Unprecedented advances in human genome science are underway with potential to benefit public health. For example, it is estimated that within a decade, geneticists and epidemiologists will complete a catalog of the majority of genes associated with common chronic diseases. Such rapid advances create possibilities, if not the mandate, for translational research in how best to apply these and other anticipated discoveries for both individual and population health benefit. Driving these discoveries are rapid advances in infrastructure (e.g., the International HapMap Project to catalog human genetic variation; http://www.hapmap.org), analytical methods, and technology. This expansion in capabilities quickly has taken us from a genetics paradigm—where the influence of individual genes on health outcomes is paramount, to a genomics paradigm—where the complex influence of individual genes is considered in concert with each other and with environmental exposures on health outcomes. We discuss these and similar groundbreaking discoveries with an eye toward understanding their importance to child health and human development, and the role of behavioral science research conducted at the interface of pediatrics and genomic discovery.
In this issue of the Journal, Nimptsch et al. (Am J Epidemiol. 2013;178(2):172–183) report significant associations between female adolescents' poultry consumption in high school and subsequent reduced risk of colorectal adenomas in adulthood. Consumption of red meat or fish was not related to risk, but replacement with poultry reduced the risk of later adenomas. Most epidemiologic studies of adult diseases lack exposure data from the distant past. By focusing on a cancer precursor lesion and using a variety of methods to assess data quality, the investigators address concerns about the quality of distant recall. These findings add to the growing evidence that links childhood and adolescent lifestyle and environmental exposures with subsequent risk of cancers arising in adulthood. Highlights of the literature on this topic and methodological challenges are summarized. Future studies would benefit from incorporating measures of lifestyle, diet, environmental exposures, and other risk factors from early in life and from validation and other data quality checks of such measurements. Sources of historical data on children's and adolescents' exposures should be sought and evaluated in conjunction with subsequent exposures in relationship to adult-onset cancers.
adolescence; diet; distant past; life course; methods; recall
Scientific research has made major contributions to adolescent health by providing insights into factors that influence it and by defining ways to improve it. However, US adolescent sexual and reproductive health policies—particularly sexuality health education policies and programs—have not benefited from the full scope of scientific understanding. From 1998 to 2009, federal funding for sexuality education focused almost exclusively on ineffective and scientifically inaccurate abstinence-only-until-marriage (AOUM) programs. Since 2010, the largest source of federal funding for sexual health education has been the “tier 1” funding of the Office of Adolescent Health’s Teen Pregnancy Prevention Initiative. To be eligible for such funds, public and private entities must choose from a list of 35 programs that have been designated as “evidence-based” interventions (EBIs), determined based on their effectiveness at preventing teen pregnancies, reducing sexually transmitted infections, or reducing rates of sexual risk behaviors (i.e., sexual activity, contraceptive use, or number of partners). Although the transition from primarily AOUM to EBI is important progress, this definition of evidence is narrow and ignores factors known to play key roles in adolescent sexual and reproductive health. Important bodies of evidence are not treated as part of the essential evidence base, including research on lesbian, gay, bisexual, transgender, queer, and questioning (LGBTQ) youth; gender; and economic inequalities and health. These bodies of evidence underscore the need for sexual health education to approach adolescent sexuality holistically, to be inclusive of all youth, and to address and mitigate the impact of structural inequities. We provide recommendations to improve US sexual health education and to strengthen the translation of science into programs and policy.
From December 1966 through December 1984, there were 561 pancreas transplants reported to the American College of Surgeons/National Institutes of Health Organ Transplant Registry, including 60 from 1966 through June 1977, 206 from July 1977 through December 1982 and 295 from January 1983 through December 1984. One-year graft function-survival rates (insulin-independent) in each of the three periods were 3%, 20% and 40%, and the corresponding patient survival rates were 40%, 72% and 77%. Currently 140 patients have functioning grafts, 76 for more than one year. Of the transplants since July 1977, one-year graft survival rates according to technique are 41% for enteric drainage (N = 155), 30% for polymer injection (N = 260) and 29% for urinary drainage (N = 47). Pancreas graft survival rates at one year according to whether or not the recipients have had a kidney transplant were 35% for recipients of simultaneous grafts (N = 281), 28% in recipients of a pancreas after a kidney (N = 112) and 26% in recipients of a pancreas only who did not have uremia (N = 106); corresponding patient survival rates were 69%, 83% and 83%. Overall, one-year pancreas graft survival rates according to whether the patients did or did not have end-stage diabetic nephropathy were 33% versus 25% and the corresponding patient survival rates were 73% versus 84% (P < .01). Patient survival rates were significantly higher in those without than in those with end-stage diabetic nephropathy. An analysis of technically successful grafts according to principal immunosuppressant showed one-year function rates of 46% in 258 cyclosporine-treated recipients and 26% in 143 azathioprine-treated recipients.
