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Defining Safety for Infants
"Safety" refers to a reasonable certainty of no harm and is described by noting a range along a continuum, rather than as an absolute point or value (Food Additives Amendment, P.L. 85-929 of the Federal Food, Drug and Cosmetic [FD&C] Act, 21 U.S.C. §301). The relationship between biology and safety is mediated through the concepts of harm, benefit, and risk.
Manufacturers may propose the addition of a new ingredient to infant formulas by demonstrating the safety, not the efficacy (the capacity to produce an intended effect under the realistic situation of product use), of the proposed ingredient. Foods are generally considered to be inherently efficacious (with inherent sensory properties and nutrition) and, thus, efficacy is not a consideration in their safety assessment. In the case of infant formulas, this assumption is modified to some degree because it has been proposed that the products must be capable of sustaining physical growth for a specified period of time. Currently, however, manufacturers are not required to demonstrate the benefits of an individual ingredient in the product. Infancy is a uniquely vulnerable period that complicates the interpretation of safety guidelines. Not all organ systems are fully mature at birth, and as they undergo further development they are highly susceptible to nutritional inputs, illnesses, care practices, and other environmental inputs. Early infancy represents a period of growth and development when a successful outcome depends on the timely emergence of critical structures and developmental processes. The gastrointestinal, renal, and immune systems, as well as brain and neurological functions, could be affected by exposure to potentially harmful substances contained in infant formulas. Optimization of nutrition and minimization of exposure to potentially harmful substances in the food supply is of heightened importance during infancy. The committee concluded that there are six issues that must be considered as important safety issues when regulating infant formulas: (1) infant formulas are the sole or predominant source of nutrition for many infants, (2) formulas are fed during a sensitive period of
development and may therefore have short- and long-term consequences for infant health, (3) animals may not be the most appropriate model on which to base decisions of safety, (4) "one size fits all" food safety models may not work for all new additions to formulas, (5) infant formulas could be considered as more than just food, and (6) potential benefits, along with safety, should be considered when adding a new ingredient to formulas.
A discussion on guidelines to ensure the safety of ingredients new to infant formulas requires a broad understanding of the concepts and models of safety regulations and an in-depth review of infancy as a unique period that requires unique safety measures. This chapter describes fundamental concepts of safety regulations, statistical considerations in assessing food safety, models of safety assessment (including the Novel Foods model of Health Canada), and special considerations for ensuring the safety of infants and regulating infant formulas.
Several federal, state, and local agencies monitor the safety and quality of substances that are ingested and inhaled by the general public. Each agency operates within its own domain using its own set of rules and procedures, but the agencies work collaboratively on some issues to ensure the safety and quality of food, water, and air. The Food and Drug Administration (FDA) has the primary responsibility for regulating ingredients new to infant formulas and other agencies serve in peripheral roles.
The terms safety, hazard, risk, harm, and benefit are central to the full understanding of safety assessment. Safety refers to a reasonable certainty of no harm (21 U.S.C §348) (e.g., for food ingredients in the U.S. regulatory system) or, in some systems (e.g., for pharmaceutical drugs in the U.S. regulatory system), a reasonable balance between costs (harm) and benefits. Safety is an intellectual concept; it is not an inherent biological property of a substance. Safety is described by noting a range along a continuum, not an absolute point or value. The relationship between biology and safety is mediated through concepts of harm, benefit, and risk. As such, the concept of safety and its assessment is influenced by many different organizations, individuals, and intellectual disciplines.
A hazard generally refers to some substance or combination of substances (organic or inorganic, or in some cases psychological) that may, under some circumstances or for some individuals, produce undesired health-related outcomes. Nearly any substance can have the potential to produce an undesired health outcome to some individual under some circumstance. Exposure to a hazard, however, does not guarantee that an undesired outcome will occur.
The likelihood that such an outcome will occur given exposure to a hazard is what is referred to as the risk of that hazard. The risk of a hazard is not a general (main effect) property of the substance, but rather it is an interaction between the nature of the hazard, the circumstances of the exposure (e.g., the magnitude, the timing, and the specific features of the individual, such as health status, age, and susceptibility), and other such conditions that moderate the actual health impact of the hazard.
Harm refers to the nature of the undesired outcome (usually a health outcome) associ-
ated with a hazard and is often expressed in terms such as cost. Not all harm is the same, and not all individuals would assess the same outcome as having equivalent harm.
Opposite harms are the benefits of the addition of substances. The ratio of costs to benefits is a critical unit in some safety assessment systems. Cost-benefit ratios may apply to individuals or groups. For example, an individual may benefit from a treatment but may experience side effects. Another example is the case of iron supplementation to reduce infant risk of anemia. Some or all of the infants within a group may benefit from receiving additional iron, while some may be harmed (e.g., experience constipation); on average, however, the population that benefits from iron fortification will be larger than the population that experiences harm.
Members of the general public, special interest advocates, lawmakers, scientists, leaders of government agencies, and industry representatives play significant roles in establishing safety guidelines. The public makes certain demands for lowering food safety risks (whether real or perceived risks as a result of misinformation) and expresses its concerns either through consumer organizations or through individual contact with appropriate government agencies. Consumer organizations may voice such concerns in a focused manner. Lawmakers weigh these concerns and, where appropriate, engage in debates that may result in new laws and regulations. In the process of establishing formal policy, other individuals and organizations often enter into the debate to influence the final statements of safety regulation. For example, scientists or professional organizations may contribute important information that derives from scientific studies, economists may provide information about the costs of implementing certain safety standards, and industry representatives may describe the impact of the regulation on manufacturers. Once laws are enacted, regulatory agencies are entrusted with the responsibility of developing, implementing, and enforcing regulations.
Among adults, guidance concerning the clinical relevance of differences in some physiological parameter (e.g., blood pressure) is derived from a body of accumulated evidence that provides a rationale for a clear definition of pathological state (e.g., hypertension). In testing an ingredient new to an infant formula, it is unlikely that investigators would detect any clear evidence of disease (which should have been ruled out by preclinical testing). Instead, more subtle differences in physiology or development may appear that lack sufficient evidence to inform clinical judgment. Investigators must determine whether a difference (e.g., level of growth) has an immediate health consequence for the infant and the level of difference that matters for the long term (e.g., a growth deficit associated with a particular ingredient rapidly disappears when other foods are added to the diet). In the absence of sufficient evidence for clinical judgment, investigators may be forced to utilize statistical or analytical approaches as the basis for making judgments about safety.
The process of establishing the safety of food products, especially infant formulas, is complex and requires empirical evidence from many disciplines. Each step in the process requires the application of the highest standards, whether using methods of bioassay, nutritional analysis, or basic chemistry. Eventually studies involving human subjects (particularly in the case of infants) must be conducted in order to demonstrate the product's safety for the human consumer. Studies involving humans are almost always conducted as randomized clinical trials and standard methods of design and analysis are followed.
The most typical analytical approach to interpreting the data from scientific studies, including clinical trials, is the statistical significance test, also known as the null hypothesis significance test (NHST). This approach, which has recently come under much scrutiny and debate, formally
applies a set of principles for establishing a "rule of evidence" in scientific inquiry. In the simplest terms, NHST provides a set of rules for decision making under uncertainty.
First, a set of two mutually exclusive alternative conditions is specified. For example, the addition of substance X to an infant formula either: (a) hinders the ability of the infant to maintain proper physical growth, or (b) it does not hinder proper physical growth. Second, a set of risk probabilities are specified (the "alpha level" of the test and the "power" of the test), which allows the researcher to control the probabilities of drawing an incorrect inference. Third, a set of assumptions is specified that, taken together with the null and alternative hypotheses, allow the complete specification of the behavior of some statistical index.
From this model one can specify a set of decision rules to draw some conclusions based on the empirical results of the experiment. The result of such a statistical test procedure does not establish with certainty the "true state of nature," but rather it expresses a degree of confidence that one of the two states is not likely to occur. The randomized clinical trial and associated NHST are the mainstays of certain safety and efficacy approaches, such as the FDA drug trials described later, but they have certain potential limitations in their application to the safety of ingredients new to infant formulas.
