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Content 7


The Doctor and the Pharmacist

Radio Show Articles:
January 25, 2014

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Nearly Half of Adults Hospitalized with Flu This Season Are Obese
Probiotics Can Help Prevent Gastrointestinal Distress in Newborns
Another Benefit of High Vitamin D Levels: Lower Risk for Diverticulitis
Study Dispels "Obesity Paradox" in Diabetes
Heavy Drinking in Middle-Aged Men Found to Speed Cognitive Decline
Cognitive Training Sharpens Some Skills in the Elderly, Helping Mostly with Daily Activities
Diuretics and Statins Are Associated with New-Onset Diabetes
Men, Melanoma, and Mortality
The Risk for Diverticulitis in Patients with Diverticulosis
Inflammation Level Predicts Cancer Risk in UC
A Molecular Link Between Itch and Inflammation
How Early Should Obesity Prevention Start?

MM: The use of proper hand-washing hygiene, taking probiotics, raising vitamin D levels and daily doses of vitamin C have been repeatedly demonstrated to diminish the incidence and intensity of flu episodes. It appears that weight control may also show significant benefits.
Nearly Half of Adults Hospitalized with Flu This Season Are Obese
Some 47% of adults hospitalized with influenza since October have been obese — substantially higher than the 30%-35% rate seen in previous flu seasons — according to the CDC's weekly FluView report.
Overall, patients under age 4 years and those aged 65 or older were most likely to be admitted with flu, but adults aged 18 to 64 still accounted for 61% of hospitalizations. Nearly all hospitalized cases were attributed to the 2009 H1N1 strain, which continues to be the dominant strain this season.
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MM: Not only does the use of probiotics in infants improve gut health but it costs less in medical bills and fewer lost work days for parents. Anyone who states that they can't afford to give their infant probiotics , truly, can't ford not to.
Probiotics Can Help Prevent Gastrointestinal Distress in Newborns
By Amy Orciari Herman
Probiotics can reduce the onset of gastrointestinal disorders in newborns and lead to substantial savings in healthcare spending, according to a JAMA Pediatrics study.
Nearly 600 term infants less than 1 week old were randomized to receive Lactobacillus reuteri or placebo daily. After 3 months, parents in the treatment group reported significantly better outcomes for mean daily infant crying time (38 vs. 71 minutes with placebo), regurgitation episodes (2.9 vs. 4.6), and evacuations (4.2 vs. 3.6).
In addition, the treatment group had fewer emergency department visits, fewer days of parental work lost, and less use of products to control GI symptoms -- translating to a mean savings of US$119 per patient (after accounting for the cost of the L. reuteri).
Editorialists call the results "encouraging," while noting that probiotics' mechanism of action in infantile gastrointestinal distress remains unknown, as do the long-term health effects.
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MM: The list of conditions that are benefitted by higher levels of vitamin D seems to be continuing to grow on a daily basis. It would appear that higher levels of vitamin D will reduce intestinal inflammation and inflammation is a source of virtually all disease. Additionally the intestinal tract largely modulates systemic inflammation and immune function. The bottom line is that safe and effective systemic levels of vitamin D must continue to be eveluated and updated in order to fight a host of epidemiological problems and issues.
Clin Gastroenterol Hepatol 2013 Dec; 11:1631
Another Benefit of High Vitamin D Levels: Lower Risk for Diverticulitis
A high level of vitamin D was protective against diverticulitis in patients with uncomplicated diverticulosis.
Normal-to-high levels of vitamin D have been associated with reduced risks for colorectal cancer (NEJM JW Gastroenterol Feb 26 2010) and inflammatory bowel disease (NEJM JW Gastroenterol Mar 30 2012). In the current study, researchers in the U.S. evaluated a possible association between vitamin D levels and diverticulitis. Using a health care provider network database, they compared serum 25-hydroxyvitamin D levels between 9116 patients with a diagnosis of uncomplicated diverticulosis but no diverticulitis and 922 patients hospitalized for diverticulitis.