Pancreas graft survival rates have progressively improved and the procedure has become safer with advances in surgical technique and immunosuppression. Pancreas transplantation is currently applicable to patients with diabetes mellitus whose complications are, or predictably will be, more serious than the possible side effects of long-term immunosuppression.
Two forms of the equation for expression of the rate constant for electron transfer through a Marcus-type treatment are discussed. In the first (exergonic) form, the Arrhenius exponential term was replaced by its classical Marcus term; in the second (endergonic) form, the forward rate constant was replaced by the reverse rate constant (the forward rate constant in the exergonic direction), which was expanded to an equivalent Marcus term and multiplied by the equilibrium constant. When the classical Marcus treatment was used, these two forms of the rate equation give identical curves relating the logarithm of the rate constant to the driving force. The Marcus term for the relation between activation free-energy, ΔG#, reorganization energy, λ, and driving force, ΔGo, derived from parabolas for the reactant and product states, was identical when starting from exergonic or endergonic parabolas. Moser and colleagues introduced a quantum mechanical correction factor to the Marcus term in order to fit experimental data. When the same correction factor was applied in the treatment for the endergonic direction by Page and colleagues, a different curve was obtained from that found than with the exergonic form. We show that the difference resulted from an algebraic error in development of the endergonic equation.
Marcus theory; Moser-Dutton treatment; endergonic reaction; rate constant
Theories of learning have historically taken, as their starting point, the assumption that learning processes have universal applicability. This position has been argued on grounds of parsimony, but has received two significant challenges: first, from the observation that some kinds of learning, such as spatial learning, seem to obey different rules from others, and second, that some kinds of learning take place in processing modules that are separate from each other. These challenges arose in the behavioural literature but have since received considerable support from neurobiological studies, particularly single neuron studies of spatial learning, confirming that there are indeed separable (albeit highly intercommunicating) processing modules in the brain which may not always interact (within or between themselves) according to classic associative principles. On the basis of these neurobiological data, reviewed here, it is argued that rather than assuming universality of associative rules, it is more parsimonious to assume sets of locally operating rules, each specialised for a particular domain. By this view, although almost all learning is associative in one way or another, the behavioural-level characterization of the rules governing learning may vary depending on which neural modules are involved in a given behavior. Neurobiological studies, in tandem with behavioural studies, can help reveal the nature of these modules and the local rules by which they interact.
associative learning; spatial learning; geometric module; place cells; grid cells
This article reviews our understanding of reading disorders in children and relates it to current proposals for their classification in DSM-5. There are two different, commonly occurring, forms of reading disorder in children which arise from different underlying language difficulties. Dyslexia (as defined in DSM-5), or decoding difficulty, refers to children who have difficulty in mastering the relationships between the spelling patterns of words and their pronunciations. These children typically read aloud inaccurately and slowly, and experience additional problems with spelling. Dyslexia appears to arise principally from a weakness in phonological (speech sound) skills, and there is good evidence that it can be ameliorated by systematic phonic teaching combined with phonological awareness training. The other major form of reading difficulty is reading comprehension impairment. These children read aloud accurately and fluently, but have difficulty understanding what they have read. Reading comprehension impairment appears to arise from weaknesses in a range of oral language skills including poor vocabulary knowledge, weak grammatical skills and difficulties in oral language comprehension. We suggest that the omission of reading comprehension impairment from DSM-5 is a serious one that should be remedied. Both dyslexia and reading comprehension impairment are dimensional in nature, and show strong continuities with other disorders of language. We argue that recognizing the continuities between reading and language disorders has important implications for assessment and treatment, and we note that the high rates of comorbidity between reading disorders and other seemingly disparate disorders (including ADHD and motor disorders) raises important challenges for understanding these disorders.