The first limitation is that NHST lacks a certain degree of direct applicability. The basic concept underlying the safety of an ingredient added to infant formulas is the "reasonable certainty of no harm" concept without a requirement for the demonstration of benefit. NHST, however, is generally formulated to demonstrate the superiority of one condition versus another. The fundamental idea in the formulation of reasonable certainty of no harm is one of equivalence, not of difference. While one can manipulate the null and alternative hypothesis in this circumstance (e.g., to make the "no difference" condition the alternative hypothesis), the resulting formulation is awkward and shifts the probabilistic control of the important error rate to that of power rather than to the more direct alpha level of the resulting test. Due to its highly unusual nature, it is likely that this test's results will not be properly understood and interpreted.
The second limitation is that NHST is concerned with demonstrating a difference rather than with the size or importance of the difference. In a number of scientific disciplines, most notably psychology, there has been a shift in emphasis from statistical significance to clinical significance. When formulated as clinical significance, the question becomes whether the difference that is detected by NHST is one that has any practical health consequences from the perspective of the individual receiving the treatment. Thus it is recognized that while a very small (potentially clinically inconsequential) difference can be detected by NHST (particularly in very large samples), the most important question is to determine whether the difference has any health implications.
In order to address these different questions, a number of approaches to testing have been adopted that include the following features:
a greater focus on effect size estimates,
the use of confidence intervals as the primary way of reporting the results of experiments, and
the use of alternative statistical tests that are not based on the sample mean as the primary way of characterizing populations.
One approach to determine clinical significance is the use of dominance statistics (Cliff, 1993). In this approach it is asked, in a probabilistic manner, how likely is it that an individual chosen at random from the group receiving treatment A will score better than an individual chosen at random from the group receiving treatment B. Using the dominance
statistic approach, the question of weight maintenance might be approached as determining the probability that an infant drawn at random from a group consuming the new formula would weigh less than an infant drawn at random from a group fed the existing formula. If this probability were not too extreme, it might argue for the safety of the new addition relative to that of a formula without that addition.
An alternative approach to NHST may also be considered. For example, Seaman and Serlin (1998) developed methodologies that allow the direct demonstration of equivalence (as opposed to the subtly different approach of NHST that is oriented to showing differences). Such approaches may be applied to establish rules to determine the safety of ingredients new to infant formulas.
In assessing the safety of ingredients new to infant formulas, investigators must consider whether the NHST approach is the most appropriate method to analyze empirical data or whether an approach that more directly assesses effect sizes, clinical significance, dominance, or equivalency is preferred. Of particular importance in the selection of a proper analytical technique is the question of whether any decrease in infant growth rate can be tolerated. If slower growth rates or other minor differences in physiology or function cannot be tolerated, then investigators may wish to demonstrate equivalency, rather than merely detect differences. In addition, the error rate that one is willing to tolerate must be carefully considered rather than routinely adopting the traditional 0.05 alpha level. It is the alpha level that indicates the "societal" values for the acceptance of risk and harm.
Virtually all other models used to assure the safety of ingested or inhaled substances are variations of the food and drug safety models (described below): the nutrients model based on dose-response relationships; the in-market monitoring and surveillance model; the novel foods and food additives models, based on a reasonable certainty of no harm; and the drug model, based on risk-benefits assessments.
Food Models
Nutrients Model
The Dietary Reference Intakes (DRIs) are a set of quantitative reference values for nutrient intake to be used for planning and assessing diets, and they are based on risk assessments. One of the DRIs, the Tolerable Upper Intake Level (UL), uses risk assessment approaches. The UL uses a substantially different approach from the one used for food additives in that it does not address any particular food product or ingredient, yet it provides useful information on the magnitude of intake of nutrients for individuals as a function of age, gender, pregnancy and lactation status, and other such factors. At the heart of the DRI methodology is a dose-response relationship (e.g., the examination of a targeted health outcome as a function of the intake of the nutrient in question). The UL is the level of intake at which one would expect virtually no risk of an adverse health outcome for almost all healthy individuals in the population. There would be an increased risk of an adverse health outcome if more than the UL were consumed. The actual risk assessment methodology of the DRI approach is quite complex; it is described in Dietary Reference Intakes: A Risk Assessment Model for Establishing Upper Intake Levels for Nutrients (IOM, 1998) and in each of the nutrient-specific DRI reports, most recently in Dietary Reference Intakes for Water, Potassium, Sodium, Chloride, and Sulfate (IOM, 2004).
In-Market Monitoring and Surveillance
A different approach to ensuring food safety is in-market monitoring and surveillance. For instance, once an infant formula is released for general consumption, FDA requires that the manufacturer maintain and analyze records of consumer complaints. Further, the manufacturer is required to report to FDA cases where the evidence suggests a reasonable possibility of a link between consumption of the formula and an infant illness, death, or a reduction in intake of required nutrients. This is currently a passive system that merely requires that a caregiver report a suspected case, but it is one more mechanism by which the safety of infant formulas can be monitored. Details of in-market monitoring and surveillance are discussed in Chapter 7.
Novel Foods Model
In 1994 Health Canada issued the Guidelines for the Safety Assessment of Novel Foods (Health Canada, 1994) to assist in the design of premarket notifications for novel foods. The manufacturer must submit a request to Health Canada 45 days prior to the sale or advertising for sale of any novel food under specific requirements laid out in Division 28 of the Food and Drug Regulations (Canada, 2001). Where it is determined that data of a scientific nature are required to support the safety of the product, a safety assessment may include an evaluation of microbiological, molecular, chemical, nutritional, and toxicological endpoints in preclinical and clinical studies. Specifically, the assessment may evaluate the process used to develop the novel food (molecular, chemical, and microbiological), the comparison of the characteristics of the novel food with that of its traditional counterpart (nutritional and toxicological), safety issues related to a source with no history of use in the food supply (nutritional and toxicological), and the potential allergenicity from proteins introduced into the food (nutritional). Health Canada may request additional information to assess the safety of the novel food and, if satisfied, will notify the manufacturer that the information is sufficient and the product is safe for consumption.
Food Ingredients Model
The food safety evaluation of food ingredients and associated regulations in the United States is based on "reasonable certainty of no harm." Sections 201(s), 201(z), 409, and 412 of the FD&C Act and FDA's Toxicological Principles for the Safety Assessment of Direct Food Additives and Color Additives Used in Food, also known as the Redbook1 (OFAS, 2001, 2003), are the regulations and guidelines that are used to assess the safety of food ingredients and infant formulas.
Regulatory oversight of the addition of new ingredients to infant formulas is governed largely by two processes: the Food Additive Petition and the Generally Recognized as Safe (GRAS) Notification. It is important to note that these procedures are to ensure the safety (a reasonable certainty of no harm)—not the benefits—of the proposed ingredient. A food additive is any product added to a food that is not generally recognized as safe by qualified experts (see Box 4-1 in Chapter 4 for the complete definition). The food additive petition
process requires that the manufacturer file a petition with FDA that provides all available data on the safety of the product and proposes the conditions under which such an additive may be safely used. FDA may issue a safety declaration upon review of the petition. In this case it is FDA that makes the affirmative declaration of the safety of the additive in the context of its proposed use.
By contrast, the GRAS Notification process requires that the manufacturer make the initial declaration of the safety of the product based on consensus by qualified experts. FDA then reviews the notification and, if all of its questions are satisfactorily answered, the agency issues a letter of no objection. Because this process has become the primary route of introduction of new ingredients to infant formulas, the GRAS Notification process is reviewed in greater detail in Chapter 4.
Infant formulas are the sole source of nutrition for many infants and, therefore, one step is required for the approval of modifications to formulas that is not required for other foods. Manufacturers seeking to market a new infant formula need to comply with regulations under Section 412 of the FD&C Act. New regulations under that section of the FD&C Act have been proposed that would require manufacturers to demonstrate that the formula containing the new ingredient in the matrix in which the product is delivered is capable of sustaining physical growth and development over 120 days, the period when the formula is likely to be the sole source of infant nutrition.
In 1982 FDA issued, and later updated, the Redbook (OFAS, 2001, 2003).2 These guidance documents were prepared to assist in the design of protocols for animal studies conducted to test the safety of food ingredients and include detailed guidelines for testing the effects of food ingredients on mothers and their developing fetuses. However, due to the special conditions surrounding infancy described below, special considerations need to be taken into account when applying the Redbook in the case of infant formulas.
