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Content 7


The Doctor and the Pharmacist

Radio Show Articles:
April 2, 2016

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Untangling the Obesity Paradox
Turns Out that Body Size Is Correlated with Heart Size
Antibiotic-Resistant E. coli in Urinary Tract Infections
Upper Respiratory Infection and Acute Otitis Media Common in Infancy
Vitamin D During Pregnancy and Risk for Multiple Sclerosis in Offspring
Prolonged Therapy Shows No Benefit for Persistent Lyme Disease Symptoms
Does Hormone Therapy slow Atherosclerosis Progression? It's All About the Timing
Metabolomic Changes with a Low-FODMAP Diet
Are PPIs, NSAIDs, and SSRIs Associated with Microscopic Colitis?
FDA Relaxes Restrictions on Medical Abortion
Parents Who Sleep Poorly Overestimate Their Children's Sleep Problems
Endometriosis Linked to Increased Risk for Heart Disease
Late Risk for Recurrence with Estrogen Receptor–Positive Breast Cancer
Metabolic Syndrome Treatment in Multiple Sclerosis
Overnight Fasting Associated with Reduced Risk for Breast Cancer Recurrence
Combination Naltrexone plus Bupropion for Weight Loss: CV Risks Are Still Unknown
On Review, NFL Concussion Research Ruled a Fumble
Risk and Benefits of Newer Diabetes Drugs Detailed
Triglycerides again Associated with Cardiovascular Risk in a 22-Year Follow-Up Study

MM: "Thin on the outside, Fat on the inside" The term TOFI, “thin-outside-fat-inside” is used to describe lean individuals with a disproportionate amount of fat (adipose tissue) stored within their abdomen. This is a growing problem for adults and children alike. It gets magnified by a variety of factors including insurance companies whose actuarial tables look at BMI but ignore other health parameters. Insurance attitudes frequently reflect those of the general public and the medical community, however, using the bathroom scale as one's primary measure of health is irresponsible and incomplete. It makes much more sense to focus on being "fit", rather than being "thin".
Ann Intern Med 2016 Mar 8
Untangling the Obesity Paradox
In a large cohort study, both higher body-fat percentage and lower body-mass index were associated with shorter survival.
Some studies have shown lower mortality among middle-aged and older people who are overweight or mildly obese compared with those who are normal-weight — a finding termed the obesity paradox. To clarify the contributions of body-mass index (BMI) and adiposity to all-cause mortality, researchers in Manitoba, Canada, examined data from a study of bone density in 49,500 women (mean age, 63) and 5000 men (mean age, 65); dual-energy x-ray absorptiometry (DEXA) scans were used to estimate percent body fat. Mean follow-up was 6.7 years in women and 4.5 years in men.
Participants were divided into quintiles based on BMI and DEXA-derived percent adiposity, with the middle quintile serving as the reference. In fully adjusted models where BMI and adiposity were examined together, lower BMI (≤25 in women and ≤24 in men) was associated with higher risk for all-cause death in both women and men, whereas higher BMI (≥28 in men and women) was not; however, high body-fat percentage was associated with higher mortality.
COMMENT: In this observational study of mostly white women, higher adiposity was associated with higher mortality after adjustment for BMI, and lower BMI was associated with higher mortality after adjustment for adiposity. This finding indicates that BMI might not be a reliable measure of adiposity as it relates to adverse health outcomes, and might help explain the obesity paradox observed in some studies.
CITATION(S): Padwal R et al. Relationship among body fat percentage, body mass index, and all-cause mortality: A cohort study. Ann Intern Med 2016 Mar 8; [e-pub]. (http://dx.doi.org/10.7326/M15-1181)
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JAMA Cardiol 2016 Feb 24
Turns Out that Body Size Is Correlated with Heart Size
In a study of professional American basketball players, cardiac dimensions correlated well to height and body surface area.
Setting normal cardiac dimensions is more than an academic exercise, as these are important for diagnosing hypertrophic cardiomyopathy (HCM) and have dramatic implications for the screening of our young athletes. Controversy exists as to whether cardiac dimensions are related to body size; for adults, criteria for left ventricular hypertrophy (LVH) and HCM are not related to body size. In addition, the criteria for upper limits of normal for the athletic heart are largely based on European studies of relatively racially unmixed cohorts.