Reading disorders; language disorders; dyslexia; reading comprehension impairment; intervention
In a recent publication (K. Ishikawa et al., 2008, Science
320, 661–664), the authors described how replacing the endogenous mitochondrial DNA (mtDNA) in a weakly metastatic mouse tumor cell line with mtDNA from a highly metastatic cell line enhanced tumor progression through enhanced production of reactive oxygen species (ROS). The authors attributed the transformation from a low-metastatic cell line to a high-metastatic phenotype to overproduction of ROS (hydrogen peroxide and superoxide) caused by a dysfunction in mitochondrial complex I protein encoded by mtDNA transferred from the highly metastatic tumor cell line. In this critical evaluation, using the paper by Ishikawa et al. as an example, we bring to the attention of researchers in the free radical field how the failure to appreciate the complexities of dye chemistry could potentially lead to pitfalls, misinterpretations, and erroneous conclusions concerning ROS involvement. Herein we make a case that the authors have failed to show evidence for formation of superoxide and hydrogen peroxide, presumed to be generated from complex I deficiency associated with mtDNA mutations in metastatic cells.
Reactive oxygen species; Fluorescent probes; Metastasis; Mitochondria; Dichlorodihydrofluorescein; Hydroethidine; Hydrogen peroxide; Superoxide; Free radicals
Pharmacotherapies for opioid addiction under active development in the US include lofexidine (primarily for managing withdrawal symptoms) and Probuphine®, a distinctive mode of delivering buprenorphine for six months, thus relieving patients, clinicians, and regulatory personnel from most concerns about diversion, misuse, and unintended exposure in children. In addition, two recently approved formulations of previously proven medications are in early phases of implementation. The sublingual film form of buprenorphine + naloxone (Suboxone®) provides a less divertible, more quickly administered, more child-proof version than the buprenorphine + naloxone sublingual tablet. The injectable depot form of naltrexone (Vivitrol®) ensures consistent opioid receptor blockade for one month between administrations, removing concerns about medication compliance. The clinical implications of these developments have attracted increasing attention from clinicians and policymakers in the US and around the world, especially given that human immunodeficiency virus/acquired immunodeficiency syndrome and other infectious diseases are recognized as companions to opioid addiction, commanding more efforts to reduce opioid addiction. While research and practice improvement efforts continue, reluctance to adopt new medications and procedures can be expected, especially considerations in the regulatory process and in the course of implementation. Best practices and improved outcomes will ultimately emerge from continued development efforts that reflect input from many quarters.
buprenorphine; naltrexone; probuphine; lofexidine; implant buprenorphine; buprenorphine film
Day and colleagues have presented the first data showing that the behavioral effects of low to moderate prenatal alcohol exposure seen in childhood and adolescence persist into adulthood. Using the Achenbach Adult Self Report, they found dose-dependent effects of prenatal exposure on Internalizing, Externalizing, and Attention problems that persist in young adults and, thus, appear to be permanent. To date, few studies have attempted to identify thresholds at which prenatal alcohol exposure is harmful, although the animal literature suggests that even 1–2 binge episodes can result in adverse effects in the offspring. Four prospective longitudinal studies have reported adverse effects at what can be characterized as moderate exposure levels based on NIAAA criteria, but moderate drinking women often concentrate their alcohol use on 1–2 days per week, thereby engaging in binge drinking. In this study binge drinking was not a strong predictor of adverse outcome when average daily dose was held constant, a conclusion that the authors note runs “counter to studies that have reported that binge drinking has a greater effect.” This inconsistency may be due to the difficulty of allocating variance that is shared (overlapping) between average daily dose and binge drinking (i.e., dose/occasion). Data from laboratory animal studies, in which dosage can be manipulated experimentally, demonstrate that a higher dose per occasion, the key feature of binge drinking, leads to more severe adverse effects. Day et al.’s findings of adverse effects at low levels of exposure provides clear evidence that there is no safe level of drinking during pregnancy and that, even at low levels, drinking results in irreversible behavioral impairment. On the other hand, given the evidence from the animal and most human studies, it is important for all women who drink during pregnancy, even at light to moderate levels, to recognize that minimizing their intake per occasion and refraining from binge drinking can reduce risk to the fetus.