As mentioned previously, since virtually all models of safety determination are based on empirical evidence, only minor variations of the basic models seen in the FDA food safety determination system are possible. These differences are based more upon emphasis and implementation than on any profound differences in methodology. One major exception to this uniformity is the food safety model based upon the "reasonable certainty of no harm" concept. As opposed to other models where benefits from the addition of the new ingredient need to be demonstrated, in that model safety is seen as no harm and no proof of beneficial effects is needed. As discussed further in Chapter 4, the committee believes that for infant formulas, the concepts of efficacy (benefit) and safety are not always mutually exclusive because of the uniqueness of the infant population and, therefore, potential benefit should be considered when allowing new ingredients to be added to infant formulas.
Drug Safety Model
Structurally the FDA drug approval process closely resembles the food additive model of food safety. A manufacturer that wishes to market a new drug submits a petition to FDA,
The original Redbook (Redbook I) was published in 1982, revised in 1993, and updated in 2001 (draft Redbook II). In 2000, FDA released a revised version of the publication as Redbook 2000: Toxicological Principles for the Safety Assessment of Food Ingredients. However, some chapters in Redbook 2000 have not yet been revised, so both the draft Redbook II and Redbook 2000 are used as guidance documents when conducting animal studies. Appendix C lists the contents of the draft Redbook II and Redbook 2000 and indicates which chapters in Redbook 2000 have been updated.
along with a specified set of empirical evidence concerning the product. FDA (with advice from an established panel of experts) evaluates the evidence and, if satisfied that the drug meets its regulatory criteria, approves the drug for commercial use. In the drug approval process, however, the evidentiary basis for the decision is quite different from that employed in the food additive model where evidence of benefit is not necessary.
First, the applicant must offer evidence through one or more clinical trials of the efficacy of the drug. That is, there must be clear and cogent evidence that the drug does what it claims to do. In addition, it must be shown to have the same effect as the current standard treatment of the condition being studied. Second, side effects (e.g., adverse reactions) of the drug must be carefully studied and reported. The criterion for approval of the applicant product is then based upon an assessment of the benefit:risk ratio.
Other Safety Models
As noted above, virtually all other models used to assure the safety of substances ingested or inhaled are variations of the food and drug safety models. Given the number of regulated substances (e.g., air, water, lead) and the number of agencies charged with regulating them at the federal, state, and local level, it is not surprising that numerous variations in safety determination practices exist. Most of these differences, however, are at the technical level rather than at the conceptual level (e.g., setting the standard for lead is conceptually very much like the establishment of upper boundaries in the DRI process).
Infancy as a Vulnerable Period
Dealing with infancy makes interpretation of safety guidelines particularly difficult. Infancy is a period of very rapid development, and change is the rule rather than the exception. Infants are nonverbal and cannot report their own experiences, and parents may not be able to accurately interpret the signals that infants provide. It is reasonable to expect that any harmful effects from an ingredient might be subtle. Throughout this report, the committee describes the period of infancy as so special and the consequences of any harm so great that the public should be unwilling to tolerate any harm due to the addition of an ingredient new to infant formulas, even if there are benefits to most who would be exposed to the new ingredient.
At birth, infants make a dramatic transition from a highly controlled prenatal environment where oxygen and nutrients are delivered directly from the mother to infant via the blood supply, to one that involves enteral feeding and thus requires an efficient gastrointestinal system and coordination of a wide range of functions. Not all organ systems are fully mature at birth, and as they undergo further development, they are highly susceptible to environmental inputs. Early infancy represents a period of growth and development when a successful outcome depends on the timely emergence of critical structures and developmental processes. At the same time, infancy is a period of heightened vulnerability to nutritional inputs, illnesses, care practices, and other environmental influences. Depending on the tissues involved and the timing and severity of insults, effects may be irreversible or the ability to compensate for differences may be limited. Furthermore, infants have a higher food consumption rate than adults when expressed on a per kilogram body-weight basis, and they typically rely on a sole nutrient source (human milk or milk substitutes) in the early months of life. Thus optimization of nutrition and minimization of exposure to potentially harmful
substances in the food supply is of heightened importance during infancy. Examples of the various systems that could be affected by exposure to potentially harmful substances contained in infant formulas are described below.
Gastrointestinal and Renal Function
With the exception of exocrine pancreatic function and bile acid metabolism, the gastrointestinal tract is anatomically and functionally fully developed in infants born at term, and dietary contents do not influence their development. Trophic factors can be found in human milk and in the gastrointestinal tract, but their function is unclear. As these factors are more fully identified and their structure, composition, and physiological effects understood, it is possible that one or several may have effects on infant organ systems.
Similar to the gastrointestinal tract, development of renal function is not influenced by dietary content. Glomular filtration does not approximate adult values until about 3 years of age, and tubular reabsorption and urine acidification reach normal values at several months of age. However both are sufficient for healthy term infants, but contribute to fluid and electrolyte abnormalities in infants who are ill and in those who are fed an inappropriate diet.
Immune Function
The infant immune system is not fully mature at birth; it has deficits in the ability to prevent invasion of pathogens and to respond to antigens. Of particular concern in the context of ingredients new to infant formulas is the increased permeability of the gut mucosal barrier in the presence of inflammation or infection or if the integrity of the epithelial cell layer is disrupted. The increased permeability allows macromolecules to be absorbed, which stimulates allergic responses to food proteins.
Brain and Behavior
There is rapid development of both brain and behavior during the first year of life. Both subcortical and cortical central nervous system (CNS) structures mature and allow the appearance of critical developmental functions, such as visually guided reaching, face recognition and orientation toward faces, explicit and working memory, focused attention, and inhibitory control (Johnson, 2001; Nelson, 1995). The quality of the young infant's nutritional intake can be an important influence on CNS development and function (Rao and Georgieff, 2000; Wauben and Wainwright, 1999). For example, iron deficiency anemia in the first year interferes with the development of functional CNS processes, such as alteration in the number of dopamine receptors or degree of myelination (Lozoff et al., 1998; Wauben and Wainwright, 1999). These functional changes in turn can have long-term cognitive and behavioral consequences that cannot be compensated for by subsequent nutritional interventions (Lozoff et al., 1998).
A similar process is also seen with regard to behavioral development. The infant's increasing behavioral competencies and patterns of social-emotional functioning during the first year can impact upon critical developmental mediators, such as patterns of parent-child relations, stress reactivity, initiation of self-regulation skills, and extent of infant interactions with the larger environment (Gunnar, 2000; Ruff and Rothbart, 1996). Interference with the development of these critical mediators also can have long-term consequences for later functional competence (Wachs, 2000). Since a large proportion of the infant's nutrition
during the first year may be supplied by formulas, changes to formulas that impact upon normally occurring brain and behavioral developmental patterns can have potential long-term consequences.
Important Safety Considerations
Most of the principles that govern the safety of ingredients new to infant formulas derive from the same principles that govern food safety for older children and adults. The committee concluded that the six issues described below and summarized in Box 2-1 must be considered as important safety issues when regulating infant formulas.
1. Infant formulas are the sole or predominant source of nutrition for many infants. Even for infants for whom formulas are a supplement to human milk, formulas can constitute a major source of nutrition. For infants, formulas represent a much larger percentage of the total nutritional intake than is any single substance for the older child, adolescent, or adult. Given the extremely high dependence on this one source of dietary input, safety rules based upon models deemed appropriate for persons with a wide range of dietary inputs may be inappropriate.
2. Formulas are fed during a sensitive period of development and may therefore have short- and long-term consequences for infant health. The first 12 to 18 months of life is a period of extremely rapid growth and development for the human infant that is only beginning to be understood. The brain and neural system change dramatically during this period, as do other organ, cognitive, and social-emotional systems. These changes are thought to have long-range implications for the human—not all of which are expressed directly during infancy. The current safety models for infant formulas only look at relatively short-term outcomes and are narrowly limited to the maintenance of physical growth.
3. Animals may not be the most appropriate model on which to base decisions of safety. In the case of infants, limitations of using experimental animals as models are due not only to species differences, as in the case of adults, but also to developmental differences in animals versus infants. The differences in growth rates and the resulting differences in biological effects of ingredients could therefore accentuate the concerns that already exist when using animal models. Given these differences, animal models may not uncover possible threats to the long-term well-being of infants due to the addition of new ingredients; this issue is of critical significance if the models used are developmentally inappropriate.
4. "One size fits all" food safety models may not work for all new additions to formu-
las. The basic models of food safety are based upon the assumption that nearly all individuals function basically in similar ways with regard to the safety of substances in their diet (although there are gross subtypes with different dietary needs, such as premature infants and infants with food allergies). However it may be speculated that there are more subtle underlying subgroups (e.g., genetic subtypes) for which new substances may or may not have the same safety characteristics as they would for individuals not in those subgroups. In clinical trials the minimum sample size required to detect systematic group differences in response to a new ingredient is likely to be entirely inadequate for subgroup analyses.