These researchers analyzed observational data from rest and stress echocardiograms in 526 National Basketball Association (NBA) players in 2013 and 2014 (mean age, 26). Most of the cohort were black (n=406; 77%). Mean height was 200.2 cm (6 feet, 7 inches); mean weight was 101.1 kg (223 lbs.); mean body surface area (BSA) was 23.8 m2.
LV size and mass were directly proportional to body size. LVH by current diagnostic criteria was present in 144 athletes (27%). The mean LV end diastolic dimension (LVEDD) was 56.8 mm. Based on current diagnostic criteria (abnormal LVEDD, ≥59 mm), LV cavity dilation was found in 192 athletes (36%), but when indexed to height and BSA, LVEDD fell within the normal range for all athletes. LV wall thickness ranged from 8 to 15 mm; an LV wall thickness of ≥13 mm, clearly abnormal according to published standards, was found in 64 athletes (12%). Again, these measurements correlated linearly with height and BSA. Aortic root dimensions also correlated with body size but plateaued at the largest measurements.
COMMENT: This NBA-sponsored study of professional basketball players demonstrates what all of us think is rational but has not previously been convincingly shown: Cardiac dimensions are directly and linearly related to body size. The findings help to establish criteria for LVH and HCM in our larger athletes (and probably in nonathletes). In addition, aortic root sizes should be indexed to height and BSA.
CITATION(S): Engel DJ et al. Athletic cardiac remodeling in US professional basketball players. JAMA Cardiol 2016 Feb 24; [e-pub].
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MM: Antibiotic use should be reserved for when there are no better choices. The use of alternative treatments such as D-Mannose for UTI's or homeopathic products for earaches and other maladies should be the first line of defense. In France, a patient with an earache typically comes out of their physician's office with two Rx's. The first one is to be used immediately and that is a homeopathic medication. If the earache has not significantly improved in 48 hours then they take the second Rx, an antibiotic. This approach may not provide the immediate, high powered response that we, as Americans are typically looking for but it is a more sensible approach that does provide a potentially effective immediate treatment with many fewer downstream potential side effects such as super-infection and constant increases of antibiotic resistance in the patient, the family and the community.
BMJ 2016 Mar 15; 352:i939
Antibiotic-Resistant E. coli in Urinary Tract Infections
E. coli is showing increased resistance to commonly prescribed antibiotics.
Antibiotic-resistant gram-negative organisms are increasingly seen in hospitalized patients. Community-acquired antibiotic resistance has been noted for S. aureus but less so for gram-negative organisms. Outpatient treatment of children with urinary tract infection (UTI) relies on oral antibiotics with narrow activity against gram-negative organisms and has been relatively unchanged for the last several decades. Now, investigators have assessed the global prevalence of antibiotic resistance among pediatric UTIs treated in the community setting.
In 58 observational studies from 26 countries, both developed (belonging to the Organisation for Economic Co-operation and Development, or OECD) and developing (non-OECD), researchers assessed resistance in almost 78,000 Escherichia coli urinary isolates and found the following:

COMMENT: Despite this study's limitations (wide age range and variable UTI inclusion criteria), the observations that resistance to commonly used antibiotics is frequent, highest in developing countries, and influenced by recent antibiotic exposure help to clarify the risk for antibiotic-resistant bacterial infections. When conducting empiric antibiotic selection for UTI, community resistance patterns and prior antibiotic exposure should be kept in mind. As noted in an accompanying editorial, the individual actions of many, including livestock producers and antibiotic prescribers, lead to broader consequences that affect us all.
CITATION(S): Bryce A et al. Global prevalence of antibiotic resistance in paediatric urinary tract infections caused by Escherichia coli and association with routine use of antibiotics in primary care: Systematic review and meta-analysis. BMJ 2016 Mar 15; 352:i939. (http://dx.doi.org/10.1136/bmj.i939)

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MM: There are many parents who have become wary of vaccines for common illnesses such as the flu. Treatments for flu and colds have become less effective due to viruses and bacteria becoming more resilient and resistant to antibiotic treatments. What we should be learning is that although an ounce of prevention may be worth a pound of cure, it is the appropriate prevention that is necessary. Changing the environment by eliminating second hand smoke, breast feeding for as long as possible, limitation of sugars and processed foods once a child stops nursing and starts eating real food are all things that can provide benefits to the child. As parents and grandparents we should focus on what changes and differences we can make rather on those that we have no control or limited control over. As a grandparent, if our children are too busy with life in general to prepare pure and wholesome foods in advance for their kids, then perhaps we should step up and offer to share the load. Remember that grandparenting does not have to end with cuddling and loving. Supportive actions can be just as rewarding and beneficial to a child's welfare and development.