Patients with uncomplicated diverticulosis had higher mean pre-diagnostic serum levels of 25-hydroxyvitamin D (29.1 ng/mL) than patients with diverticulitis (25.3 ng/mL; P< 0.0001). Patients in the highest quintile of vitamin D levels had a 50% lower risk for hospitalization with diverticulitis compared with patients in the lowest quintile (relative risk, 0.49; 95% confidence interval, 0.38–0.62; P<0.0001). Lower vitamin D levels were associated with all subtypes of diverticulitis analyzed: acute diverticulitis without other sequelae, diverticulitis with abscess, diverticulitis requiring emergent laparotomy, and recurrent diverticulitis.
Comment: Vitamin D seems to modulate inflammation and play an important role in maintaining normal colon health.
Citation(s): Maguire LH et al. Higher serum levels of vitamin D are associated with a reduced risk of diverticulitis. Clin Gastroenterol Hepatol 2013 Dec; 11:1631.

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MM: Earlier studies that indicated a lower level of death and all-cause mortality among the diabetic obese were always suspect in my mind. They simply never made sense to me. As human individuals, we need encouragement to accomplish difficult tasks such as weight loss and control, not obstacles or a false sense of security from misinformation. This study is much more in line with common sense medicine and it is reassuring that the science based medicine is more in agreement.
Study Dispels "Obesity Paradox" in Diabetes
By Amy Orciari Herman
A study in the New England Journal of Medicine finds no evidence of a so-called "obesity paradox" in type 2 diabetes — that is, the suggestion that mortality is lower among diabetics who are overweight or obese than among those who are normal weight.
Researchers studied over 11,000 healthcare professionals who were free of cardiovascular disease or cancer at the time of diabetes diagnosis. During 16 years' follow-up, roughly 3000 participants died.
Overall, the association between baseline BMI and all-cause mortality was J-shaped: Compared with normal-weight participants, underweight participants and those with BMIs of 30 or above had significantly increased mortality risks, with the highest risk at BMIs of 35 or higher (hazard ratio, 1.33).
Previous studies that suggested an obesity paradox were limited by short follow-ups and few deaths, the authors write. They conclude that maintaining a healthy weight "should remain the cornerstone of diabetes management."
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MM: Really, is this a joke? Is a group of civil servants the best choice to study to possibly increase the risk of diminished mental acuity? In any case, a loss of 2-6 years of mental function over a 10 year period in heavily drinking men is pretty substantial and makes one look at the data that promotes a glass or 2 of red wine daily to improve cardiovascular (CV) mortality.
Heavy Drinking in Middle-Aged Men Found to Speed Cognitive Decline
By Joe Elia
Middle-aged men drinking 36 g or more of alcohol per day (roughly equivalent to three 12-oz. bottles of beer, or three glasses of wine, or three shots of liquor) experience more rapid cognitive decline than those drinking moderately or less, according to a Neurology study.
Some 5000 men and 2000 women — all British civil servants — self-reported their alcohol consumption levels three times over a 10-year period. Then, over the ensuing 10 years, beginning at roughly age 56, they underwent cognitive testing on three occasions to measure age-related declines.
Declines were steeper among men who were heavy drinkers. In women, an effect was seen starting at the 19-g/day consumption level, but it did not reach statistical significance. The authors say the decline among heavy-drinking men showed an effect size ranging from 2 to 6 extra years of cognitive decline over the 10 years of observation.
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Cognitive Training Sharpens Some Skills in the Elderly, Helping Mostly with Daily Activities
By Joe Elia
Older people undergoing cognitive training that's focused on one of three domains show modest benefits over the long term, with the greatest effect being on their instrumental activities of daily living, according to a study in the Journal of the American Geriatrics Society.
Some 2800 community-living older adults were randomized to one of four training groups: memory, reasoning, speed-of-processing, or none (the control group). Training occurred over roughly 12 hours spanning 6 weeks.
At 10 years, the subjects (now averaging age 82) underwent testing in all three domains. Those who'd undergone memory training did no better on memory tests in comparison with the other groups. The reasoning and speed-of-processing groups excelled in their areas, but with modest effect sizes.
All trained groups did significantly better than controls in measures of instrumental activities of daily living such as meal preparation, shopping, finances, and hygiene.
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BMJ 2013 Dec 9; 347:f6745
Diuretics and Statins Are Associated with New-Onset Diabetes
These drugs — but not β-blockers or calcium-channel blockers — were associated with new-onset diabetes in patients with impaired glucose tolerance.
