Rare LRP6 Variants Identified in Spina Bifida Patients

Several single‐nucleotide variants (SNVs) in low‐density lipoprotein receptor‐related protein 6 (Lrp6) cause neural tube defects (NTDs) in mice. We therefore examined LRP6 in 192 unrelated infants from California with the NTD, spina bifida, and found four heterozygous missense SNVs, three of which were predicted to be deleterious, among NTD cases and not in 190 ethnically matched nonmalformed controls. Parents and siblings could not be tested because of the study design. Like Crooked tail and Ringleschwanz mouse variants, the p.Tyr544Cys Lrp6 protein failed to bind the chaperone protein mesoderm development and impaired Lrp6 subcellular localization to the plasma membrane of MDCK II cells. Only the p.Tyr544Cys Lrp6 variant downregulated canonical Wnt signaling in a TopFlash luciferase reporter in vitro assay. In contrast, three Lrp6 mutants (p.Ala3Val, p.Tyr544Cys, and p.Arg1574Leu) increased noncanonical Wnt/planar cell polarity (PCP) signaling in an Ap1‐luciferase assay. Thus, LRP6 variants outside of YWTD repeats could potentially predispose embryos to NTDs, whereas Lrp6 modulation of Wnt/PCP signaling would be more essential than its canonical pathway role in neural tube closure.     

Noise-Induced Variability of Immuno-PET with Zirconium-89-Labeled Antibodies: an Analysis Based on Count-Reduced Clinical Images

Purpose

Positron emission tomography (PET) with Zirconium-89 (Zr-89)-labeled antibodies can be used for in vivo quantification of antibody uptake. Knowledge about measurement variability is required to ensure correct interpretation. However, no clinical studies have been reported on measurement variability of Zr-89 immuno-PET. As variability due to low signal-to-noise is part of the total measurement variability, the aim of this study was to assess noise-induced variability of Zr-89 -immuno-PET using count-reduced clinical images.

Procedures

Data were acquired from three previously reported clinical studies with [⁸⁹Zr]antiCD20 (74 MBq, n?=?7), [⁸⁹Zr]antiEGFR (37 MBq, n?=?7), and [⁸⁹Zr]antiCD44 (37 MBq, n?=?13), with imaging obtained 1 to 6 days post injection (D0–D6). Volumes of interest (VOIs) were manually delineated for liver, spleen, kidney, lung, brain, and tumor. For blood pool and bone marrow, fixed-size VOIs were used. Original PET list mode data were split and reconstructed, resulting in two count-reduced images at 50 % of the original injected dose (e.g., 37 MBq_74inj).Repeatability coefficients (RC) were obtained from Bland-Altman analysis on standardized uptake values (SUV) derived from VOIs applied to these images.

Results

The RC for the combined manually delineated organs for [⁸⁹Zr] antiCD20 (37 MBq_74inj) increased from D0 to D6 and was less than 6 % at all time points. Blood pool and bone marrow had higher RC, up to 43 % for 37 MBq_74inj at D6. For tumor, the RC was up to 42 % for [⁸⁹Zr]antiCD20 (37 MBq_74inj). For [⁸⁹Zr]antiCD20, (18 MBq_74inj), [⁸⁹Zr]antiEGFR (18 MBq_37inj), and [⁸⁹Zr]antiCD44 (18 MBq_37inj), measurement variability was independent of the investigated antibody.

Conclusions

Based on this study, noise-induced variability results in a RC for Zr-89-immuno-PET (37 MBq) around 6 % for manually delineated organs combined, increasing up to 43 % at D6 for blood pool and bone marrow, assuming similar biodistribution of antibodies. The signal-to-noise ratio leads to tumor RC up to 42 %.