Pediatrics 2016 Apr; 137:e20153555
Upper Respiratory Infection and Acute Otitis Media Common in Infancy
Breast-feeding reduced the risks for both.
Researchers investigated the prevalence of viral respiratory infections and acute otitis media (AOM) in a prospective cohort of 367 healthy infants born between 2008 and 2014 in Texas. Infants were closely followed until the first episode of AOM or up to 12 months; 311 (85%) completed the study. Nasopharyngeal swabs were obtained for bacterial culture and viral polymerase chain reaction assays monthly for the first 6 months and at 9 months.
By 12 months, the prevalence of upper respiratory infection (URI), AOM, and lower respiratory infection was 3.2, 0.67, and 0.24 per child-year, respectively. By 12 months, 46% of infants had at least one episode of AOM, nearly all within 28 days after an episode of URI (average time to diagnosis after URI, 5 days). Infants with AOM had significantly more episodes of URI than those without AOM (4.7 vs. 2.3 per child-year).
Presence of any of the 13 viruses tested or Moraxella catarrhalis or Streptococcus pneumoniae increased risk for URI; presence of any virus or S. pneumoniae increased risk for AOM. Breast-feeding was associated with reduced risk for both URI and AOM. Birth after introduction of 13-valent pneumococcal conjugate vaccine (PCV-13) was also associated with reduced risk for URI.
COMMENT: Deborah Lehman, MD
Upper respiratory tract infections are common in the first year of life and increase the risk for AOM. PCV immunization and longer breast-feeding each reduce the risk for URI and AOM. Rates of AOM have significantly declined over the last 3 to 4 decades, and the authors suggest that these factors, in addition to a decline in exposure to cigarette smoke, are responsible.
CITATION(S):Chonmaitree T et al. Acute otitis media and other complications of viral respiratory infection. Pediatrics 2016 Apr; 137:e20153555. (http://dx.doi.org/10.1542/peds.2015-3555)
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JAMA Neurol 2016 Mar 7
Vitamin D During Pregnancy and Risk for Multiple Sclerosis in Offspring
A case-control study finds a twofold risk for MS in offspring when the mother's vitamin D was low in the first trimester.
Low vitamin D has been associated with increased risk for multiple sclerosis (MS). Peripartum sunlight and vitamin D have been hypothesized to explain the seasonal birth effect in MS (NEJM JW Neurol Jan 2013 and J Neurol Neurosurg Psychiatry 2013; 84:427 and Neurology 2012; 79:2140).
In this prospective case-control study, researchers evaluated serum 25(OH)D samples obtained during pregnancy in mothers within the Finnish Maternity Cohort (FMC) whose offspring were born between 1983 and 1991.
Of the offspring, 193 were diagnosed with MS during follow-up (up to age 27). Of the cases, 173 were matched to 326 controls for region of birth, date of sample collection, date of mother's birth, and date of child's birth. A 20.03 ng/mL higher maternal 25(OH)D level was associated with a nonsignificant 48% reduced risk for MS in the offspring (P = 0.12). Mothers with deficient levels of 25(OH)D, defined as less than 12.62 ng/mL (quintiles 1 and 2), had offspring with a nonsignificant trend toward higher MS risk (P for trend = 0.09). Values less than 12.02 ng/mL during pregnancy were associated with a significant relative risk of 1.9 for having offspring with MS, compared with values above 12.02 ng/mL.
COMMENT: These findings add to other epidemiologic research implicating vitamin D deficiency in risk for multiple sclerosis. Maternal vitamin D levels, regional sunlight exposure, and vitamin D levels in childhood and early adulthood may all be important factors. The present study focused on one of these elements, vitamin D during pregnancy, and found inconsistent associations within this nice dataset. Although it is too early to recommend vitamin D supplementation during pregnancy for the prevention of MS in offspring, some groups are advocating for more-routine use of vitamin D within a pregnant population for a variety of potential health benefits.
CITATION(S): Munger KL et al. Vitamin D status during pregnancy and risk of multiple sclerosis in offspring of women in the Finnish Maternity Cohort. JAMA Neurol 2016 Mar 7; [e-pub]. (http://dx.doi.org/10.1001/jamaneurol.2015.4800)
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MM: Continuous antibiotic therapy may show limited or no significant patient benefits but other treatments such as Low Dose naltrexone (LDN) should not be lumped in this assessment. LDN helps to modulate the immune system and has shown marked benefit to Lyme patients with prolonged use. The patient and the infection do not develop a tolerance to the medication and the benefits appear to continue with continued use.
