Early-Term Birth Tied to Poor Cardiorespiratory Fitness Later

Early-Term Birth Tied to Poor Cardiorespiratory Fitness Later

QUEENSLAND, AUSTRALIA — Children born early term at 37 to 38 weeks of gestation are at increased risk of poor cardiorespiratory fitness (CRF) during adolescence and young adulthood relative to their peers born later term, at 39 to 42 weeks, a new study shows^[1].

“The increasing trends toward earlier deliveries and the strong links between CRF and metabolic and cardiovascular health in youth and later in life support the importance of our findings,” lead author Dr Isabel Ferreira (University of Queensland, Australia), told theheart.org | Medscape Cardiology.

“Mothers and clinicians should thus refrain from planned deliveries (induction of labor or cesarean sections) before 39 weeks of gestation unless there is a medical indication to anticipate deliveries,” she advised.

The study was published online September 27, 2017 in the Journal of the American Heart Association.

Novel Study

Other cohort studies have shown that shorter gestation, even within the at-term period, may lead to adverse health outcomes, such as neonatal and infant neurological, cognitive, and respiratory morbidity and mortality. But this is the first study to examine the extent to which CRF varies across different gestational lengths within the at-term range (37 to 42 weeks) and the first to characterize such differences in CRF from childhood through adolescence to adulthood, Ferreira explained.

The researchers assessed CRF at age 12, 15, and 22 years in 791 children in the Northern Ireland Young Hearts Study who were born at different gestational ages within the at-term range. All were singleton births. CRF was estimated from field and laboratory tests and expressed by maximal oxygen uptake level through adolescence to young adulthood.

Mean levels of CRF at age 12, 15, and 22 were 45.6, 43.7, and 33.0 mL/kg per minute, respectively.

Gestational age was significantly associated with CRF through adolescence to young adulthood. For each week increase in participants’ gestational age, their CRF was 0.46-mL/min/kg (95% CI 0.14–0.79) higher, the researchers report.

After adjustment for all relevant cofactors, each week increase in gestational age correlated with a 14% relative risk reduction of poor CRF (risk ratio [RR] 0.86, 95% CI 0.76–0.96).

Notably, write the researchers, when comparing individuals according to categories of gestational age, those who born full term (39 to 40 weeks) or late term (41 to 42 weeks) had a similarly lower risk for poor CRF than those who were born early term at 37 to 38 weeks (RR 0.65 [95% CI, 0.47–0.89] and 0.59 [95% CI 0.40–0.90], respectively).

Conversely, compared with individuals born full term or late term (combined), individuals who were born early term had a 57% higher risk of poor CRF throughout adolescence to adulthood (RR 1.57, 95% CI 1.14–2.16). Diet, physical activity, and smoking behavior did alter the results.

‘Worrisome’ Trend in Early-Term Births

“We believe that earlier births—even within the at-term range—may interrupt normal development and lead to permanent changes of tissues and organs, thereby affecting cardiorespiratory fitness. As such, recent trends toward deliveries at shorter gestational lengths within the at-term period are worrisome,” Ferreira said in a news release.

“Although there are guidelines that warn against planned deliveries before 39 weeks of gestation (eg, from the American College of Obstetricians and Gynecologists), increasing rates of early-term births in countries such as the US and Australia observed over the past decades can be almost fully attributed to planned deliveries before labor,” Ferreira said.

The current study, she added, “illustrates the heterogeneity in long-term health risk by gestational age at term.”

In an interview with theheart.org | Medscape Cardiology, American Heart Association (AHA) spokesperson Dr Mary Ann Bauman called the study interesting.

“We’ve typically considered term to be a homogenous group, and this study suggests that maybe there is some heterogeneity in there in terms of development for the baby,” Bauman said.

“Women are always anxious toward the end of pregnancy to have the pregnancy end, but women will probably want to know that waiting a little longer when there is a voluntary choice is not a bad way to go because the development of that child is still occurring right up to delivery,” she said.

“I certainly don’t think this study is definitive,” she added, “and there will need to be more studies looking at this. Even if cardiorespiratory fitness is lower, moderate to vigorous exercise can overcome that, so that’s another point that says our children need to be exercising.”