5. Infant formulas could be considered as more than just food. The rules governing the safety of infant formulas are regulated under the logic of infant formulas being a "food product," and there is no doubt that the primary purpose of infant formulas is nutrition. However infant formulas can also be seen as a potential delivery system for non-nutritional agents. This potential as a delivery system should cause one to consider the question of what are the appropriate (both legal and ethical) boundaries for additions to infant formulas. Consideration must be given to constructs that will appropriately set the limits and provide the definitions for an addition being "nutritional." The presence of the substance in human milk may not be a sufficient definition of a nutritional substance, and other factors, such as whether the substance is produced from genetically modified sources, need to be considered. In addition, the regulatory steps to follow to ensure the safety of a substance whose purpose is non-nutritional (e.g., a substance whose purpose is to reduce infant discomfort) need to be determined.
6. Potential benefits, along with safety, should be considered when adding a new ingredient to formulas. Food products are generally considered to be inherently beneficial or efficacious (with inherent sensory properties and nutrition) and thus efficacy (i.e., health benefits) has not been a consideration in the safety assessment of foods. In the case of infant formulas, this starting assumption may be modified through the additional requirement in proposed regulations (FDA, 1996) that the product be capable of sustaining physical growth for a specified period of time, that is, it is already required that the final formulated product be demonstrated to be efficacious from the point of view of physical development. (This proposed requirement, however, is usually stated as a safety criterion rather than as an efficacy criterion, that is, a lack of efficacy would be a risk to the organism and therefore a safety concern.)
Other than this proposed requirement for sustaining physical growth, however, the manufacturer would not need to demonstrate the benefits of any proposed new ingredient to infant formulas. Given the special circumstances of the use of infant formulas and the fact that is it virtually impossible to understand the long-term outcomes of adding any given ingredient (the clinical trials are, of necessity, of relatively short duration), prudence would seem to dictate that an ingredient not be added to an infant formula unless it can be shown that some benefit is accrued to the infant through its addition. Since the committee was not charged with addressing efficacy, it recommends that consideration be given to convening a group of experts to explore if benefit could be an appropriate requirement for adding a new ingredient to infant formulas.
Infancy is a uniquely vulnerable period that complicates the interpretation of safety guidelines. Manufacturers may propose the addition of a new ingredient to infant formulas by demonstrating the safety of the proposed ingredient. They are not required to demonstrate the benefit of an individual ingredient in the product. Although the committee believes
that, in the case of infant formulas, efficacy is an important consideration, the committee did not discuss this issue because it was beyond its charge.
The six safety considerations discussed in this chapter are important when developing safety guidelines for adding ingredients new to infant formulas. In making recommendations in the chapters that follow, the committee considers these six special issues that set infant nutrition apart from that of toddlers, children, and adults.
Canada. 2001. Departmental Consolidation of the Food and Drugs Act and the Food and Drug Regulations. Ottawa: Minister of Public Works and Government Services Canada.
Cliff N. 1993. Dominance statistics: Ordinal analyses to answer ordinal questions. Psychol Bull 114:494–509.
FDA (Food and Drug Administration). 1996. Current good manufacturing practice, quality control procedures, quality factors, notification requirements, and records and reports, for the production of infant formula. Proposed rule. Fed Regist 61:36153–36219.
Gunnar MR. 2000. Early adversity and the development of stress reactivity and regulation. In: Nelson CA, ed. The Effects of Early Adversity on Neurobehavioral Development. The Minnesota Symposia on Child Psychology. Vol. 31. Mahwah, NJ: Lawrence Erlbaum Associates. Pp. 163–200.
Health Canada. 1994. Guidelines for the Safety Assessment of Novel Foods. Ottawa: Food Directorate, Health Protection Branch, Health Canada.
IOM (Institute of Medicine). 1998. Dietary Reference Intakes: A Risk Assessment Model for Establishing Upper Intake Levels for Nutrients. Washington, DC: National Academy Press.
IOM. 2004. Dietary Reference Intakes for Water, Potassium, Sodium, Chloride, and Sulfate. Washington, DC: The National Academies Press.
Johnson MH. 2001. Functional brain development in humans. Nat Rev Neurosci 2:475–483.
Lozoff B, Klein NK, Nelson EC, McClish DK, Manuel M, Chacon ME. 1998. Behavior of infants with iron-deficiency anemia. Child Dev 69:24–36.
Nelson CA. 1995. The ontogeny of human memory: A cognitive neuroscience perspective. Dev Psychol 31:723–738.
OFAS (Office of Food Additive Safety). 2001. Toxicological Principles for the Safety Assessment of Direct Food Additives and Color Additives Used in Food. Redbook II-Draft. Washington, DC: OFAS, Center for Food Safety and Applied Nutrition, Food and Drug Administration.
OFAS. 2003. Redbook 2000. Toxicological Principles for the Safety of Food Ingredients. Online. Center for Food Safety and Applied Nutrition, Food and Drug Administration. Available at http://www.cfsan.fda.gov/~redbook/red-toca.html. Accessed November 19, 2003.
Rao R, Georgieff MK. 2000. Early nutrition and brain development. In: Nelson C, ed. The Minnesota Symposia on Child Psychology. The Effects of Adversity on Neurobehavioral Development. Vol. 31. Mahway, NJ: Lawrence Erlbaum Associates. Pp. 1–30.
Ruff HA, Rothbart MK. 1996. Attention in Early Development. Themes and Variations. New York: Oxford University Press.
Seaman MA, Serlin RC. 1998. Equivalence confidence intervals for two-group comparisons of means. Psychol Methods 3:403–411.
Wachs TD. 2000. Necessary but Not Sufficient. The Respective Roles of Single and Multiple Influences on Individual Development. Washington, DC: American Psychological Association.
Wauben IP, Wainwright PE. 1999. The influence of neonatal nutrition on behavioral development: A critical appraisal. Nutr Rev 57:35–44.


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Francois Azambourg is the modern embodiment of the quintessential renaissance man, Leonardo daVinci: part scientist, part inventor and full-fledged artist,designer, and visionary. His designs are birthed from his deep commitment to the lightness and economy of materials, re-imagining the construction of everyday objects and creating sophisticated forms that reference the many interesting, and complex organic structures found in nature. Azambourg's … Read More
Swarovski Crystal Palace Carbon Crystal Sails at Design Miami 2009
Magnificent Swarovski Crystal Palace Carbon Crystal Sails designed by Greg Lynn. The Carbon Crystal Sails installation was located at the entrance to the Design Miami VIP lounge. Elegantly sparkling and billowing sails spanning more than 80 square meters, reaching heights of over 7 square meters, and encrusted with more than 1,500,000 Swarovski crystals, made the Swarovski Crystal Palace installation the … Read More
Maarten Baas Designer of the Year Design Miami 2009
Maarten Baas commission piece (exterior view) for Design Miami 2009. Interior view of Maarten Baas designed wardrobe commissioned for Design Miami 2009. Baas furniture collections from left to right: Clay chair, The Chankley Bore, Plastic Chair in Wood, Sculpt Dining Chair, and Hey, Chair be a Bookshelf. The "Hey, Chair be a Bookshelf" is a composition of various furniture pieces … Read More
Christian Louboutin at Design Miami 2009
A quick look at the recently opened Christian Louboutin boutique in the Miami Design District. More photos to come. Christian Louboutin will be on the Design Miami 2009 "Design Talk" panel (with Mattia Bonetti and Jacques Grange) on Thursday, December 3rd (5:30PM to 6:30 PM EST) . 00000

subset: commoncrawl


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Macquarie's Cavey Says China Constrained in Increasing Rates
Dec. 10 (Bloomberg) -- Paul Cavey, China economist at Maquarie Securities Ltd. in Hong Kong, comments on the People's Bank of China's decision to raise banks' required deposit reserve ratio today. The central bank said it will raise the ratio by 50 basis points effective Dec. 20.
On whether the central bank is less likely to raise interest rates this month:
"It does make it less likely, but it doesn't make it impossible. The government knows quantitative measures like the reserve ratio work immediately and consequently are controllable and understandable. Raising interest rates creates much more uncertainty.
"Today's move clearly shows that the government is more constrained in raising interest rates. The message seems to be that they don't want to raise rates."