Prolonged Therapy Shows No Benefit for Persistent Lyme Disease Symptoms
By Larry M. Baddour, MD
Longer-term therapy does not improve quality of life in patients with Lyme disease symptoms months or years after diagnosis, according to a study in the New England Journal of Medicine.
Investigators in the Netherlands conducted a multicenter, randomized, double-blind, placebo-controlled trial involving 280 Lyme disease patients with persistent musculoskeletal pain, arthritis, arthralgia, neuralgia, sensory disturbances, dysesthesia, neuropsychological disorders, or cognitive disorders, with or without persistent fatigue. The median duration of symptoms was longer than 2 years.
Patients received initial intravenous ceftriaxone for 2 weeks followed by one of three oral regimens: doxycycline, clarithromycin plus hydroxychloroquine, or placebo for 12 weeks. The primary outcome was health-related quality of life at the end of treatment; a secondary outcome was fatigue.
Health-related quality-of-life and fatigue scores were similar across the groups, as was the rate of treatment discontinuation (5%). Four serious adverse events occurred, none of which were drug-related.
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MM: Doing studies is a good idea but as consumers we must be cautious when we see the results. This study looked at oral estrogen which is, in my opinion, and supported by numerous data sources, to be the most dangerous means that estrogen may be administered. Additionally, transdermal estrogen has demonstrated numerous quality of life (QOL) benefits far past 10 years of administration without demonstrating significant increases to risk factors commonly associated with oral estrogens. Finally, bio-identical progesterone was only administered to patients with an intact uterus to prevent endometrial hyperplasia or increase the risk of uterine or cervical cancer commonly associated with oral estrogens, thereby ignoring all the other potential benefits that progesterone offers to women such their bones, breasts and brains.
Does Hormone Therapy Slow Atherosclerosis Progression?
It's All About the Timing

By Andrew M. Kaunitz, MD, and JoAnn Manson, MD, DrPH
Dr. Kaunitz is the editor-in-chief and Dr. Manson is a guest editor forNEJM Journal Watch Women's Health, from which this story was adapted. Full coverage is available at the link below.
Hormone therapy (HT) slows atherosclerosis progression in recently menopausal women but not in those who are at least a decade past menopause onset, finds a New England Journal of Medicine study.
Nearly 650 healthy women (<6 years or ≥10 years past menopause) without cardiovascular disease (CVD) were randomized to oral estradiol (1 mg daily) or placebo. Women with a uterus also received vaginal progesterone or placebo gel. Subclinical atherosclerosis was assessed using measures of carotid-artery intima-media thickness (CIMT). Coronary artery atherosclerosis was evaluated using computed tomography (CT).
After roughly 5 years' treatment, among the younger women, the estradiol group had significantly less progression of CIMT than the placebo group. In contrast, among the older women, CIMT progression rates were similar with HT and placebo. Coronary artery CT parameters did not differ significantly between the placebo and HT groups, regardless of age.
Comment: Editorialists conclude — and we agree — that although estrogen had a favorable effect on atherosclerosis in early menopause, recommending HT for preventing cardiovascular events would be premature. Our takeaway message is that this important new clinical trial provides additional reassurance about the cardiovascular safety of HT when initiated by recently menopausal women for bothersome vasomotor symptoms.
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Gut 2016 Mar 14
Metabolomic Changes with a Low-FODMAP Diet
Changes included reduction of urinary histamine levels and redistribution of colonic microbiome species.
A metabolome is the collection of all the metabolites in a biological system. Dietary changes such as lowering levels of fermentable oligosaccharides, disaccharides and monosaccharides, and polyols (FODMAPs) can improve symptoms of irritable bowel syndrome (IBS) and are known to affect the types of bacteria in the bowel. To determine the possible systemic effect of FODMAPs, researchers evaluated their effect on metabolomes such as urinary metabolomes.
Forty patients with IBS were randomized to a low-FODMAP or high-FODMAP diet for 3 weeks. In the low-FODMAP group, the IBS symptom score improved by 28%, including a 52% improvement in abdominal pain, whereas the IBS symptom score increased in the high-FODMAP group. The low-FODMAP diet resulted in changes in the colonic microbiome, including more Actinobacteria species. There were also differences in the urinary metabolome between groups; for example, urinary histamine levels decreased in the low-FODMAP group but increased slightly in the high-FODMAP group.