     

Legal Action Against Health Claims on Foods and Beverages Marketed to Youth

The prevalence of obesity among US children raises numerous health concerns. One pathway to reduce childhood obesity is by decreasing energy intake through the ingestion of fewer calories. Yet, food and beverage manufacturers often promote energy-dense items for children via varied health claims.Deceptive health claims are prohibited, and may be addressed through litigation or governmental regulatory efforts. While the amount of legal action against these potentially deceptive claims has increased, no comprehensive assessment has been conducted.This article, which analyzes litigation and governmental regulatory activities, considers key factors that may influence decisions to take legal action against potentially deceptive health claims on foods and beverages, including scientific support, forum selection, selection of plaintiffs, and potential public health impact.During the last 3 decades, the prevalence of obesity among US children has increased.1 Today, one third of youths are overweight or obese, and 17% are obese.2 Childhood obesity raises numerous health concerns, including greater likelihood of cardiovascular disease risk factors, presence of pre-diabetic indicators, and psychosocial issues.3–5 Obese children are more likely to become overweight or obese adults, with attendant risks for cardiovascular disease, metabolic challenges, and certain cancers.6–9Decreasing energy intake through the ingestion of fewer calories represents one pathway to reduce childhood obesity.10 Yet, companies that advertise foods and beverages often promote energy-dense items for children (i.e., items high in sugar, fat, or calories, such as sugar-sweetened beverages or certain breakfast cereals).11,12 This may be particularly confusing for parents seeking nutritious choices for their children, since some companies use health-related claims to promote energy-dense products (e.g., “good source of vitamin C”).13By law, however, “deceptive” claims are prohibited.14 A deceptive claim is one that: (1) is likely to mislead consumers when viewed by those acting reasonably under the circumstances; and (2) contains a message directly tied to a consumer’s purchasing decision.15 Federal regulatory authority for health claims is shared by the US Food and Drug Administration (FDA), for food labeling, and the Federal Trade Commission (FTC), for food advertising.16 In addition, state attorneys general, other state-level regulators, and private individuals may take legal action against potentially deceptive health claims.17Although federal agencies such as the FDA and FTC may use varied administrative tools to address allegedly deceptive health claims on foods and beverages, litigation brought by federal or state governments or private individuals may also encourage food and beverage manufacturers to limit their risk. This litigation often relies on federal or state consumer protection or false advertising laws, which require that consumers receive product information that is truthful and not misleading. In response to threatened litigation, or to avoid future litigation, manufacturers may voluntarily remove deceptive health claims from their products.18,19Although several analyses have examined specific claims that received regulatory attention,20,21 no comprehensive assessment of these actions has been conducted. We conducted a comprehensive review of federal, state, and private litigation and governmental regulatory activities regarding potentially deceptive health claims on foods and beverages marketed to children. We identify trends in these legal actions and discuss lessons learned for policymakers, practitioners, and other stakeholders seeking to limit the untruthful or misleading marketing of foods and beverages to children.     

Adverse Birth Outcomes in Colorado: Assessing the Impact of a Statewide Initiative to Prevent Unintended Pregnancy