Evidence suggests that β-blocker, diuretic, or statin use increases risk for new-onset diabetes. In this reanalysis of the randomized, controlled NAVIGATOR trial (NEJM JW Cardiol Mar 14 2010) data, investigators assessed whether β-blocker, thiazide diuretic, statin, or calcium-channel blocker (CCB) use in >9300 patients with impaired glucose tolerance and cardiovascular risk factors was associated with new-onset diabetes.
During a median follow-up of 5 years, β-blockers, thiazide diuretics, statins, and CCBs were each started in about 20% of patients who had not been exposed to these drugs previously. After adjustment for multiple variables, risk for new-onset diabetes was significantly higher in patients who initiated diuretics (hazard ratio, 1.2) or statins (HR, 1.5) than in patients who were not treated with diuretics or statins, respectively. The number needed to harm for diuretics was 17 and for statins was 12. Risk for new-onset diabetes did not change among patients who initiated β-blockers or CCBs.
Comment: In this study, thiazide diuretics and statins, but not β-blockers and calcium-channel blockers, were associated with excess risk for new-onset diabetes in patients with impaired glucose tolerance and cardiovascular risk factors. The authors recommend that glycemia be monitored when these drugs are initiated in patients at high risk. Although confounding is possible given the study's design, other studies have linked statin use (NEJM JW Gen Med Jul 19 2011) and diuretic and β-blocker use (NEJM JW Gen Med May 30 2006) with new-onset diabetes. Nonetheless, the benefits of these drugs probably outweigh this risk in selected patients.
Citation(s): Shen L et al. Role of diuretics, β blockers, and statins in increasing the risk of diabetes in patients with impaired glucose tolerance: Reanalysis of data from the NAVIGATOR study. BMJ 2013 Dec 9; 347:f6745.

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MM: Sun-damaged associated bulky melanomas of the head and neck in older men are cited as an increased clinical risk but overall avoidance of the sun is still suspect in my mind. Those persons who have the highest risk of sun-damaged melanomas show a preponderance in geographic areas that have less year round sunlight such as the Pacific northwest and Atlantic northeast. Over-exposure to the sun will certainly increase the risk of wrinkles and pre-mature cosmetic aging along with drier, more weathered skin but moderate exposure will increase endogenous vitamin D production, improve overall immune function, reduce systemic inflammation and enhance telomere activity.
J Clin Oncol 2013 Nov 20; 31:4172
Men, Melanoma, and Mortality
Since 1950, melanoma incidence has increased more than 20-fold in older men, and the rate of associated mortality in men has tripled.
The Connecticut Tumor Registry, the longest-operating population-based cancer registry in the U.S., has been a vital source of cancer information for the past 60 years. A recent trend analysis revealed an emerging vulnerability for melanoma among men.
The reviewers examined trends from 1950 to 2007 in the incidence of invasive melanoma and in situ melanoma, mortality, and the mortality-incidence ratio among 19,973 Connecticut residents diagnosed with invasive melanoma and 3635 with melanoma-related deaths. A diagnosis of invasive melanoma was rare from 1950 to 1954: 1.9 per 100,000 in men and 2.6 per 100,000 in women. By 2007, overall incidence rates had risen more than 17-fold in men (to 33.5 per 100,000) and more than 9-fold in women (to 25.3 per 100,000). In men older than 50, rates increased more than 20-fold, with a 45-fold increase in men aged 65 to 69. From 1950 to 2007, the rate of melanoma-related mortality tripled in men and doubled in women.
Comment: The most compelling findings in this study are the greater than 20-fold increase in melanoma incidence and the tripling of related mortality in men. In men older than 70, 1 death occurs for every 5 melanoma cases versus 1 death per 14 melanoma cases in men aged 45 to 49. Trends to higher rates were also noted among women, but not to the same extent, which resonates with my personal clinical experience. Even though thick melanomas are less common these days, bulky melanomas seem to occur most often on the sun-damaged head and neck areas of older men.
Citation(s): Geller AC et al. Melanoma epidemic: An analysis of six decades of data from the Connecticut Tumor Registry. J Clin Oncol 2013 Nov 20; 31:4172.