COMMENT: These findings provide additional evidence that a low-FODMAP diet improves symptoms in IBS, produces changes in fecal microbiota, and induces changes in the metabolome. Histamine is a mediator of inflammation in the gut, and lower histamine levels from low FODMAP intake may contribute to improved symptoms.
CITATION(S):McIntosh K et al. FODMAPs alter symptoms and the metabolome of patients with IBS: A randomised controlled trial. Gut 2016 Mar 14; [e-pub].
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Aliment Pharmacol Ther 2016 Mar 9
Are PPIs, NSAIDs, and SSRIs Associated with Microscopic Colitis?
New evidence suggests an interaction between PPIs and NSAIDs.
Population-based studies suggest an association between microscopic colitis and a variety of medications, including proton-pump inhibitors (PPIs), nonsteroidal anti-inflammatory drugs (NSAIDs), selective serotonin reuptake inhibitors (SSRIs), and statins. To further evaluate these potential relationships, investigators compared drug use in 1211 adults with microscopic colitis (including collagenous colitis and lymphocytic colitis) and 6041 age- and sex-matched controls identified from a U.K. research database.
Current use of PPIs, NSAIDs, or SSRIs (adjusted odds ratios, 1.9, 3.4, and 2.0, respectively) but not statins was associated with elevated risk for microscopic colitis. Recent use of NSAIDs or PPIs was also associated with microscopic colitis (AORs, 2.1 and 4.0, respectively). Risk was higher with concomitant use of NSAIDs and PPIs compared with use of either drug alone and was highest with continuous use for a duration of 4 to 12 months for both current NSAID use (AOR, 3.9) and current SSRI use (AOR, 2.7). For NSAID use, the association with microscopic colitis lost statistical significance when concomitant PPI use was excluded.
COMMENT: The authors conclude that co-therapy with PPIs was responsible for the association between NSAID use and microscopic colitis. The mechanisms of any associations between these drug classes and microscopic colitis remain unclear. NSAIDs have a well-known effect of increasing small bowel permeability. As the authors note, it is possible that changes in the microbiome from PPI therapy may be greater in the setting of NSAID-induced changes in bowel permeability (NEJM JW Gastroenterol Jan 2016 and Clin Gastroenterol Hepatol 2015 Oct 29; [e-pub]). Additional studies are needed to confirm these associations and determine their underlying mechanisms.
CITATION(S):Verhaegh BPM et al. High risk of drug-induced microscopic colitis with concomitant use of NSAIDs and proton pump inhibitors. Aliment Pharmacol Ther 2016 Mar 9; [e-pub]. (http://dx.doi.org/10.1111/apt.13583)
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FDA Relaxes Restrictions on Medical Abortion
By Amy Orciari Herman, Edited by Susan Sadoughi, MD
Mifepristone, used in combination with misoprostol to induce abortion, may now be taken as late as 70 days after the start of a woman's last menstrual period, according to label changes announced by the FDA on Wednesday. Previously, the label advised taking the drug by day 49.
The dosage of the drug has also been lowered from 600 to 200 mg, theNew York Times reports.
In a statement, Dr. Mark S. DeFrancesco, president of the American Congress of Obstetricians and Gynecologists, said the group was "pleased that the updated FDA-approved regimen for mifepristone reflects the current available scientific evidence and best practices."
"We know that medication abortion has been subject to legislative attacks in various states across the country, including mandated regimens that do not reflect the current scientific evidence," DeFrancesco said. "We hope that these states take the FDA label into account, making safe, effective medication abortion available in a way that is medically appropriate."

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Pediatrics 2016 Apr; 137:e20153425
Parents Who Sleep Poorly Overestimate Their Children's Sleep Problems
Parents who sleep poorly more frequently reported sleep problems in their children, regardless of objective measurement of the children's sleep quality.
Diagnostic decisions in pediatrics often rely on parent reports of their child's signs and symptoms, but reliability of such reports can vary. Sleep problems in parents and children have been linked, but the causal relationship is unclear, and the role of parental reporting biases unknown.