The study was funded by the British Heart Foundation. The authors and Bauman have no relevant financial relationships.  

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Nobel Prize in Medicine Awarded to Circadian Rhythm Researchers

Nobel Prize in Medicine Awarded to Circadian Rhythm Researchers

For their discoveries of molecular mechanisms controlling circadian rhythm, three US scientists have been awarded the 2017 Nobel Prize in Physiology or Medicine.

Jeffrey C. Hall, Michael Rosbash, and Michael W. Young. (REX/Shutterstock)

Jeffrey C. Hall, PhD, Michael Rosbash, PhD, and Michael W. Young, PhD, were able to “peek inside our biological clock and elucidate its inner workings. Their discoveries explain how plants, animals and humans adapt their biological rhythm so that it is synchronized with the Earth’s revolutions,” according to a press statement from the Nobel Assembly at the Karolinksa Institutet, Stockholm, Sweden.

Working with fruit flies, the Nobel laureates isolated the period gene, which controls normal daily biological rhythm. They demonstrated that this gene encodes a protein called PER, which accumulates in the cell during the night and degrades during the day. “Thus, PER protein levels oscillate over a 24-hour cycle, in synchrony with the circadian rhythm,” the organization explains.

The scientists subsequently identified additional protein components of this machinery, exposing the mechanism governing the self-sustaining clockwork inside the cell. “We now recognize that biological clocks function by the same principles in cells of other multicellular organisms, including humans,” the organization said.

“With exquisite precision, our inner clock adapts our physiology to the dramatically different phases of the day. The clock regulates critical functions such as behavior, hormone levels, sleep, body temperature and metabolism,” they note.

“The paradigm-shifting discoveries by the laureates established key mechanistic principles for the biological clock,” the Nobel organization said. “Since the seminal discoveries by the three laureates, circadian biology has developed into a vast and highly dynamic research field, with implications for our health and wellbeing.”

Dr Hall received his doctoral degree in 1971 at the University of Washington in Seattle and was a postdoctoral fellow at the California Institute of Technology in Pasadena from 1971 to 1973. He joined the faculty at Brandeis University in Waltham, Massachusetts, in 1974. In 2002, he became associated with University of Maine.

Dr Rosbash received his doctoral degree in 1970 at the Massachusetts Institute of Technology in Cambridge. During the following 3 years, he was a postdoctoral fellow at the University of Edinburgh in Scotland. Since 1974, he has been on faculty at Brandeis University in Waltham, Massachusetts.

Dr Young received his doctoral degree at the University of Texas in Austin in 1975. Between 1975 and 1977, he was a postdoctoral fellow at Stanford University in Palo Alto. From 1978, he has been on faculty at the Rockefeller University in New York City.

The winners will share a prize of 9 million Swedish crowns ($1.1 million).

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In High-Risk Endometrial Cancer, Adding Chemo No Help, but…

In High-Risk Endometrial Cancer, Adding Chemo No Help, but…

SAN DIEGO — In women with early-stage, high-risk endometrial cancer, adding chemotherapy to radiation therapy was not superior to the standard treatment of radiation alone, according to new findings.

In a head-to-head trial of two adjuvant strategies, vaginal cuff brachytherapy  plus chemotherapy (VCB/C) was compared with the standard of pelvic radiation therapy (PXRT).

However, the rates of recurrence-free and overall survival were not improved with VCB/C compared with PXRT. In addition, there was a great risk for pelvic and para-aortic nodal recurrence in patients who received brachytherapy and chemotherapy, explained lead author, Marcus Randall, MD, a professor of radiation medicine at the University of Kentucky, Lexington.

Dr Randall presented his findings here during a plenary session at the American Society for Radiation Oncology (ASTRO) 2017 Annual Meeting.

“Pelvic radiation therapy remains an appropriate, and probably preferable, treatment for high-risk, early-stage endometrial carcinoma,” Dr Randall said. “But we need better treatment strategies to address the risk for systemic disease to further improve outcomes for these patients.”

He explained that the management of high-risk, early-stage endometrial cancer is controversial, and adjuvant pelvic radiation therapy has become standard for those at significant risk for local recurrence after surgery.