On why the PBOC raised the reserve ratio rather than interest rates:
"Raising interest rates is difficult while raising the reserve ratio isn't. The government is more reluctant to raise interest rates because it could encourage hot money inflows and because of the indebtedness of local governments.
"In the short term, the government has complete flexibility in raising the reserve ratio because it doesn't affect the rest of the world whereas raising interest rates has far more implications.
"The reserve ratio and interest rates are tackling two different problems. If the government thinks the biggest problem is credit growth it uses the reserve ratio because that will constrain bank lending and they don't need to raise interest rates to change bank lending.
"If the biggest problem is asset market prices, then they will use interest rates. The way to affect the flow of deposits in and out of the banks is through interest rates.
"The stock market is down, the property market is not so hot and the release of bank deposit data from the central bank today suggests there was a pickup in deposit growth in November. If we had seen a massive outflow of deposits they would probably have raised rates."
To contact Bloomberg news staff for this story: Nerys Avery in Beijing at firstname.lastname@example.com
To contact the editor responsible for this story: Chris Anstey at email@example.com


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- Filed Under
Royce and Fay Brown of Asheville, NC celebrated thier 50th Wedding Anniversary on November 17th. Family and friends celebrated with the Browns at a reception held at Oakely Baptist Church on Nov. 10th.
Royce and Fay were married on Nov. 17th, 1962 at the home of Rev. Bryce Parker in Asheville.
They have two children, Rhonda (Brown) Willis, husband Frank, of Dallas, GA, and Robert Brown, wife Brenda, of Candler, NC. They have three grandchildren, Jordan and Julia Willis, and Isaiah Brown.
The couple met at the Grove Park Inn in Asheville on Feb. 11, 1962 while both were employed with Southern Bell Telephone Co. Royce retired in 1997 with 42 years service.


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Tag Archive
Top 10 Hawks Facebook Posts of the 2013-14 Season
We had a lot of fun with you all on social media this season. So much fun, in fact, that we've decided to share our 10 most engaging Facebook, Twitter and Instagram posts! Keep in mind these were selected by you based on what you react to, liked, shared, etc. #10 – Fans wish... »
East Out To Reclaim Dominance
The East has the past five NBA MVP award winners and the past two NBA Champions, but the West has been the more dominant conference in 2013-14. While the All-Star Game (8 ET, TNT) is largely just a show and hardly indicative of which conference is actually more talented, the East still feels they have... »
Hawks Well-Represented At All-Star Weekend
The Atlanta Hawks will be well represented at the 2014 All-Star Weekend in New Orleans. Paul Millsap was selected to his first All-Star Game, voted by coaches around the league as one of seven Eastern Conference reserves. Joining Millsap at All-Star weekend will be rookie Pero Antic, who catapulted up the rookie ladder after... »
Mike Scott Goes Bonkers After Millsap Makes All-Star Team
Paul Millsap was named to the Eastern Conference All-Star roster Thursday night, as selected by coaches from around the league. It's Millsap's first All-Star appearance, and the first-year Hawk got plenty of love from his teammates on Twitter: Congratulations to @Paulmillsap4 on being named to his 1st All-Star Team!! He has been incredible for... »
Paul Millsap Named Eastern Conference All-Star
Paul Millsap has been named an All-Star for the first time in his career, coinciding with his first season as a member of the Atlanta Hawks. Millsap was selected by coaches around the league as one of seven Eastern Conference reserves, and I think it's highly justified. He's been a force since Al Horford's... »


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SportsNation Blog Archives Denver Broncos
Von Miller says Broncos players fine each other for flatulence ... and he's the most frequent offender
The NFL and its teams are known to be rather strict.
But if Von Miller's claims are true, the players themselves can be downright draconian. Nicki Jhabvala of The Denver Post describes a fine system devised by the players:
Von Miller said the Broncos have a fine system for, um, flatulence in meetings. Said he thinks he's been fined the most.— Nicki Jhabvala (@NickiJhabvala) June 3, 2015
Wait, what? Look, it's not great to let it go in confined spaces, but isn't the shame of committing a social faux pas enough?
Miller elaborated:
Since I've received numerous inquires about the Broncos' Fart Tax, I'm gonna let Von explain. NFL dieting ain't easy. pic.twitter.com/OTAAaI8t82— Nicki Jhabvala (@NickiJhabvala) June 3, 2015
Miller is right! Although a cursory search turns up no scientific studies on such a thing, physicians from the University of Copenhagen, via the New Zealand Medical Journal, said the following in 2013, according to the University of California, Berkeley's Wellness website:
"Holding in gas can cause bloating, indigestion, heartburn and, sometimes, even pain, they noted. Intestinal distension resulting from trapped gas may also increase blood pressure and heart rate. Then there's the mental stress of trying to keep the gas from escaping. The doctors' advice: Just let it go."
You see that, Broncos players? Your policies are endangering your own health! Add to this the possibility of wrongful accusations, and it's a wonder this team hasn't fallen apart.
H/T Bleacher Report
DeMarcus Ware might have stiffed a waiter because the waiter cheered for Washington (Update -- it was all a joke!)
The service industry is difficult. Waiters and waitresses rely on tips, especially in states where tipped employees are paid less than minimum wage, and the pressure to please customers is great.
But according to Denver Broncos defensive end DeMarcus Ware, who used to play for the Dallas Cowboys, there is one thing you simply do not do when serving members of certain NFL teams:
1) Pre-judge
2) Assume
3) Assume u gonna get a tip after you say "Go Skins" pic.twitter.com/mmbHQisdws— D-Ware (@DeMarcusWare) April 5, 2015
Now, this of course might be fake, as much on the Internet tends to be (it is still kind of April Fools' week, after all).
Then again, Ware was in D.C. this weekend to participate in the annual White House Easter Egg Roll, so ... maybe?
In which case, ouch. At the 20 percent rate, that cheer cost the waiter almost $18.50.
Update: It was a joke!
To everyone concerned about my last tweet - I was having fun with a fan. I did in fact tip ...I have a sense of humor and so did he.— D-Ware (@DeMarcusWare) April 6, 2015
Conclusion: Good to know the waiter got his money, and that there's still love among fans and players of rival teams.
Still, pretty sneaky there, Ware ...
H/T SB Nation
Vote: Peyton Manning greatest QB ever?
Peyton Manning the greatest ever?
Peyton Manning added another record to his resume Sunday, passing Brett Favre for most touchdown passes of all time. Manning ended the night with 510, two more than Favre's 508. Is Manning the greatest QB ever? Will he ever win a second Super Bowl?
What to make of last 3 NFL unbeatens?
Three unbeatens left in NFL
We're three whole weeks into the 2014 NFL season, and only three teams haven't lost. The final unbeatens: Cincinnati Bengals, Arizona Cardinals and Philadelphia Eagles, all winning teams from 2013, but none exactly thought to be sure-fire contenders before the season. On the other end, a host of playoff teams from last season are just 1-2. What do you make of it all?
Vote: Your 2014 NFL predictions?August 31, 2014Aug31Getty Images
Your 2014 NFL predictions?
The 2014 NFL season kicks off Thursday night, with the Super Bowl-winning Seattle Seahawks hosting the Green Bay Packers in the first of what should be many intriguing games in this wide-open league. What will happen this year? Read our experts' NFL preview, then cast your votes below!
More: Predict: Over/unders | Your Power Rankings? | Rank: #NFLRank top 20


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JavaFX binding is neat, but ... beware
An interesting chains of discussions has been triggered about JavaFX features and how it can be possibly used beyond the GUI scope.
Osvaldo has just published an interesting post. Actually I like binding a lot, but I was wondering about some adverse effects that can arise out of binding use.
There is a basic conceptual problem: binding is an evolution of getters/setters, that is exposure of naked properties. According to OO principles it is a breakage of information hiding, that should implemented by encapsulation, but we got used of it because of fourteen years of Java, as most of the Java frameworks use it (not only Swing, but also JPA etc...). So we can live with it - but I'd say I'm fine with it for some mundane uses such as populating a UI or a persistence bean; it would be probably better if we learned to avoid it for core business classes.