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Clin Gastroenterol Hepatol 2013 Dec; 11:1609
The Risk for Diverticulitis in Patients with Diverticulosis
The incidence of acute diverticulitis was estimated at 4% — lower than the oft-cited risk estimate of 10% to 25%.
In patients who have diverticulosis, the risk for acute diverticulitis is often estimated at between 10% and 25%. However, this estimate is based on studies conducted before population-based screening colonoscopies were performed. Now, investigators have assessed the risk for diverticulitis among patients with diverticulosis identified on colonoscopy, thus providing a more accurate denominator than in past studies.
Using administrative and clinical data from the U.S. Veterans Affairs system in Los Angeles, investigators retrospectively analyzed the incidence of acute diverticulitis in a cohort of 2222 patients (97% men) with baseline diverticulosis detected by colonoscopy. Patients with a history of diverticulitis prior to their diagnosis with diverticulosis were excluded.
During a mean follow-up of 6.75 years, 95 patients (4.3%) developed acute diverticulitis.
Comment: I find that patients often ask about the risk for diverticulitis when they receive a diagnosis of diverticulosis after colonoscopy. These findings suggest a lower risk for diverticulitis than is commonly quoted.
Citation(s): Shahedi K et al. Long-term risk of acute diverticulitis among patients with incidental diverticulosis found during colonoscopy. Clin Gastroenterol Hepatol 2013 Dec; 11:1609.

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MM: There are several good ways to decrease inflammation in this patient group. Vitamin D-3, 5000-10000IU daily, Probiotics (20-50 Billion units daily) and prescription Low Dose Naltrexone 1.5-4.5mg daily. Combine these with dietary changes to reduce inflammation such as elimination of individual foods and food classes that a person is sensitive to and overall risk of colon cancer may be reduced.
Clin Gastroenterol Hepatol 2013 Dec; 11:1601
Inflammation Level Predicts Cancer Risk in UC
Each 1-point increase in a histologic inflammation activity scale more than tripled the odds of developing colorectal cancer.
Previous evidence suggests that increasing extent and severity of inflammation in ulcerative colitis (UC) are associated with increased risk for colorectal cancer (CRC). Treatment with thiopurines, which can reduce inflammation and produce healing in colitis, has also been associated with reduced risk for CRC. Now, investigators have further assessed the relationship between inflammation and risk for CRC in this setting.In a case-control study, 141 patients with UC without neoplasia and 59 patients with UC who had developed neoplasia were compared. A 6-point histologic inflammatory activity scale was used to score 4449 biopsy fragments.
In a multivariate analysis controlling for risk factors identified from univariate analysis (sex, use of immune modulators, and use of nonsulfasalazine mesalamine), a higher inflammation score was associated with increased risk for colorectal cancer (odds ratio, 3.68 per 1-unit increase in the histologic inflammatory activity scale; P=0.001).
Comment: Factors associated with an increased risk for colorectal cancer in ulcerative colitis have included duration and extent of disease, concomitant primary sclerosing cholangitis, and a family history of colorectal cancer. These findings demonstrate that chronic inflammation by histology is associated with an increased risk. They also confirm that immunomodulators (thiopurines and methotrexate) reduce the risk for colorectal neoplasia, presumably by reducing inflammation.
Citation(s): Rubin DT et al. Inflammation is an independent risk factor for colonic neoplasia in patients with ulcerative colitis: A case-control study. Clin Gastroenterol Hepatol 2013 Dec; 11:1601.

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MM: This is a very interesting interactive relationship that we seldom consider
Cell 2013 Oct 10; 155:285
A Molecular Link Between Itch and Inflammation
Keratinocyte-derived TSLP directly stimulates sensory neurons to produce itch.
Atopic dermatitis (AD) remains an incredibly common condition, and associated chronic itch one of the most difficult symptoms to treat.