In a study of 100 children aged 4 to 6 years recruited from daycare centers in Finland, researchers compared parents' reports of their own and their children's sleep quality and objective measurement of the children's sleep for 7 nights. Parents filled out sleep diaries and questionnaires; children's sleep was measured objectively by actigraphy (with a wrist-worn device that detects motion). Possible confounders analyzed included parental mental health and education; child's age, gender, and health history; and family characteristics.
Parents who reported poor sleep more frequently reported sleep problems in their children than parents who slept well. This association was not affected by adjustment for actigraphy results or potential confounders.
COMMENT: Parent reports of children's problems vary in their reliability but often serve as the only information available to the pediatrician. This study shows that parents with disturbed sleep appear to over-report their children's sleep problems. When evaluating possible sleep problems in children, providers should ask about parents' sleep quality and take the effects of parental sleep issues into account.
CITATION(S): Rönnlund H et al. Poor parental sleep and the reported sleep quality of their children. Pediatrics 2016 Apr; 137:e20153425.
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Endometriosis Linked to Increased Risk for Heart Disease
By Amy Orciari Herman, Edited by David G. Fairchild, MD, MPH, and Lorenzo Di Francesco, MD, FACP, FHM
Women with endometriosis — particularly those aged 40 and under — face increased risk for coronary heart disease (CHD), according to a prospective study in Circulation: Cardiovascular Quality and Outcomes.
In the Nurses' Health Study II, over 116,000 women aged 25 to 42 without histories of CHD or stroke were followed for roughly 20 years. During that time, nearly 1500 experienced CHD. After multivariable adjustment, women with laparoscopically confirmed endometriosis — compared to those without it — had increased risks for myocardial infarction (relative risk, 1.52), angina (RR, 1.91), and coronary surgery (1.35).
Relative risks were highest in the youngest women. In addition, greater frequency of hysterectomy and oophorectomy accounted for 42% of the increased CHD risk in those with endometriosis.
The researchers note that "endometriosis has been linked to systemic chronic inflammation, heightened oxidative stress, and an atherogenic lipid profile." Dr. Andrew Kaunitz, editor-in-chief of NEJM Journal Watch Women's Health, adds that the findings suggest that "women with this relatively common gynecologic condition may warrant extra attention to lifestyle and other cardiovascular risk factors."

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J Clin Oncol 2016 Mar 20; 34:927
Late Risk for Recurrence with Estrogen Receptor–Positive Breast Cancer
During extended follow-up, recurrence risk was significantly higher with ER-positive versus ER-negative disease.
Large datasets with long-term follow-up offer insights into the natural history of disease. Such information has always been important, but it is becoming more actionable, particularly in hormone receptor–positive breast cancer, for which consideration is given to longer durations of adjuvant endocrine therapy and molecular assays are being developed to help identify patients most appropriate for long-term treatment. The International Breast Cancer Study Group (IBCSG) previously conducted a series of pivotal trials evaluating chemotherapy and endocrine therapy in patients with early-stage breast cancer (EBC).
Now, the investigators report on long-term follow-up of IBCSG clinical trials I to V, which accrued EBC patients from 1978 to 1985. Trials I to IV assessed the use of CMF (cyclophosphamide, methotrexate, and 5-flourouracil) with tamoxifen, oophorectomy, and/or prednisone in premenopausal patients (trials I–II) and postmenopausal patients (trials III–IV). Trial V assessed the use of CMF in axillary node–positive patients or single-cycle perioperative CMF in axillary node–negative patients.
Results were as follows:

COMMENT: These data emphasize the need for long-term follow-up of patients with ER-positive EBC and for tools to identify patients at greatest risk for late recurrences who may derive the most benefit from extended endocrine therapy or novel treatment strategies.
CITATION(S): Colleoni M et al. Annual hazard rates of recurrence for breast cancer during 24 years of follow-up: Results from the International Breast Cancer Study Group trials I to V. J Clin Oncol 2016 Mar 20; 34:927.

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JAMA Neurol 2016 Mar 7
Metabolic Syndrome Treatment in Multiple Sclerosis
In MS patients with obesity, imaging and immunologic profiles improved with oral hypoglycemic agents.
Metabolic syndrome due to obesity is associated with elevated blood pressure, dyslipidemia, and insulin resistance. Epidemiologic research suggests an association between obesity and autoimmune disease, such as multiple sclerosis (MS; NEJM JW Neurol Mar 2013 and Neurology 2013; 80:548). Adipokines produced by adipose tissue are hypothesized to have several pro-inflammatory effects. Now, researchers have evaluated two oral hypoglycemic medications for diabetes within 50 obese patients with MS and metabolic syndrome in a prospective, open-label cohort study. Of the 50 patients, 20 received metformin, 10 received pioglitazone, and 20 elected not to take medication (included as controls).