Anyway, this is just a general premise; now let's consider a specific example. Consider the following JavaFX class:
It's fine, right? You can even unit test it without problems, so you declare it stable. Now, you use Breakable in this context:
class Breakable
public var theProperty = 0;
public function breakIt(): Void
theProperty = 4;
var breaker = 1;
def breakable = Breakable
theProperty: bind breaker;
public function run(): Void
Run it, and you get a
com.sun.javafx.runtime.AssignToBoundException: Cannot assign to bound variable
You can't execute theProperty = 4, since theProperty is bound and, by definition, at every moment can only hold the same value as breaker.
Do you see my point? An external class has broken Breakable, that was fine by itself. We have injected a problem. This is a worse breakage than breaking information hiding in Java by getters/setters, as not only we can change the internal status of Breakable (forgivable as explained in the premise), but we changed also the behaviour of theProperty, that now can't be assigned any longer; it is now incompatible with the original behaviour of Breakable.
I'd be worried about using this in a core business class. OO exists to make our software more robust, but binding in this perspective can make it more brittle.
I propose to address this issue by introducing an unbindable keyword such as:
class Breakable
public unbindable var theProperty = 0;
public function breakIt(): Void
theProperty = 4;
This would make the compiler stop with an error when you try to bind theProperty (the problem is unidirectional binding; bidirectional binding is ok). You might think that the enhancement of the compiler could be done without a specific modifier, as the compiler could induce the unbindable status of theProperty by just finding the assignment theProperty = 4; but this is just a simple example, and theProperty could be a protected variable manipulated by a subclass.
This small example can be checked out as a NetBeans project from:
svn co -r 45 https://kenai.com/svn/javafxstuff~svn/trunk/Binding1
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by mikeazzi - 2009-06-12 13:17Also, I would imagine there would be some kind of restrictions on what kind of code is allowed in a validate block so as not to circumvent the constraints.
by mikeazzi - 2009-06-12 13:09With regard to validating, vetoing changes, this also has been discussed on the JFX mailing, and the consensus back then was leaning toward adding true "full-blown properties" support to the language, which would support such functionality (i.e. validation phase first, followed by mutation phase). As to when, I don't know. Anyway below is a snippet of that discussion that I could track down: Brian Goetz wrote: > I agree that attribute validation is an important element of creating robust components. > > Having triggers throw exceptions / silently reject modifications is not going to work, though, because it could leave the application in an inconsistent state. > > There are two approaches we've discussed for attribute validation: first-class properties, and declarative constraints. But both suffer from the problem that modifications can come at the end of a chain of bindings or trigger updates, and simply rejecting them would leave things in an inconsistent state. To really make this work, transactions are needed -- there needs to be a way to reject (and roll back) the entire chain of modifications that caused the update. I agree having some way of defining at least simple constraints is nice. However, I think you need to have either full-blown properties, or at least something comparable. For example, in this case I want to clip the values < 0 to 0, and > 1 to 1. It is more than a constraint; it is logic that I want executed prior to attribute mutation, and have it possibly change the value finally set on the attribute. Transactions are an interesting idea. I think what you don't want is to update values twice. So if variables a, b, and c are updated whenever x changes, you don't want to update a and b, find out with c that there is an error, and then reset a and b to their prior values. The problem being that there could be side-effects in triggers based on mutating the state. This would suggest that the validation phase should be separate from the mutation phase, and prior to it. So you would validate with each binding target that the new value would pass any and all constraints/validation, and then set all the values. Richard
by cloj - 2009-06-12 12:22@opinali: I'm mostly happy that I will be able to run 6 on my 32-bit Intel machine, which I couldn't do in Leopard.
by opinali - 2009-06-12 11:20@cloj, @fabriziogiudici: The 32/64 choice seems good, but is this really necessary in a post-JDK 6u14 world? As soon as Apple catches up to that release (or better), they could use the Compressed References optimization, which delivers similar performance (both speed and memory usage) to a 32-bit VM, but without the disadvantages of not running in the same process model that is preferred on a 64-bit OS.
by opinali - 2009-06-12 11:12@felipegaucho: I agree that 99% of all JS code out there stinks... but this phenomenon has several causes, including coders that don't really get JS (which draws more from Scheme than from C-family langs), and its long role as a language for tiny web 1.0 scripts (simple event handlers or validators etc.) so people got used to hack code in text or HTML editors without worrying about good programming practices or even asking for proper tools. So, I don't see the connection to JavaFX, other than the very superficial "both were created for GUIs but will expand to other tasks". Any language or tool can be abused. I remember when JSP 1.0 was in beta and I adopted it for a big web project... this resulted in a monstrous codebase with some JSPs having thousands of lines due to scriptlets; that was the "recommended" way of doing JSP before we had taglibs and other improvements. (Thanks god that application is not in production anymore, I'd rather change my name and disappear than maintain it.) In this case, it's the Java language that was abused as a web scripting language.
by fabriziogiudici - 2009-06-12 10:20A bit of a surprise. Thanks for pointing out, I'll eventually blog about it.
by cloj - 2009-06-12 10:00Hey Fabrizio, you may be interested in http://www.flickr.com/photos/michaelflux/3614619669/ (snow leopard has 32-bit java 6).
by opinali - 2009-06-12 06:27@fabriziogiudici: It's easy to produce a StackOverflow with indirect recurson, like this: var i = 0 on replace old { i = 5; } var j = bind f(i); function f(x) { ++i; } Now this is pretty stupid code, but we both may have written code that did something similar... the JavaFX runtime will not check if a activation of the var's trigger is already active, to avoid recursion of the trigger (that would be a possible, but expensive check, requiring either a stack walk or some per-trigger "running" flag... better not doing that, triggers and binding are already expensive enough).
by opinali - 2009-06-12 06:20@felipegaucho: Any successful language will inevitably expand its reach to domains it was never intended for. Just look this: http://ask.slashdot.org/story/09/06/11/1228209/Should-Undergraduates-Be-... (people promoting Python as a replacement for Fortran, for scientific stuff... although Python is up to 300X slower than Fortran: http://shootout.alioth.debian.org/u32q/benchmark.php?test=all&lang=pytho...) Let's just assume that JavaFX becomes a very successful RIA platform, OK? This means thousands of trained developers, libraries, tools, books, etc. And JavaFX Script is not 300X slower than Java; in fact it is very often just as fast. Why not enjoying a more productive, expressive language for your non-GUI code, if you already know and like that language? And I didn't understand your comparison with JavaScript... could you be more specific, or that was just part of the trolling? ;-)
by fabriziogiudici - 2009-06-12 06:17So... what the f**k were those stack overflows that I saw too? :-/
by opinali - 2009-06-12 06:01@diverson: That's odd, I was pretty sure that a self-assignment inside the trigger (at least w/o a conditional guard) would result in recursive call of the trigger. That's because I actually experienced a stack overflow involving that. But this was some time ago and probably involving other factors, like binding. I tested again on JavaFX 1.0, 1.1.1 and 1.2 and they all behaved well without recursive calls. This is good news. OTOH, the interaction with binding, causing listener expressions to see the invalid results before rollback, is important like Fabrizio points. In theory I can avoid any trouble by having only purely functional code (side-effect free) in bound expressions; but that's a workaround (at best a good practice), not a full solution for the problem.
by felipegaucho - 2009-06-12 03:42as presentation layer, JavaFX has a chance.. .small but has one.. as mixed up solution business+presentation+persistence all-crap-old-javascript-style, I prefer to quit JavaFX for this life :) eheh serious, JavaFX is already so questionable technology and so hard to sell out there, if we start to repeat the errors from javascript we are just eating the elefant again :( we don't need that :) IMHO
by fabriziogiudici - 2009-06-11 23:35"But note that any bound variable will see the invalid change as well as the roll back." Which is not the same as vetoing a change: you have the invalid value go everywhere, potentially causing harms. For what concerns sequences, the compiler can do the perfect optimization, but the point doesn't change, you can't change semantics. You can mix Java code and use whatever you like, but you're forced to completely change the way you manipulate the object (i.e. square brackets vs get(i)) and your client code gets affected by the change. No, I tried a few times to improve the formatting of code samples in comments, but I don't think it's possible and I gave up. Thanks for pointing to that discussion on the mailing list. Indeed, Richard's comment: "Yes, this is a big problem from my perspective as I have to basically wrap all "sets" to public variables in try/catch blocks because the user may have bound one of them." is very good, as it demonstrates that in order to design robust code you have to pollute it with a lot of try / catch, jeopardizing the compactness of the language. BTW, I don't see the isBound() as a good solution: you have to replace try / catch with if, but the code pollution is still here. Furthermore, I'm again with a conceptual point: if you're assigning that variable in your code, that's incompatible with unidirectional binding, that's a design thing, you've not designed it with binding in mind. I'd really like I could declare it to the compiler, so I can enforce the prohibition of binding.