Most local recurrences occur at the vaginal cuff, and about 1 in 5 high-risk patients develop metastatic disease.  “Combination chemotherapy has demonstrated improved outcomes in more advanced disease, and there has been a trend toward increased use of vaginal brachytherapy,” he said. “Data suggests similar excellent ability to limit cuff recurrences compared to external radiation therapy.”

Some physicians have begun treating high-risk patients with early-stage disease using VCB/C. Therefore, a head-to-head study was needed.

But the jury is still out with regard to the use of chemotherapy in this setting, observed one expert, who was not involved with the study.

“But the way the study was designed — we can conclude that we don’t know the true benefit of chemotherapy in this population,” said Sushil Beriwal, MD, deputy director of radiation services at the Cancer Center at the University of Pittsburgh Medical Center, Pennsylvania.

“The radiation therapy was different in the two arms,” Dr Beriwal said. “One arm got 5 weeks of radiation therapy for 5 weeks and the other arm got brachytherapy, so they thought that the radiation toxicity would be higher in the other arm but it didn’t turn out to be the case.”

No Differences Between Groups

The GOG-249 was a phase 3 randomized trial designed to determine whether VCB/C could increase recurrence-free survival. The secondary objectives included comparisons of overall survival, patterns of failure, and adverse events.

This was not an equivalency study, Dr Randall explained, but was designed to test whether VCB/C was superior to PXRT.

A total of 601 patients were enrolled in the study; 74% had stage I disease and 89% underwent lymphadenectomy. Histologic types were as follows: endometrioid in 71%, serous in 15%, and clear-cell carcinomas in 5%. The median patient age was 63 years, and all patients had undergone hysterectomy before receiving radiation therapy or chemoradiation therapy.

Women in the PXRT group (n = 301) received a median radiation dose of 45 Gy delivered with intensity-modulated radiation therapy or standard four-field techniques over 5 weeks, while the VBC/C cohort (n = 300) was treated with high- or low-dose rate vaginal cuff brachytherapy with paclitaxel (175 mg/m² for 3 hours) and carboplatin (area under the curve, 6 – 21 days). Most patients completed therapy: 91% in the PXRT group and 87% in the VBC/C group.

At a median follow-up of 53 months, the 3-year, relapse-free survival rate was 82% for both groups. Overall survival at 3 years was 91% for PXRT and 88% for VCB/C.

Vaginal and distant failure did not significantly differ between the two study groups; the estimated 5-year rates of vaginal and distant recurrences were, respectively, 2.5% and 18% for both groups.

Dr Randall also pointed out that there was no significant treatment heterogeneity between the two groups with respect to the survival outcomes.

However, the cumulative incidence of pelvic or para-aortic nodal recurrence at 5 years in the VCB/C group (9.2%; 25 recurrences, 20 in the pelvis) was twice as high as in the PXRT cohort (4.4%; 12 recurrences, 6 in the pelvis) (hazard ratio, 0.47; 95% confidence interval, 0.24 – 0.94).

Acute toxicity was significantly greater in the VCB/C group, while late toxicity was similar between both groups. Grade 3 or higher adverse events were reported in 187 patients in the VCB/C group vs only 32 in the PXRT group.

Severe late effects were similar in both groups (35 events in the VCB/C group vs 37 events in the PXRT group).

Value of Chemo Still Unclear

Commenting on the study, Vishal Gupta, MD, associate professor of radiation oncology at the Icahn School of Medicine at Mount Sinai in New York City, noted that “surprisingly, chemotherapy did not reduce the rate of distant metastases, which was 18% in both arms. Even patients with high-risk histologies, including papillary serous carcinoma and clear cell carcinoma, did not benefit from chemo.”

Surprisingly, chemotherapy did not reduce the rate of distant metastases.
Dr Vishal Gupta

“It is unclear if more cycles of chemotherapy would result in a difference, but it is unlikely to be tested in this patient population,” he said.  “Another unexpected finding was that among patients receiving EBRT [external-beam radiation therapy], those receiving IMRT [intensity-modulated radiation therapy] had more acute and late toxicity compared to 3D [three-dimensional] conformal radiation therapy.  Intensity-modulated radiation therapy was expected to reduce acute and late toxicity, but this study found the opposite.”

