenoic acid. Of 15 trials using one-carbon–cycle agents, 10 reported positive effects, which were replicated for SAMe and folic acid (including methylfolate and folinic acids). However, in rigorous meta-analyses of folic acid studies, results were not significant. Four of seven tryptophan studies and one on L-5-HTP were positive; missing data prevented meta-analysis. Regarding the 10 studies on other nutraceuticals, data were too limited to permit meta-analyses although individual studies had positive findings for vitamin D, creatine, and amino-acid combination. Findings were mixed for zinc and vitamin C and negative for inositol.
COMMENT: Many of the larger industry-sponsored trials might contain design bias. Cost too is a concern. Adverse effects are generally mild; still, folic acid supplements and omega-3 fatty acids have been associated with increased cancer risk (notably prostate cancer), SAMe with switch to hypomania/mania; tryptophan/L-5-HTP with serotonin syndrome; and high doses of vitamin D, zinc, and vitamin C with hypercalcemia, copper deficiency, and renal stones, respectively. Although these results might support recommending omega-3 fatty acids (and possibly some one-carbon–cycle agents) as adjunctive depression treatments, much more research is needed.
CITATION(S): Sarris J et al. Adjunctive nutraceuticals for depression: A systematic review and meta-analyses. Am J Psychiatry 2016 Apr 26; [e-pub]. (http://dx.doi.org/10.1176/appi.ajp.2016.15091228)
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Roughly a Third of Outpatient Antibiotic Prescriptions may be Inappropriate
By Amy Orciari Herman, Edited by David G. Fairchild, MD, MPH, and Lorenzo Di Francesco, MD, FACP, FHM
Some 30% of outpatient, oral antibiotic prescriptions in the U.S. in 2010–2011 may have been inappropriate, a JAMA study suggests.
Researchers used CDC survey data on roughly 184,000 ambulatory care visits in 2010–2011 to estimate national antibiotic prescribing rates. Nearly 13% of the visits resulted in antibiotic prescriptions. Overall, an estimated 506 antibiotic prescriptions per 1000 population were written each year, but just 353 per 1000 were deemed to be appropriate (based on national guidelines and other parameters). Respiratory infections in particular (e.g., sinusitis, pharyngitis) accounted for 221 antibiotic prescriptions per 1000, but just 111 per 1000 were considered appropriate.
Editorialists point to several study limitations — for example, the researchers didn't have access to patients' medical records, so they simply assumed that antibiotics were indeed necessary for any diagnoses coded as urinary tract infections or pneumonia. These limitations, the editorialists write, "may have led to an underestimation of the burden of inappropriate antibiotic use."
http://jama.jamanetwork.com/article.aspx?articleid=2518263
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Medical Errors — Third-Leading Cause of U.S. Deaths?
By Joe Elia, Edited by David G. Fairchild, MD, MPH, and Lorenzo Di Francesco, MD, FACP, FHM
Death certificates should allow "medical error" to be listed as a cause, researchers argue in The BMJ.
Evaluating estimates published over the past decade, the authors figure that there are roughly 250,000 deaths attributable to medical errors in the U.S. each year. That would rank such errors behind heart disease and cancer, but ahead of chronic obstructive pulmonary disease, as the third most common cause of death in the country.
The authors argue that acknowledging medical errors openly and making them more visible for wider review would create a "culture of learning from our mistakes."
http://www.bmj.com/content/353/bmj.i2139
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Infecting Mosquitoes with Bacteria could help fight Zika
By Amy Orciari Herman, Edited by André Sofair, MD, MPH, and William E. Chavey, MD, MS
Infecting mosquitoes with Wolbachia — an endosymbiotic bacterium frequently found in insects and currently being used to help control dengue in Brazil — might help limit the spread of Zika virus, according to a brief report in Cell Host & Microbe. Wolbachia can rapidly invade host insects and, ultimately, inhibit the transmission of many human pathogens.
Researchers in Brazil fed Zika-infected human blood to mosquitoes that were infected with Wolbachia and also to Wolbachia-free mosquitoes. Two weeks later, Zika levels were significantly lower in the Wolbachia-infected mosquitoes. The researchers then injected the mosquitoes' saliva into Zika-free mosquitoes: saliva from Wolbachia-infected mosquitoes did not cause any new Zika infections, while saliva from Wolbachia-free mosquitoes led to new Zika infections 85% of the time.