by mikeazzi - 2009-06-11 20:22Interestingly enough, this particular issue has been discussed on the JFX-Compiler mailing list a while back. Below is a snippet of that discussion. I wonder what the final resolution were. I also wonder whether the compiler can be made smart to detect such conflicts (i.e by detecting assignments) at compile time and flag an error, rather than getting a runtime exception. Which in my view would the better option since it spares us all these runtime checks. --- On Wed, 3/4/09, Brian Goetz wrote: More precisely, what you want is isAssignable(). On Mar 4, 2009, at 6:59 AM, Richard Bair wrote: > I think in this case what I want is a isBound function so I can check whether a var is bound before I try to set it. > > > > On Mar 3, 2009, at 4:15 PM, Robert Field wrote: > >> OK, my question is, after initialization, do you ever want the user to be able to set this? >> >> If not, the 'public-init' is the access modifier that you want. 'public-init' does not allow bind. >> >> We certainly discussed general access modifiers that prohibited bind, but we reasoned that if this is a variable which is controlled by the class (set at its whim) then it is probably not going to be one that the class wants randomly externally set. >> >> Even if you do want it externally set, this could still be done with 'public-init' and a setter method, though admittedly this isn't the most elegant solution. >> >> -Robert >> >> >> Richard Bair wrote: >>> Yes, this is a big problem from my perspective as I have to basically wrap all "sets" to public variables in try/catch blocks because the user may have bound one of them. >>> >>> On Mar 2, 2009, at 2:17 PM, Michael Heinrichs wrote: >>> >>>> Hmmm, it looks like my original intent got lost in this discussion. The attributes stage.width and stage.height were meant as examples to demonstrate this is a real life issue. >>>> >>>> The question is, how can a user determine, if a public variable can be bound. The documentation does not provide enough information right now. So the only way at present seems to be to try it and see if one gets a runtime exception. >>>> >>>> This gets even worse, if we have a public variable, which is only rarely changed by the runtime. If a user binds this variable it would usually work, but throw an exception in these rare cases. >>>> >>>> Michael
by diverson - 2009-06-11 16:41opinali: Maybe I'm misunderstanding your problem, but you can assign an old value back to a variable in a replace trigger without causing a stack overflow. class A { var aVar = 0 on replace oldValue { println( "aVar being set to {aVar}" ); if (aVar < 0) { aVar = oldValue; } } } var aRef = A { aVar: -1 } def boundAVar = bind aRef.aVar on replace { println( "boundAVar being set to {boundAVar}" ); } aRef.aVar = 3; aRef.aVar = -2; println( "aVar is {aRef.aVar}" ); Results in the following output: aVar being set to -1 aVar being set to 0 boundAVar being set to 0 boundAVar being set to 3 aVar being set to 3 boundAVar being set to -2 aVar being set to -2 boundAVar being set to 3 aVar being set to 3 aVar is 3 It doesn't allow you to approve the change before it's made, but you can roll it back. But note that any bound variable will see the invalid change as well as the roll back. p.s. Anyone know how to preserve code indenting in these comments?
by opinali - 2009-06-11 16:29Overriding [] would be cool, but the sequence type is parte of the language, it's not APIs. This is a common tradeoff of most (all?) languages that have built-in high level types, since LISP with its lists, is that you don't muck with such types... comapring JavaFX Script's sequences with Java's similiar List Collections, you cannot pick a specific implementation (e.g. array or linked), or specify creation-time tuning like initial size, you can't define your own variant etc. But it's a tradeoff, as javafxc does a very respectable amount of automatic optimizations and that's only going to improve.
by fabriziogiudici - 2009-06-11 15:48Yes, this is another problem, as you can't enforce the feasible values for a variable. More generically (subject for another post), a lot of things in JavaFX occur behind the scenes, and there's not a method that can be made polymorphic. For instance, the square bracket operator of sequences is neat for a compact syntax, but you can't override it, thus you can't have lazy-loaded sequences etc...
by opinali - 2009-06-11 15:34Agree with mikeazzi... except that JavaFX Script's triggers don't allow me to validate and veto changes. I would want to write something like that: var age on replace { if (age < 0) // ... some code that blocks the requested assignment } Right now, triggers are invoked after the assignment was already performed. and you can't assign the old value back because this results in a StackOverflow as the trigger is invoked recursively. You can throw some exception, invalidate the object..., but that's not as good as blocking invalid assignments. I guess I'll look at the JIRA and make a RFE for this if there's none yet. One idea for concrete syntax: var age on before replace newAge { if (newAge >= 0) age = newAge; } I'm reusing the before keyword, and changing semantics: (a) the assignment made by triggering code doesn't assign a new value, only invokes the trigger; (b) the newValue parameter is mandatory (similar to the optional parameter for old values in normal triggers); (c) assigning a value to the var inside that trigger will be a raw assignment, without invoking the trigger again.
by fabriziogiudici - 2009-06-11 15:28Information hiding has only to do with private, and possibly protected. Anything that is public breaks information hiding (including public-read). Anyway, this is just a picky observation ;-) the point is that none of the existing JavaFX access modifiers help me: in this example, I want theProperty to be publicly readable *and* writable; it's just that breakIt() can write on its own, too (think of theProperty as a counter that you can read and write, and breakIt() is a reset() method). Note that I wouldn't have this problem in Java: I'd only need to take care, in the setter method, if some special processing must be done whenever theProperty changes value. The difference is that JavaFX binding enforces the binding behaviour, while BeansBinding in Java doesn't (you can assign a "bound" property, thus breaking the binding). I'd say that it's the right decision for JavaFX, because of its functional nature; but it introduces the new problem I'm talking of. Of course, one could argue that this is bad design, and I might agree - but, at this point, I say that using "public" is the root of the problem, and JavaFX binding favours a lot the use of public variables, much more than Java.
by mikeazzi - 2009-06-11 15:11Yeah, but I am sure you are aware of JavaFX access modifiers: public, public-read, etc. These modifiers are JavaFX's version of information hiding. So I don't think JavafX is breaking this OO principle per se if proper use of these modifiers is being applied. So in your particular case if internal functions perform writes on a certain variable then it should be made public-read for instance. Unless I am missing something.
by zebraitis - 2009-06-13 14:35It wulld be great to have a replace trigger "before replace" and a "cancel replace;" when some codel (ex.validation of the new value) fails or just to attach a block of code thet return a boolean result indicating to continue the "replace"
by opinali - 2009-06-13 08:15@mikeazzi: The whole problem is indeed difficult, but "the perfect is enemy of the good". If I can just veto changes to a single object without any side effects (no listeners notified of the change before it's vetoed), at least I don't let any object enter a corrupt internal state... I can still have a bad state in a graph of dependent objects because object A was changed and dependent object B was not changed as expected by the A-B binding (that we can see as a kind of contract); but this is certainly a less severe case of corruption, and in really important cases (e.g. if A and B are part of some security-sensitive API) there are always workarounds like A invoking a validation method of B before A accepts the change. The separate validate block would be a good idea, solving the problem above, I agree that the system must trust the programmer to have only side effect free code in the validation blocks but that would be a perfectly fine compromise... lint tools could enforce this if javafxc wouldn't (as detection of functional purness would be a bigger RFE to javafxc at this time - but a good idea in the long run; JavaFX Script has very good potential to evolve its functional side, but that's another debate).


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- Friday 11th Sep: Paul Sinha announced a new Bedford date
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We saw Paul at our local comedy night in Tewkesbury last week and he left us crying with laughter! Not only is this man one of the funniest stand ups we've ever seen, but his fantastic talent for weaving stories around his act turns his performance into a conversation and… (cont'd) Little Lil from Northway
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DeFeet Cyclismo Wool Socks - Performance ExclusiveIn the fastest stage ridden in the history of the Giro d'Italia, the DeFeet Cyclismo Wool Socks crossed the finish line first. Now, they're available to you and provide comfort in a wide range of temperatures. American Merino Wool manages moisture, absorbs odors and dries fast. Thermo-Cool Duoregulation keeps the inner climate constant, so you'll never overheat. Meta-pad soaks up the rough stuff and arch support reduces foot fatigue. AeroSpeed cuff stays put and offers protection from the elements. Exclusively available at Performance Bicycle.