Patients were followed quarterly for at least 24 months. Brain magnetic resonance imaging (MRI) beginning at 6 months demonstrated reduced numbers of gadolinium-enhancing lesions and new or enlarging T2-weighted lesions in metformin and pioglitazone recipients compared with controls. Metformin and pioglitazone treatments were associated with significantly reduced serum leptin, increased adiponectin, and increased T regulatory cells. In addition, metformin was associated with reduced interferon-gamma–producing cells and decreased interleukin (IL)-17–producing cells, and pioglitazone with reduced IL-6 and tumor necrosis factor.
COMMENT: These pilot data support a potential benefit from hypoglycemic agents on MS in obese patients with “prediabetes.” Positive effects were observed on MRI and immunologic profiles. Before recommending metformin or pioglitazone for obese patients with MS, a larger, randomized, blinded trial is warranted. For patients with established type-2 diabetes mellitus and MS, tight glucose control could be recommended.
CITATION(S): Negrotto L et al. Immunologic effects of metformin and pioglitazone treatment on metabolic syndrome and multiple sclerosis. JAMA Neurol 2016 Mar 7; [e-pub]. (http://dx.doi.org/10.1001/jamaneurol.2015.4807)
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Overnight Fasting Associated with Reduced Risk for Breast Cancer Recurrence
By Kelly Young, Edited by André Sofair, MD, MPH, and William E. Chavey, MD, MS
Laying off the bedtime snacks might help reduce the risk for breast cancer recurrence, suggests a study in JAMA Oncology.
Researchers estimated nightly fasting duration through food recall data, gathered periodically from over 2400 women with breast cancer who were free of diabetes at baseline. During roughly 7 years' follow-up, fasting fewer than 13 hours per night was associated with a 36% increased risk for breast cancer recurrence, compared with longer fasts.
Longer nightly fasting was also associated with reduced hemoglobin A1c levels, and, the authors note, "there may be a subset of tumors for which hyperglycemia confers a growth advantage." In addition, longer fasting was associated with longer sleep duration.
The authors conclude: "Our study introduces a novel dietary intervention strategy and indicates that prolonging the length of the nightly fasting interval could be a simple and feasible strategy to reduce breast cancer recurrence."
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JAMA 2016 Mar 8. Sharfstein JM and Psaty BM. JAMA 2016 Mar 8
Combination Naltrexone plus Bupropion for Weight Loss: CV Risks Are Still Unknown
This obesity drug's cardiovascular outcomes trial was terminated prematurely because of leaked interim results.
Although phase III trials showed that combination naltrexone plus bupropion led to weight loss in obese patients (NEJM JW Gen Med Oct 1 2010 and Lancet 2010; 376:595), the drug's approval was deferred because of cardiovascular (CV) safety concerns. Thus, the FDA required the manufacturer to conduct a placebo-controlled, noninferiority, CV-outcomes trial of this combination; ≈8900 overweight or obese patients with or at elevated risk for CV disease participated. Prespecified interim analysis after accrual of 25% of predicted CV events (i.e., CV-related death, nonfatal myocardial infarction, nonfatal stroke) revealed fewer events with active treatment than with placebo (35 vs. 59; hazard ratio, 0.59).
The 25% interim data were to be kept confidential until the end of the study but became public after the drug's sponsor cited them in a patent application. In response, investigators terminated the study. After 50% of predicted CV events, 90 and 102 events had occurred in the treatment and placebo groups, respectively (HR, 0.88). Analysis of final data revealed a further rise in HR to 0.95, signifying no difference between groups. At 1 year, adherence was 38% and 26% in the treatment and placebo groups, respectively; at trial completion, mean weight loss was 3.9 kg and 1.2 kg, respectively. Adverse effects (in particular, nausea, constipation, vomiting, tremor, and dizziness) were significantly more common in the treatment group.
COMMENT: Editorialists describe the approval and policy implications of the study's early termination, and their comments are worth reading. The FDA approved combination naltrexone and bupropion (Contrave) in 2014, based largely on the drug's favorable CV profile in the 25% interim analysis, but the product label notes that CV safety has not been established. To address this issue, the FDA has required the drug's sponsor to conduct a new CV-safety trial — a trial that will be completed in 2022 and is estimated to cost US$200 million. Clinicians should be aware that combination naltrexone plus bupropion is associated with very modest weight loss, excess risk for adverse effects, low medication adherence, and uncertain CV safety.