In the course of studying genes highly expressed in the dorsal root ganglia, where the cell bodies of neurons that transmit itch reside, Wilson and colleagues were surprised to find the cytokine thymic stromal lymphopoietin (TSLP). Seeking to elucidate the mechanisms that regulate TSLP secretion and promote TSLP-evoked itch, they injected TSLP directly into mouse skin. The TSLP evoked scratching behavior that did not depend upon lymphocytes or mast cells. The protein induced electrical activity in a subset of neurons that responded to histamine and chloroquine, specifically neurons that express TSLP receptor and the ion channel TRPA1. It was already known that keratinocytes are the source of TSLP. These authors established that this process is dependent on calcium influx through the ORAI1 ion channel and linked to calcineurin-dependent transcription of TSLP, which is inhibited by cyclosporine.
Comment: Prior to this work, TSLP had always been considered a mediator of effects downstream of immune cells in the atopic triad, as lymphocytes, basophils, mast cells, and eosinophils all respond to TSLP and then secrete mediators that were thought to stimulate itch. Instead, these results show that keratinocyte-derived TSLP directly stimulates sensory neurons to produce itch. Furthermore, the findings show that TSLP secretion (and not just T cells) may be an important target of cyclosporine. The ORAI1 ion channel may be a new target for treating AD. Importantly, the TRPA1-expressing neurons are present in the lung and in the gut, suggesting a direct link not only between skin and the nervous system, but also other epithelia that are affected in the atopic march.
Citation(s): Wilson SR et al. The epithelial cell-derived atopic dermatitis cytokine TSLP activates neurons to induce itch. Cell 2013 Oct 10; 155:285.

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How Early Should Obesity Prevention Start?
Matthew W. Gillman, M.D., and David S. Ludwig, M.D., Ph.D.
N Engl J Med 2013; 369:2173-2175 December 5, 2013 DOI: 10.1056/NEJMp1310577
Obesity has pervaded the United States and is spreading throughout the world. Following in its wake is type 2 diabetes, which will affect at least half a billion people worldwide by 2030. A majority of U.S. women of childbearing age are overweight or obese (as defined by a body-mass index [BMI, the weight in kilograms divided by the square of the height in meters] >25). These women are likely to gain excessive weight when they're pregnant, making it harder for them to return to their pre-pregnancy weight after delivery. Postpartum weight retention not only portends increased lifelong risks for obesity-related complications but also an increased BMI at the inception of future pregnancies. During pregnancy, excessive weight gain, along with other risk factors such as gestational diabetes, can alter fetal growth and metabolism, leading to higher adiposity in the offspring. If the child is female, grows up obese, and becomes pregnant, the cycle begins again. It is time to interrupt this vicious cycle to prevent obesity and chronic diseases in mothers and children.
Once obesity is present, it is challenging to treat because of multiple physiological, behavioral, and cultural feedback loops. The good news is that the prenatal period and the first postnatal year hold critical clues that may lead to interventions to reduce obesity in women and prevent it in children. In a range of animal models (from rodents to nonhuman primates), dietary, hormonal, mechanical, and other perturbations that occur prenatally and during infancy induce lifelong, often irreversible derangements in the offspring's adiposity and metabolism. These changes involve the environmental alteration of genetic expression, in part through epi-genetic mechanisms, rather than changes in the genome itself. Thus, timely intervention during the early, plastic phases of development — unlike corrective efforts made later in life — may lead to improved lifelong health trajectories.
Because of challenges in measuring fetal exposures and the long latency between initial determinants and salient health outcomes, however, it is difficult to translate such proofs of principle in animals to human populations. The first generation of developmental-origins studies in humans linked birth weight to adult obesity-related morbidity and mortality. We now recognize that birth weight and each of its components, gestational duration and fetal growth, are low-resolution, momentary markers for myriad prenatal and perinatal influences. In the past decade, many such influences have been identified and quantified in epidemiologic studies that have involved the period before birth, used modern methods to mitigate confounding, and incorporated biomarkers. These studies have identified prenatal risk factors for obesity ranging from lifestyle factors such as the mother's smoking status to psychosocial factors including antepartum depression, medical conditions such as gestational diabetes, physiological stress as reflected by fetal exposure to glucocorticoids, and epigenetic markers such as gene-specific DNA methylation levels in umbilical-cord tissue.