Dr Randall has disclosed financial relationships with the American Cancer Society, Peloton Therapeutics, Threshold Pharmaceuticals,  and V Foundation for Cancer Research and a family member’s relationship with Threshold Pharmaceuticals. Dr Gupta and Dr Beriwal have disclosed no relevant financial relationships.

American Society for Radiation Oncology (ASTRO) 2017 Annual Meeting. Abstract LBA-1.  Presented September 25, 2017.

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Vancomycin-Piperacillin-Tazobactam Combo Ups AKI Risk in Kids

Vancomycin-Piperacillin-Tazobactam Combo Ups AKI Risk in Kids

Treating hospitalized children with the widely used combination antibiotic therapy of intravenous vancomycin hydrochloride and piperacillin-tazobactam (TZP) significantly increases their risk for acute kidney injury (AKI), new data from a large, multicenter study indicate.

Previous studies had made the association in adults. Now Kevin J. Downes, MD, from the Division of Infectious Diseases at The Children’s Hospital of Philadelphia in Pennsylvania, and colleagues find that when hospitalized children are given the combination therapy, their risk increases for AKI, which is linked to a higher risk for chronic kidney disease and death.

Results were published online October 2 in JAMA Pediatrics.

In hospitals, β-lactam antibiotics are often given together with intravenous vancomycin hydrochloride for children when serious infections are suspected. Vancomycin is the go-to drug when providers suspect serious gram-positive infection, and the β-lactam antibiotics provide gram-negative coverage.

Dr Downes and colleagues say pediatricians should be aware of the AKI risk in choosing antibiotics, and “must limit the duration of vancomycin plus TZP combination therapy, as is feasible, and closely monitor children for whom both of these drugs are necessary,” adding that when there are good substitutes for TZP, other broad-spectrum β-lactam antibiotics should be considered.

The study looked at children aged 6 months to 18 years entering through the emergency department, who were hospitalized for 3 or more days, and who received intravenous vancomycin plus 1 other antipseudomonal β-lactam combination therapy at one of six large children’s hospitals from 2007 through 2012. Its primary outcome was AKI on hospital days 3 to 7 and within 2 days of combination therapy.

After researchers adjusted for age, level of care, receipt of nephrotoxins, and hospital, they found that intravenous vancomycin plus TZP therapy was linked to higher odds of AKI each hospital day compared with vancomycin plus one other antipseudomonal β-lactam antibiotic combination (adjusted odds ratio, 3.40; 95% confidence interval, 2.26 – 5.14).

They identified 1915 hospitalized children who received combination therapy. Of those who received intravenous vancomycin plus one other antipseudomonal β-lactam antibiotic, 157 patients (8.2%) had antibiotic-associated AKI. Among recipients of any combination therapy on at least hospital days 1 and 2, antibiotic-associated AKI was detected most often in children who received vancomycin plus TZP (117 [11.7%]).

A limitation of this study is that it includes only children admitted through the emergency department, who started combination therapy right away. Risk factors for AKI in children starting antibiotics later in their hospital stay may be different, as they may be sicker or have more comorbidities, so results may not be generalizable to those in other settings.

Dr Downes received research support (unrelated to this study) from Merck and Pfizer. Coauthors report receiving research support (unrelated to this study) from Pfizer, Merck, Ansun Biopharma, and T2 Biosystems, and providing consultant services to T2 Biosystems and Nabriva Therapeutics. A coauthor also reports receiving support from the National Institute of Diabetes and Digestive and Kidney Diseases.

JAMA Pediatr. Published online October 2, 2017.

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Medicare Patients With Diabetes at Risk of Overtreatment

Medicare Patients With Diabetes at Risk of Overtreatment

More Medicare recipients are overtreated than undertreated for diabetes, yet rarely have their regimens been scaled back or deintensified, leaving them at increased risk of potentially life-threatening complications, say researchers.

Analysis of claims data and prescription refills from 78,792 Medicare recipients with diabetes in 10 states shows that 8560 (10.9%) were potentially overtreated compared with 6.9% who were potentially undertreated, according to Matthew L Maciejewski, PhD, of Duke University and Durham Veterans Affairs Medical Center, NC, and colleagues, reporting in the Journal of General Internal Medicine.

Only 14% of those who were overtreated were taken off previously recommended treatments, the study authors say.