CITATION(S): Nissen SE et al. Effect of naltrexone-bupropion on major adverse cardiovascular events in overweight and obese patients with cardiovascular risk factors: A randomized clinical trial. JAMA 2016 Mar 8; 315:990.

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On Review, NFL Concussion Research Ruled a Fumble
By Joe Elia, Edited by André Sofair, MD, MPH, and William E. Chavey, MD, MS
The National Football League's internal research that played down the game's concussion risks "was far more flawed than previously known," according to a New York Times report.
Times reporters examined the NFL-sponsored research, which was published in Neurosurgery in a series of 13 articles. The research omitted more than 10% of concussions, according to an examination of the League's own injury reports.
One reason for the omissions was that at least one team, the Dallas Cowboys, did not report any concussions to the researchers during the 6-year study, yet NFL injury reports document four concussions to the team's quarterback during the same period. Other teams had reporting gaps lasting "years at a time." (The published research based its risk calculations on all games played, whether the teams submitted data or not.)
The Times reports that the studies' lead author, the epidemiologist, and the then-editor of the journal were unavailable for comment.
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Risk and Benefits of Newer Diabetes Drugs Detailed
By Amy Orciari Herman, Edited by André Sofair, MD, MPH, and William E. Chavey, MD, MS
A study in The BMJ offers data on the risks and benefits of newer diabetes drugs, including glitazones and gliptins. An editorialist, however, is skeptical.
Using a large U.K. primary care database, researchers followed nearly 470,000 adults with type 2 diabetes, about 60% of whom received prescriptions for antidiabetes drugs during the 8-year study. Among the findings:

An editorialist is cautious: "To my knowledge, no antihyperglycemic agent has been shown to convincingly reduce the risk of any diabetes-related complication to any greater extent than other agents. ... Sadly, when it comes to antidiabetes drugs, reports of exciting benefits and catastrophic harms are often exaggerations.
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Circ Cardiovasc Qual Outcomes 2016 Mar; 9:100
Triglycerides Again Associated with Cardiovascular Risk in a 22-Year Follow-Up Study
But does lowering triglycerides improve risk?
The role of high levels of triglycerides in cardiovascular disease remains poorly understood. Now, investigators have reported long-term mortality data on the 15,355 patients initially screened for the placebo-controlled Bezafibrate Infarction Prevention (BIP) trial, which enrolled 3122 patients with coronary heart disease and found a statistically nonsignificant 9.4% reduction in the primary endpoint (fatal and nonfatal myocardial infarction plus sudden death) with bezafibrate, a triglyceride-lowering drug (Circulation 2000; 102:21).
At follow-up (median, 22.8 years), successively higher baseline fasting triglyceride levels were linked to successively higher age- and sex-adjusted mortality rates, even in multivariate analysis controlling for multiple potential confounders. Each logarithmic unit increase in triglycerides was associated with a 26% increase in age- and sex-adjusted all-cause mortality. Patients with the highest triglyceride levels (≥500 mg/dL) had a significantly lower 22-year survival rate than those with “low-normal” levels of <100 mg/dL (25% vs. 41%). Even high-normal triglyceride levels (100–149 mg/dL) were associated with increased mortality.
COMMENT: Some limitations of this study are the lack of adjudication of deaths and the lack of information during follow-up about lipid values, medication use, and comorbidities such as diabetes. In addition, this study needs to be put into the context of present-day clinical care. When the trial was conducted, the standard of care was to provide lipid management only to patients with considerably higher LDL cholesterol levels. The authors point out that >90% of the patients in the BIP trial were receiving no lipid-modifying medications at enrollment. We currently do not know whether triglyceride elevations will hold similar predictive value in patients whose LDL cholesterol levels are optimally controlled. And we must always remember: Simply because something may be a cardiovascular risk factor, altering it pharmacologically doesn't always lower risk.
CITATION(S): Klempfner R et al. Elevated triglyceride level is independently associated with increased all-cause mortality in patients with established coronary heart disease: Twenty-two-year follow-up of the Bezafibrate Infarction Prevention study and registry. Circ Cardiovasc Qual Outcomes 2016 Mar; 9:100.

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