After birth, rapid weight gain in the first 3 to 6 months of life is a potent predictor of later obesity and cardiometabolic risk. Lactation cannot be the entire explanation, because breast-fed babies tend to gain more weight than formula-fed babies in the first few months of life. The perinatal hormonal milieu may very well be a contributing factor. In one study, higher leptin levels in umbilical-cord blood, chiefly reflecting placental production, were associated with slower gain in infant weight-for-length and lower adiposity at the ages of 3 years and 7 years. In contrast, higher leptin levels at 3 years of age were associated with faster gains in BMI from 3 to 7 years, suggesting that leptin resistance develops between birth and 3 years of age.1 These findings are consistent with studies in animals showing a critical period of perinatal leptin exposure that allows normal maturation of appetite-regulating neurons in the hypothalamus. Features of infant feeding other than breast versus bottle may also play a role. Among formula-fed infants, the introduction of solids before 4 months was associated with a sixfold increase in the odds of obesity 3 years later.2
Emerging risk factors for obesity include exposure to endocrine disruptors, which appear to do the most damage during times of maximum developmental plasticity, and the gut microbiota. Our bodies contain about 1013 cells but as many as 1014 microorganisms. Certain modifications in the number and type of microorganisms during infancy are associated with excess weight gain, at least in rodents. The infant gut is normally colonized during transit through the birth canal, which could be one reason why children delivered by cesarean section appear to be at elevated risk for obesity.3
Given obesity's numerous developmental determinants, it is logical that effective prevention would target multiple modifiable factors. In combination, two well-studied prenatal risk factors, excessive gestational weight gain and maternal smoking during pregnancy, and two postnatal factors, fewer months of breast-feeding and a shorter duration of daily sleep during infancy, are associated with wide variation in childhood obesity. In one study, preschool-age children whose mothers did not smoke or gain excessive weight during pregnancy and who were breast-fed for at least 12 months and slept for at least 12 hours per day during infancy had a predicted obesity prevalence of 6%, as compared with 29% among children for whom the opposite was true for all four risk factors4; the rates were similar (4% and 28%, respectively) when the children reached 7 to 10 years of age
These observational data raise the possibility that avoiding some or all of these risk factors could substantially reduce the proportion of childhood obesity.
Preventing racial and ethnic disparities in obesity risk will also require a developmental approach. By school age, rates of obesity among black and Hispanic children in the United States are higher than the rates among white children, even after adjustment for socioeconomic circumstances. Many of the risk factors during pregnancy and early childhood are more prevalent among nonwhite persons, and they explain a substantial proportion of racial and ethnic differences in obesity in mid-childhood.5
Several features of pregnancy and infancy make the prenatal and postnatal periods conducive to behavior change to reduce the risk of obesity and its complications. First, women appear especially willing to modify their behavior during these periods to benefit their children. Second, since pregnant women and infants receive frequent routine medical care, interventions involving improved health care delivery have great potential. Third, these periods are relatively brief, and we know that behavior-change interventions are typically most successful in the short term. Fourth, if effective interventions begun during pregnancy are maintained after birth, they will reduce the risk of maternal obesity for future pregnancies and thus help to interrupt the intergenerational cycle.
Ongoing intervention studies promise to inform medical practice and public health. Many current trials target excessive gestational weight gain, including seven randomized, controlled trials funded by the National Institutes of Health that will together include more than 1000 overweight or obese women and follow infants through at least 1 year of age. It remains to be proven, however, that reducing gestational weight gain reduces the obesity risk in offspring. An alternative approach focuses on dietary quality, independent of calorie content, to ameliorate maternal insulin resistance and excessive placental nutrient transfer. Pilot studies have suggested that a multiple-risk-factor approach during infancy, targeting mothers as conduits for changes in their infants, can improve sleep duration and delay the introduction of solid foods.
But even as we await the results of obesity-prevention trials, some recommendations are warranted because of their beneficial effects on other health outcomes. Pregnant women should not smoke. Treatment of gestational diabetes reduces macrosomia at birth, although such treatment hasn't been proven to prevent obesity. U.S. rates of elective cesarean sections have apparently leveled off, but reducing these rates, especially of cesarean sections performed before 39 weeks of gestation, is a public health goal. Simple sleep-hygiene measures are worth trying, even in early infancy. The ideal age, in terms of allergy prevention, for introducing solid foods appears to be 4 to 6 months, and further research may show that the same is true in terms of obesity prevention.
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