light to moderate prenatal alcohol exposure; fetal alcohol spectrum disorders; binge drinking; adult behavior; prospective longitudinal studies; internalizing and externalizing behavior; attention
A substantial body of research supports comorbidity between eating and anxiety disorders, and articles in this special section explore the nature of this association using severity different research designs. This commentary reviews findings from these articles included, focusing on inferences that may be drawn from each design. Collectively, articles support the need for future studies to examine whether eating and anxiety disorders share underlying mechanisms. If identified, such mechanisms could create opportunities for transdiagnostic interventions that ameliorate suffering from both eating and anxiety disorders
The Society for Neuro-Oncology (SNO) is the premier organization dedicated to the cause of central nervous system (CNS) tumors. Although it is primarily located in North America, it attracts considerable memberships from all over the world with truly multi-disciplinary representations from not only neuro-oncology, neurosurgery, radiation oncology, medical oncology and basic scientists, but also in recent years from imaging, psychology, epidemiology, public health and industry, etc. SNO annual meetings are very much looked forward to with presentations of the latest cutting edge data as well as several educational sessions for trainees and updates for senior members too. The meeting is unique in the way that almost the entire scientific agenda is based on submitted abstracts with very few invited lectures.
Brain tumours; glioblastoma; novocure; society for neuro oncology
In 1673, Martin Lister explored the preservation of ‘St Cuthbert's beads’ plus other fossil crinoid remains from approximately 350 Ma Carboniferous limestone in northern England. He used taphonomic evidence (transport, disarticulation, burial and cementation) to infer an origin as petrified plant remains, in contrast with his views expressed elsewhere that fossil mollusc shells could have formed abiogenically, by ‘plastic forces’ within rock. Lister also observed pentagonal symmetry, now seen as characteristic of living echinoderm skeletons. A postscript from John Ray supports Lister's ‘taphonomic’ observations and accepts the biogenicity of these fossil ‘vegetables’. Ray then concluded with a prophecy, predicting the discovery of comparable living fossils in remote ocean waters. These early discussions compare with current debates about the character of candidate microfossils from the early Earth and Mars. Interesting biomorphs are now tested against the abiogenic null hypotheses, making use of features such as those pioneered by Lister, including evidence for geological context, rules for growth and taphonomy. Advanced techniques now allow us to extend this list of criteria to include the nanoscale mapping of biology-like behaviour patterns plus metabolic pathways. Whereas the science of palaeobiology once began with tests for biogenicity, the same is now true for geobiology and astrobiology. This commentary was written to celebrate the 350th anniversary of the journal Philosophical Transactions of the Royal Society.
Martin Lister; palaeobiology; astrobiology; crinoid fossils; biogenicity; taphonomy
The moral arguments and the decision-making processes arising from them in the context of the dilemmas that arise in considering the appropriateness and implementation of withholding or withdrawing treatment in certain neonates form the basis of this commentary. It is concluded that the differing opinions on management of these babies by individual paediatricians results from their differing moral outlooks rather than from any incoherence in the moral arguments set out in the Dutch report.
This paper addresses Colin Holmes's suggestion that the psychopathic disorder is best regarded not as a psychiatric concept, but as an ethical one. The paper argues that the concept of psychopathy, like many other concepts, can span both psychiatry and ethics, and that it is not clear what removing if from the realm of psychiatry would entail. Also, the question of whether the concept of psychopathy is useful for psychiatrists must be separated from the question of whether psychopaths should be exonerated from the moral and legal responsibility for their actions.
OBJECTIVES--To provide a commentary on the economic evaluations of the Oxcheck and British family heart studies: direct comparison of their relative effectiveness and cost effectiveness; comparisons with other interventions; and consideration of problems encountered. DESIGN--Modelling from cost and effectiveness data to estimate of cost per life year gained. SUBJECTS--Middle aged men and women. INTERVENTIONS--Screening for cardiovascular risk factors followed by appropriate lifestyle advice and drug intervention in general practice, and other primary coronary risk management strategies. MAIN OUTCOME MEASURES--Life years gained; cost per life year gained. RESULTS--Depending on the assumed duration of risk reduction, the programme cost per discounted life year gained ranged from 34,800 pounds for a 1 year duration to 1500 pounds for 20 years for the British family heart study and from 29,300 pounds to 900 pounds for Oxcheck. These figures exclude broader net clinical and cost effects and longer term clinical and cost effects other than coronary mortality. CONCLUSIONS--Despite differences in underlying methods, the estimates in the two economic analyses of the studies can be directly compared. Neither study was large enough to provide precise estimates of the overall net cost. Modelling to cost per life year gained provides more readily interpretable measures. These estimates emphasise the importance of the relatively weak evidence on duration effect. Only if the effect lasts at least five years is the Oxcheck programme likely to be cost effective. The effect must last for about 10 years to justify the extra cost associated with the British family heart study.