- American Wool Merino fabric is the highest grade USA wool and it's been cleaned, dyed and knit in the USA
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DeFeet Cyclismo Wool Socks - Performance Exclusive
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- height:
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- rating:
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Catterick Betting Odds
Catterick Bridge in North Yorkshire has hosted horse racing since 1783. Today it features at least one meeting every month of the year, with flat in the summer and National Hunt in the winter.


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ARLINGTON, Va.The Office of Naval Research (ONR) Global is reaching out to global maritime security and defense community members at MAST Europe 2011, June 27-29, in Marseille, France, assessing the world's best science and technology inventions and showcasing the organization's efforts.
Maritime Systems and Technology, or MAST, gathers senior leaders from more than 40 countries to discuss future capabilities and concepts and evaluate state-of-the-art innovations related to maritime security, systems and technology. By attending, ONR Global will be able to build relationships with foreign naval and defense industry personnel that can help anticipate changes in global military forces and avoid technological surprise.
"ONR Global is the interface between science and technology and future naval forces. Having a presence at MAST is especially important because it provides ONR Global with the valuable international exchange of ideas in science and technology that can help us to successfully deliver new and innovative capabilities to the U.S. Navy and Marine Corps," said Cmdr. Mark Williams, ONR Global's regional director and London Office officer-in-charge.
With offices in Washington, London, Prague, Tokyo, Singapore and Santiago, Chile, ONR Global pursues international partnerships with organizations conducting basic and early applied research. The objective is to drive the execution of long-term strategic efforts that address future naval fleet and force needs.
Featuring more than 35 defense-industry exhibits, MAST includes focused discussions on surface, undersea, air and space-related issues and centers on the conference theme of "Global cooperation towards future maritime security." The event will also include keynote addresses, panel debates and plenary and breakout sessions centered on the topics of maritime security, operations and capabilities, platforms, systems and technologies.
"ONR Global understands the pow
|Contact: Peter Vietti
Office of Naval Research


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The demise of the United States as the global superpower could come far more quickly than anyone imagines. Perhaps even decades before this article predicts...
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horse.com > Clearance > Apparel & Footwear > Item # E002943
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Credits & Info
- Uploaded
- Apr 19, 2010 | 1:14 PM EDT
- Daily 3rd Place April 20, 2010
If you liked this, check these out!
Author Comments
Rated 3 / 5 stars
Nice Music, didn't like the stylistic choices
The music was awesome, like seriously, but the design choices were a little, well, they left a lot to be desired. I mean i understand why you did it, but i still didn't enjoy it, sorry.
Rated 4 / 5 stars
good looking but
Booooooring. Such great art and music for scenes that took too many seconds. It would be 10+ if you did the same thing, twice, and played it 2X speed. Heavy metal won't forgive slow animation. So why am I scoring 8? cause u're good at this, you just need to spend more time in your projects.
Rated 3 / 5 stars
I understand how difficult and tedious frame by frame can get, but even so the action wasn't that interesting. There were a lot of shots where the frame would just tween for a bit and all I'm doing is waiting for a character to move. Especially in the beginning when the guy is just standing there. I'm assuming you were waiting for the song to reach a certain part, but still. I gave you a 7 because the style looked cool, but just wish it could have been used more. Good luck with future submissions!
Rated 4 / 5 stars
I think I may know what IS missing... During the entire thing, I felt like he had no emotions. Yes in the beginning, but when he was done killing, then fall down to his knees in realization that all he did won't resurrect his brother or something? Because that is kinda what I was hoping for...
Rated 3.5 / 5 stars
Not bad.
I have to agree with some of the others, that something is missing. I by no means underestimate the difficulty of frame by frame animation, but what you have here seems like its missing a few high quality shots. Almost all action is implied. This works as long as you make up for it with demonstrated action here and there (see any reasonably budgeted anime)
I also feel that several shots hold for far too long, such as the explosion. Long hold shots are very hard to get right (I don't think I've ever nailed it). Too short, and it feels strange, too long and its distracting and irritating.
In the future, I hope you spend a little more time on a few high content scenes, instead of several comic book style action shots with minimized movement. I applaud your music choice though, and your style is on point.


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Cycling On The Island Of Rhodes
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This is my first post on this site. I'm heading Rhodes early next month, taking my road bike as I'm training for a London to Paris ride in July and wondered if anyone has any experience of cycling on the Island? We're staying in Pefkos.
Thanks in advance


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BackgroundCreated in a covert labotatory by splicing DNA from the Green Army's strongest and most skilled soldiers, the "Omega Soldier" is the Tan army's worst high-tech threat. Army Men: Green Rogue incorporates a 3rd person shooter with a coin-op, shoot'em up style of gameplay that will raise the heartbeat of anyone who dares to accept the challenge.
- High-tech character with 24 extreme weapons.
- 16 diverse levels.
- Head-to-head battle with 5 outrageous bossers.
- Amazing 3D graphics.
- Battle from the ground or amphibious assault vehicles.
- 2 player cooperative gaming.
- Dual analog features - shoot and move in 360 degrees.
Official URLOfficial Site
Recent threads
- What is this game about? Feb 10
- Online Action Dec 29
- Cheat codes Jul 20
- Level 7 Jul 20
DooMgod played Army Men: Green Rogue
DooMgod owns Army Men: Green Rogue
Twin_MasterFrustrating and felt kind of pointless. ArmyMenGreenRogue PS2
Aug 18, 10 8:54pm
Mar 26, 01 5:28pm
Forget Sarge. Get ROGUE!
I don't have a lot of time to play games, and I work hard enough with my head during...
Mar 25, 01 8:00am
Guestadded 5 new screenshots
Nov 18, 00 6:08am
- Genre: Adventure (PS2)
- Theme(s): Military
- Perspective(s): Third Person
- Developer: 3DO
- Publisher: 3DO
Released North America Mar 20, 2001
Army Men Series
- Army Men: Gold
- Army Men: Sarge's Heroes 2
- Army Men: Air Attack 2
- Army Men: World War Land Sea Air
- Army Men World War
- Army Men: Air Attack


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COLLINS - Just one ceremonial piece was missing when the Fraternal Order of Leatherheads Society conducted its fire service rite in May 2006, at the funeral of Jim Tucker, a 15-year member of the Townsend Township Volunteer Fire Department.
It was the bell the last-call bell that is tolled at firefighters' funerals.
The local chapter, a group of 23 fire service members from departments both inside and outside the county, needed a bell and set out to get one.
It didn't take long.
Norwalk businessman Jim Ewell, a close friend of the Tucker family, spearheaded an immediate fund drive. What seemed like overnight, the $1,600 bell became a reality.
It was cast in Sweden and weighs 40 pounds.
The bell has the name "In Memory of Jim Tucker" in raised lettering on one side and the inscription "Honor Our Fallen" on the other. On the placard at the base are all the names of firefighters who have passed away since the chapter was formed.
"I feel honored that the bell carries the inscription of my husband," Celeste Tucker said. "Like all volunteer firefighters, Jim just wanted to be known as one of those who served."
Tucker died May 30, 2006. He was 58.
The bell was used the first time in Norwalk at the February funeral of former Norwalk resident Jeff Murray, a Sharon Township firefighter who died in the line of duty. The bell tolled three sets of five for Murray because of his line-of-duty-death.


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TARTA lets UT students ride free on route 3 bus
University of Toledo students can ride city buses for free on any route 3 TARTA bus through Dec. 21.
The Toledo Area Regional Transit Authority is offering the free fare to students who show their Rocket Card. Route 3 includes all three of Toledo's shopping malls, Westgate Village Shopping Center, the University of Toledo, Medical College of Ohio, and Point Place.
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Satguru Engineering WorksView mapNavi Mumbai, Maharashtra(Verified Supplier)
Call Us: +91-8042536020
Products & Services
Company Profile
Design considerations include safety reliability and feasibility. Products are cad cam designed. To supply quality core and web products at a competitive price that will give trouble free service to machinery builders and end users.
Fact Sheet
|Year of Establishment
|Nature of Business
|Number of Employees
Upto 10 People
Contact UsSatguru Engineering WorksManish RaneCall Us: +91-8042536020
View mapNo. 22/13, Sahayog Apartment, Al- 5, Airoli West Thane, Belapur Road
Navi Mumbai - 400701
Maharashtra, India
Navi Mumbai - 400701
Maharashtra, India
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