Objectives. We assessed whether living in counties with Title X clinics and increased use of long-acting reversible contraception (LARC) in Colorado are associated with decreased risk of adverse birth outcomes.Methods. We linked Title X clinic counties to the Colorado birth data set by using the mother’s county of residence. We compared low birth weight (LBW) and preterm birth (PTB) in 2008 and 2012, in counties with and without Title X clinics. We compared the relationship between LARC use and the incidence of LBW or PTB in 2012 for women living in counties with Title X clinics.Results. For women living in counties with Title X clinics, the odds of PTB were significantly lower in 2012 compared with 2008 (odds ratio = 0.85; 95% confidence interval = 0.81, 0.89; interaction P = .02). For women living in Title X clinic counties in 2012, a higher proportion of LARC use (> 12.4%) was significantly associated with decreased risk of PTB (P = .02) compared with a low proportion of LARC use (≤ 4.96%).Conclusions. Improved access to family planning services and increased use of LARC are associated with lower risk of PTB.Unintended pregnancy is a significant public health issue in the United States. According to the most recent published estimates, 51% of pregnancies in the United States were unintended, and 60% of unintended pregnancies resulted in a live birth.1 Unintended pregnancies are associated with increased risk of adverse pregnancy outcomes, such as preterm birth (PTB) and delivery of low–birth weight (LBW) infants.2–8 In a large systematic review, Shah et al. reported increased odds of PTB (odds ratio [OR] = 1.31; 95% confidence interval [CI] = 1.09, 1.58) and LBW (OR = 1.36; 95% CI = 1.25, 1.48) among unintended pregnancies ending in live birth compared with intended pregnancies.2 The link between unintended pregnancy and poor birth outcomes is likely multifaceted, and may be associated with maternal socioeconomic risk factors, inadequate prenatal care, and preconceptual and prenatal maternal behavioral risk factors such as smoking and alcohol use.9–11 As part of the national effort to improve overall public health, increasing the proportion of pregnancies that are intended and decreasing the rates of PTB and LBW deliveries are all objectives of the Healthy People 2020 initiative.12In 2008, 37% of live births in Colorado resulted from unintended pregnancies according to the Pregnancy Risk Assessment Monitoring System.13 To address this issue, the Colorado Initiative to Reduce Unintended Pregnancy (Colorado Initiative) was developed and enacted in 2009 with the generous support of an anonymous donor.14 As part of the effort, the Colorado Family Planning Initiative was implemented through the Colorado Department of Public Health and Environment. Two of the primary goals of the initiative were (1) increasing the number of women accessing family planning services and (2) increasing the adoption of long-acting reversible contraceptive (LARC) methods such as intrauterine devices and contraceptive implants.14 Long-acting reversible contraceptive methods are safe and highly effective forms of contraception that have been shown to reduce rates of unintended pregnancy.15–18To help achieve these objectives, the Colorado Initiative provided funding to 28 Title X–funded agencies across the state of Colorado from 2009 to 2013, serving 37 of 64 Colorado counties. Those 37 counties were home to 95% of the state’s low-income population (defined as individuals with incomes at or below 150% of the federal poverty level).14 The locations of Colorado Title X clinics are shown in Figure 1. This distribution of resources in Colorado is important, in light of the known disparities of unintended pregnancy rates for women on the basis of socioeconomic status, age, race/ethnicity, and level of education.1Open in a separate windowFIGURE 1—Counties and locations of Title X clinics: Colorado, 2008 and 2012.The funding for the Colorado Initiative specifically supported the provision of intrauterine devices and contraceptive implants to women seeking care at Title X clinics, training for providers and staff on the counseling and provision of LARC methods, and technical assistance to Title X agencies related to increasing the use of these methods.14 Many of the Title X clinics across the state successfully executed the primary objectives of the Colorado Initiative, resulting in a rise in the total number of clients accessing family planning services per year from 46 201 to 64 148 and the proportion of women choosing LARC methods out of all women using contraception at Title X clinics from 0.8% to 8.6% from 2008 to 2012 (G. Klinger, Colorado Department of Public Health and Environment, e-mail communication, April 1, 2014).Although LARC use is on the rise in the United States, there is little in the published literature demonstrating an association between the use of LARC methods and rates of adverse birth outcomes.19 Given the scale of the Colorado Initiative, there is a unique opportunity to evaluate this possible association. As a result of improved use of family planning services in general and LARC use in particular, we hypothesized the following: (1) there will be a significant decrease in LBW and PTB in Colorado from 2008 to 2012; (2) for women living in Colorado counties in 2012 compared with 2008, LBW and PTB will differ by whether there is a Title X clinic in that woman’s county of residence; and (3) for women living in Colorado counties with Title X clinics in 2012, there will be a significant inverse association between LARC use at Title X clinics and LBW and PTB.     

A Review: Associations Between Attention-deficit/hyperactivity Disorder,Physical Activity,Medication Use,Eating Behaviors and Obesity in Children and Adolescents

In the past few years we have become increasingly aware of strong associations between obesity and ADHD. Both conditions are major public health issues, affecting children, adolescents and adults alike.