The researchers say their findings show that Wolbachia's protective effects could extend beyond dengue and chikungunya viruses. They add, however, that "extensive public engagement will be required before releases of Wolbachia-infected mosquitoes can be scaled up for use."
http://www.cell.com/cell-host-microbe/fulltext/S1931-3128(16)30157-3
http://www.nytimes.com/2016/05/05/science/zika-virus-moquitoes-microbe.html?_r=0
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JAMA Intern Med 2016 Apr 27
Fasting isn't Required before Lipid Levels are Measured
Predictive value for adverse cardiovascular events is as good, and sometimes better, for nonfasting levels.
In this evidence-based clinical review, the author identified three meta-analyses and five clinical practice guidelines that addressed whether fasting was required to measure lipid levels accurately and whether prediction of incident cardiovascular disease (CVD) events differed between fasting and nonfasting lipid levels.
The reviewer came to the following conclusions:
- Nonfasting testing results in clinically insignificant changes compared with fasting results in total, high-density, and low-density lipoprotein cholesterol levels and in only modest changes in triglyceride levels.
- Nonfasting and fasting lipid levels are at least equally predictive for adverse CVD events; nonfasting levels sometimes were more strongly predictive, presumably because nonfasting is the predominant metabolic condition for most people.
- Clinical practice guidelines have shifted during the past 5 years to endorse nonfasting testing in most routine circumstances.
- The recent European Atherosclerosis Society/European Federation for Laboratory Medicine guidelines recommend that, when triglyceride levels are >400 mg/dL with nonfasting testing, ordering a fasting test is appropriate
(Eur Heart J 2016 Apr 26; [e-pub]). - No studies directly compared the cost or convenience of nonfasting versus fasting testing, but a Danish study (where nonfasting testing has been the standard since 2009) showed that only 10% of patients who underwent nonfasting testing required repeat fasting testing.
COMMENT: Nearly all clinicians have had the common experience of requiring patients to return for fasting lipid tests that frequently result in extra expense and inconvenience for patients and breakdowns in care for patients who do not return. The author believes that nonfasting lipid–level assessment should become routine clinical practice. Having already practiced this way for many years, I agree.
CITATION(S):Mora S.Nonfasting for routine lipid testing: From evidence to action. JAMA Intern Med 2016 Apr 27; [e-pub].
(http://dx.doi.org/10.1001/jamainternmed.2016.1979)
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J Clin Endocrinol Metab 2016 Apr; 101:1647
Can Vitamin D Supplementation prevent Type 2 Diabetes?
In prediabetic adults, supplementation did not stop progression to overt diabetes.
Animal experiments and observational studies in humans suggest that vitamin D deficiency might play a role in development of diabetes. To examine whether supplementation affects progression to diabetes, investigators in Norway randomized 511 adults with prediabetes (impaired fasting glucose or impaired glucose tolerance) to receive either vitamin D3 (20,000 IU weekly) or placebo for 5 years. At baseline, mean serum 25-hydroxyvitamin D (25(OH)D) level was 24 ng/mL; during the study, levels doubled in the treatment group and remained unchanged in the placebo group.
At 5 years, the proportions of patients who developed type 2 diabetes were similar in the vitamin D and placebo groups (40% vs. 44%; P=0.45); annual rates of progression to diabetes also were similar in the two groups. In addition, vitamin D supplementation did not prevent diabetes in a subgroup of 112 patients who were vitamin D–deficient at baseline (i.e., 25(OH)D level <20 ng/mL).
COMMENT: Vitamin D supplementation did not prevent progression from prediabetes to type 2 diabetes in this 5-year trial (the largest such trial to date); vitamin D should not be given for this purpose. Whether supplementation might alter the natural history of prediabetes or diabetes in patients with severe vitamin D deficiency remains unclear.
CITATION(S): Jorde R et al. Vitamin D 20 000 IU per week for five years does not prevent progression from prediabetes to diabetes. J Clin Endocrinol Metab 2016 Apr; 101:1647. (http://dx.doi.org/10.1210/jc.2015-4013)
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