Major trials have shown that in older patients and in those with comorbidities, aggressive diabetes control carries substantial risks.

Severe hypoglycemia, cardiovascular events, cognitive impairment, fractures, and death associated with overtreatment of diabetes “can happen at any time,” note Dr Maciejewski and colleagues. “Optimizing glucose control is clinically difficult, but it is a public-health imperative.”

Over-75s Most Likely to Be Overtreated

To compare the rates and patient characteristics associated with overtreatment and undertreatment of diabetes in the same cohort of patients, the researchers examined records for Medicare patients with at least one HbA_1c lab result available between January 1, 2011, and June 30, 2011.

Patients with an HbA_1c of < 6.5% at a single point in 2011, with fills for any diabetes medications beyond metformin, were considered potentially overtreated; those with HbA_1c > 9% were considered undertreated.

Overtreatment of diabetes was more common among Medicaid recipients older than 75 years of age (12%). It was also more common in those who qualified for both Medicare and Medicaid because of low incomes or serious disability (13.4%) and ranged from 11% for non-Hispanic blacks to 9.6% for those of “other” race/ethnicity.

Overtreatment was less likely and rates of deintensification were highest for Hispanic beneficiaries as well as for Medicare beneficiaries with six or more chronic conditions, those with more outpatient visits, those living in urban areas, and in 15% of those aged 65 to 70 years of age.

“Deintensification of diabetic therapy is often clinically appropriate for older adults, because the benefit of aggressive diabetes treatment declines with age, while the risks increase,” the study authors note.

“It is troubling that the oldest Medicare beneficiaries were more likely to be overtreated and less likely to have their medication regimens deintensified, because these older adults are least likely to benefit from tight glycemic control and most likely to be harmed.”

Individualize Treatment to Maximize Care While Avoiding Unnecessary Harm

Effective treatment of diabetes requires a major shift toward individualized treatment, and this study will help identify those who may benefit from more intensive treatment as well as those who may need less, they explain.

“By focusing at both the overtreatment and undertreatment ends of the diabetes quality spectrum, we can best begin to truly improve the quality of diabetes care, ensuring that patients get needed care while avoiding unnecessary potential harm.”

Although this is the first study to examine overtreatment and deintensification in a Medicare population, the investigators acknowledge that clinical practice may have changed since 2011.

Several major studies as well as new clinical guidelines for diabetes management have followed with recommendations for relaxed glycemic-control targets in older adults with multiple chronic conditions, limited life expectancy, diabetic complications, or functional impairment.

For instance, the “Choosing Wisely” campaign has set out to reduce overtreatment by asking clinicians to focus on the risks and benefits of evidence-based tests and procedures.

And in 2013, the American Geriatrics Society (AGS) updated its guidelines for improving the care of older adults with diabetes, recommending that medications other than metformin be avoided in the older patient with an HbA_1c of <7.5% (J Am Geriatr Soc. 2013;61:2020-2026).

“Current rates of overtreatment may be somewhat lower than what we report here,” Dr Maciejewski and colleagues admit.

“Future studies should examine whether rates of overtreatment and deintensification of diabetes regimens have changed over the past 6 years and whether the disparities observed here have narrowed,” they suggest.

More work is also needed to determine whether distinct subgroups of patients with both Medicaid and Medicare might benefit from specific approaches to diabetes management, they say.

Changing Prescribing Habits May Not Be Easy

In an interview, coauthor Jeremy Sussman, MD, MS, of Ann Arbor Veterans Affairs Medical Center and the University of Michigan Medical School, said that more attention to overtreatment is warranted but changing diabetes-care practices may be difficult.

“The first issue is simple awareness, he said, noting that clinical guidelines and performance measures for diabetes permit or encourage less aggressive care for older patients “because it’s safer.”

In 2008, the ACCORD trial showed that aggressive management of diabetes in elderly patients can be risky but “influenced care less than we’d hoped,” Dr Sussman told Medscape Medical News.

Standards of medical care in diabetes issued by the American Diabetes Association have also stipulated less intensive treatment for patients at high risk of hypoglycemia, including those with a history of hypoglycemia, those with a lower life expectancy, and those with multiple comorbidities.

“This [current] study and others show that current clinical care does not have that nuance,” Dr Sussman said. “Those factors had almost no influence on rates of overtreatment.”

Results from a previous study by Dr Sussman and colleagues showed that only one in four of almost 400,000 older patients with diabetes had their prescriptions changed when deintensification was indicated.

Study limitations include the fact that glycemic control was based on a single cross-sectional measurement in 2011 and the fact that the investigators weren’t able to examine whether potential overtreatment or lack of deintensification was associated with adverse outcomes. They also couldn’t determine the reasons that patients were overtreated.

Funding for this study was provided by the Centers for Medicare & Medicaid Services and by the Department of Veterans Affairs. Dr Maciejewski reports a relationship with Amgen; Dr Sussman reports no potential conflicts of interest. Disclosures for the coauthors are listed inthe paper.

J Gen Intern Med . Published online on September 13, 2017. Article

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Association Reported Between Fluoride and Reduced IQ

Association Reported Between Fluoride and Reduced IQ

A mother’s exposure to fluoride during pregnancy could lower the intelligence of her children, researchers say.

Following a group of Mexican children from the time of their mother’s pregnancy to early adolescence, an international team of researchers found an association between high fluoride levels in the mothers’ urine and reduced scores on the children’s cognitive tests.

Contrary to the claims of fluoride activists, however, the study does not seal the case against fluoride, said first author Morteza Bashash, PhD, an assistant professor of public health at the University of Toronto in Canada.

“This is a piece of a puzzle,” he told Medscape Medical News. “We need to do more work to identify the nature of the effect. And we have a lot uncertainty in the results.”

Published September 19 in Environmental Health Perspectives, the study adds significantly to the body of data on fluoride’s effects because it followed a relatively large group for more than a decade, Dr Bashash said. “This kind of birth cohort study is considered a gold standard to determine what happened over time that eventually leads to some sort of outcome.”

Studies in rodents have shown that fluoride can alter their cognition and behavior, and researchers in China have found an association between human intelligence quotient (IQ) deficits and exposure to high levels of fluoride in water, as reported in a National Research Council review.

To probe this association further, Dr Bashash and colleagues examined data from the Early Life Exposures in Mexico to Environmental Toxicants (ELEMENT) project, a longitudinal study designed to explore the effects of toxins in Mexican children.

Two cohorts from the ELEMENT study comprised 997 mothers recruited from hospitals serving populations with low or moderate incomes from 1997 to 2001.

The women were all in at least their 14th week of gestation at the time of recruitment; planned to stay in the Mexico City area for at least 5 years; did not report a history of psychiatric disorders, high-risk pregnancies, or gestational diabetes or current use of daily alcohol, illegal drugs, or continuous prescription drugs; and were not diagnosed with preeclampsia, renal disease, circulatory diseases, hypertension, and seizures during the index pregnancy. For the current analysis, the researchers excluded mothers younger than 18 years, those without adequate urine samples, and those whose fluoride concentrations were extreme outliers.

When the children reached 4 years of age, they took the McCarthy Scales of Children’s Abilities test. Between ages 6 and 12 years, they took the Wechsler Abbreviated Scale of Intelligence test.

The researchers were able to obtain 287 mother–child pairs with data for the McCarthy test and 211 with data for the Wechsler test. On both tests, an average score is between 85 and 115, with a higher score indicating better performance.

The researchers found a significant correlation between General Cognitive Index (GCI), as measured by the McCarthy test, and IQ, as measured by the Wechsler test (Spearman r = 0.55; P < .01).

They found that for every increase of 0.5 mg/L in fluoride in the mother’s urine, the children’s GCIs changed by a mean score of −3.76 (95% confidence interval [CI], −6.32 to −1.19).

Likewise, every increase of 0.5 mg/L in the mother’s urinary fluoride was associated with a change of −2.37 in IQ (95% CI, −4.45 to −0.29).

The association remained after the researchers adjusted for child-related factors (gestational age and weight at birth, sex, being the first child, and age at outcome measurement) and maternal factors (smoking history, marital status, age at delivery, IQ, education, and cohort). The adjustments changed the decrease per 0.5 mg/L of maternal urinary fluoride in GCI to −3.15 (95% CI, −5:42 to −0:87) and changed the decrease in IQ to −2.50 (95% CI, −4.12 to −0:59).

For a subset of children with data available on socioeconomic status, maternal bone lead, and blood mercury, the researchers controlled for these variables as well and found that the association between maternal urinary fluoride and GCI and IQ did not change substantially.

The researchers found that GCI decreased with each increase in maternal urinary fluoride in a linear relationship. But the decrease in IQ only began at 0.8 mg fluoride per liter of maternal urine.

When they focused their analysis on fluoride in the children’s urine, they found no significant association with the prenatal concentration of fluoride in the mothers’ urine.

In addition, they found no statistically significant association between fluoride in the children’s urine and their IQ. (The authors did not report on a relationship of children’s urinary fluoride and GCI.)

The results justify further research, Dr Bashash said. He would like to follow the children to look for cognitive associations with fluoride as they get older, and he would like to look for other adverse events. Some colleagues are analyzing data on sexual maturation, he said.

However, whether enough evidence has accumulated to make policy recommendations, he could not say. “Decision making in medicine and public policy requires some sort of compromise and measurement of the risk and benefit,” he said. “There is a big argument. We know that fluoride has some beneficial effect in preventing caries. We show that there is a potential that it has some negative impact, too. Our piece of work gives the opportunity to help policymakers to make an informed decision.”

Others were less hesitant. In a press release, the antifluoride group the Fluoride Action Network wrote that the study “confirms” that fluoride is harmful to the fetal brain.

Philippe Grandjean, MD, PhD, adjunct professor of environmental health at Harvard University in Cambridge, Massachusetts, did not go quite that far, but said it adds to the evidence for rethinking fluoridation. “I think the study is a red flag,” he told Medscape Medical News. “And when you take it into consideration with the Chinese studies, I think the time is way overdue for a broad-scale reevaluation of fluoride exposure.”

Other methods of preventing dental caries might be more effective, making fluoridated water obsolete, he suggested.

The American Dental Association, in contrast, released a statement calling into question the applicability of the data to the United States. In both the United States and Mexico, naturally occurring levels of fluoride in water vary widely, but in the United States, many communities add fluoride to water, whereas in Mexico, fluoride is added to salt, the organization pointed out, so it is difficult to compare levels of exposure. The American Dental Association declined to respond to questions about its analysis.

Scott Tomar, DMD, MPH, DrPH, who has served as a consultant to the American Dental Association, challenged the study’s conclusions. “I think it’s more hypothesis-generating in my view than any definitive evidence of any association between fluoride content in either salt or water and either IQ or cognitive development,” he told Medscape Medical News.

The scatter plot of the data appears almost random for both IQ and GCI, said Dr Tomar, professor of community dentistry and behavioral science at the University of Florida in Gainesville. And the level at which the IQ data becomes significant is above the level at which fluoride in urine would be found in someone drinking fluoridated water in the United States, he said. (The recommended level of fluoridation in the United States varies between 0.7 and 1.2 mg/L, depending on a region’s mean temperature.)

The study was well designed, Dr Tomar said, but still it could not rule out other factors that might confound the results, such as toxins other than lead and mercury.

Furthermore, he said, children’s IQs in the United States have been increasing since the 1980s, even as more communities fluoridated their water.

“It’s not that I’m closing my mind to potential adverse effects,” he said. “But I’d say at a minimum we’d want to see a similar kind of observational study repeated in another environment, whether it’s in the United States or another country.”

This study was supported by the National Institutes of Health, the National Institute of Environmental Health Sciences/the US Environmental Protection Agency, and the National Institute of Public Health/Ministry of Health of Mexico. The authors, Dr Tomar, and Dr Grandjean have disclosed no relevant financial relationships.

Environ Health Perspect. 2017;125(9):097017. Full text

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Twice-Daily Aspirin Better to Prevent CVD in Diabetes?

Twice-Daily Aspirin Better to Prevent CVD in Diabetes?

LISBON, PORTUGAL — Differences in platelet response to aspirin in blood samples from patients with type 2 diabetes compared with controls hint that the former might benefit from twice-daily, rather than once-a-day, aspirin dosing for primary prevention of cardiovascular events.

However, these findings are from a small early study, and it is not known whether this different dosing would ultimately affect cardiovascular outcomes.

Specifically, in this research involving 42 aspirin-naïve individuals, patients with diabetes had higher levels of platelet aggregation than controls before aspirin therapy was initiated.

Then, after a week of aspirin therapy, patients with diabetes had a higher number of immature platelets — indicating that they had a higher platelet turnover and more newly produced platelets that were not inhibited by aspirin — although the difference was not significant.

Liv Vernstrøm, a master’s student in the department of endocrinology and internal medicine at Aarhus University in Denmark, reported these findings in a poster at the European Association for the Study of Diabetes (EASD) 2017 Annual Meeting.

“Given that platelets in people with diabetes are characterized by increased aggregation and increased turnover rates, our study indicates that patients with type 2 diabetes may achieve additional benefit from twice-daily rather than once-daily dosing of aspirin,” she and her colleagues comment in an EASD press release.

“We suggest that [patients with type 2 diabetes] might benefit from a more frequent dosing,” but “I need to stress that we do not [yet] recommend people with diabetes take aspirin twice a day,” Ms Vernstrøm emphasized to Medscape Medical News in an email.

“We have not tested this, and it needs to be evaluated in large-scale clinical outcome trials before any conclusions can be made.”

Invited to comment, Dominick J Angiolillo, MD, University of Florida, Jacksonville, told Medscape Medical News in an email that “the data from this study are in line with prior investigations in the field and suggest that a twice-daily [aspirin] regimen may allow for better antiplatelet protection.”

However, he too cautioned that “whether these laboratory findings translate into better clinical outcomes remains unknown,” and further studies are needed to investigate this.

Aspirin’s Antiplatelet Effect in Diabetes

The antiplatelet effect and platelet turnover with aspirin therapy has not been explored in patients with type 2 diabetes who do not have cardiovascular disease, Ms Vernstrøm and colleagues explained.

To investigate this, they measured platelet aggregation and immature platelet count in blood samples from 21 patients with type 2 diabetes and 21 age- and sex-matched controls.

The patients had a mean age of 62, and 67% were male.

Patients with type 2 diabetes had had it for a mean of 9 years and were more likely to be taking antihypertensive drugs (76% vs 33%, P = .01) and lipid-lowering drugs (52% vs 5%, P < .001) and have a higher heart rate (68 vs 59 beats/min, P = .01) than the control individuals. More than one in 10 participants (14%) were current smokers.

At baseline, patients with diabetes had higher levels of platelet aggregation than controls (P = .03). An hour after the first dose of aspirin, platelet aggregation was reduced in both groups.

After a week of daily low-dose aspirin, when a steady state of aspirin had been reached, platelet aggregation levels an hour after ingesting aspirin were much lower than they had been after the first aspirin dose in both groups.

Platelet aggregation also increased from 1 hour to 24 hours after patients received aspirin in both groups (indicating a declining antiplatelet effect over this dosing interval).

However, compared with controls, patients with type 2 diabetes had a greater number of immature platelets (indicating a higher platelet turnover), although this was not statistically significant (P = .09)

Daily Aspirin for Primary CV Prevention in Diabetes in ACCEPT-D, ASCEND

Results of the ongoing Aspirin and Simvastatin Combination for Cardiovascular Events Prevention Trial in Diabetes (ACCEPT-D) and A Study of Cardiovascular Events in Diabetes (ASCEND) trials will “hopefully establish whether patients with diabetes benefit from once-daily aspirin dosing” for primary prevention of CVD, Ms Vernstrøm noted.

“If these studies show a net benefit from aspirin treatment, our study indicates that [patients with type 2 diabetes] may achieve additional benefit from an alternate [twice-daily] dosing regimen, which could be interesting to investigate in the future,” she added.

“The same phenomenon of a reduced effect of aspirin is also seen in patients with diabetes and known cardiovascular disease, so another approach could be to test the effect of twice-daily dosing in this [secondary-prevention] patient group first,” Ms Vernstrøm suggested.

The study was supported by the Danish Council for Independent Research, Aase og Ejnar Danielsens Fond. The authors report no relevant financial relationships.  

European Association for the Study of Diabetes 2017 Annual Meeting; September 13, 2017; Lisbon, Portugal. Poster 1132

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