Risk of cardiovascular disease is driven by different combinations of environmental, medical and behavioral factors: Building a conceptual model for cumulative risk assessment.

The U.S. Environmental Protection Agency (EPA) and National Institute of Environmental Health (NIEHS) held a workshop in 2012 to discuss principles and applications of cumulative risk assessment (CRA). The workshop organizers chose cardiovascular disease (CVD) as an example health outcome for which cumulative risk considerations could illuminate environmental and health management strategies. To guide discussions, we developed a series of conceptual models illustrating factors influencing CVD. The CVD conceptual model represents complex processes across varying space and time scales, different causal pathways, and multiple chemical and non-chemical stressors and factors. It includes causal influences of environmental exposures and lifestyle choices, in the context of genetics and medical factors. The representation of cumulative risk as a network of interrelated nodes and arrows helps define and organize the problem and available information, determine the scope and scale, and creates a platform for analysis. It provides an interface for discussing how different entities (e.g., environmental versus health-driven organizations) can work together on different parts of the problem, and facilitates relative risk ranking and management triage. Color coding is used to distinguish categories of stressors and possible oversight responsibility. This work informs guidelines for CRA planning and assessment of factor combinations affecting real-world risk.

An Overview of Literature Topics Related to Current Concepts, Methods, Tools, and Applications for Cumulative Risk Assessment (2007-2016).

Cumulative risk assessments (CRAs) address combined risks from exposures to multiple chemical and nonchemical stressors and may focus on vulnerable communities or populations. Significant contributions have been made to the development of concepts, methods, and applications for CRA over the past decade. Work in both human health and ecological cumulative risk has advanced in two different contexts. The first context is the effects of chemical mixtures that share common modes of action, or that cause common adverse outcomes. In this context two primary models are used for predicting mixture effects, dose addition or response addition. The second context is evaluating the combined effects of chemical and nonchemical (e.g., radiation, biological, nutritional, economic, psychological, habitat alteration, land-use change, global climate change, and natural disasters) stressors. CRA can be adapted to address risk in many contexts, and this adaptability is reflected in the range in disciplinary perspectives in the published literature. This article presents the results of a literature search and discusses a range of selected work with the intention to give a broad overview of relevant topics and provide a starting point for researchers interested in CRA applications.

Major transitions in human evolution.

Evolutionary problems are often considered in terms of 'origins', and research in human evolution seen as a search for human origins. However, evolution, including human evolution, is a process of transitions from one state to another, and so questions are best put in terms of understanding the nature of those transitions. This paper discusses how the contributions to the themed issue 'Major transitions in human evolution' throw light on the pattern of change in hominin evolution. Four questions are addressed: (1) Is there a major divide between early (australopithecine) and later (Homo) evolution? (2) Does the pattern of change fit a model of short transformations, or gradual evolution? (3) Why is the role of Africa so prominent? (4) How are different aspects of adaptation-genes, phenotypes and behaviour-integrated across the transitions? The importance of developing technologies and approaches and the enduring role of fieldwork are emphasized.This article is part of the themed issue 'Major transitions in human evolution'.

Ecosystem services as assessment endpoints for ecological risk assessment.

Ecosystem services are defined as the outputs of ecological processes that contribute to human welfare or have the potential to do so in the future. Those outputs include food and drinking water, clean air and water, and pollinated crops. The need to protect the services provided by natural systems has been recognized previously, but ecosystem services have not been formally incorporated into ecological risk assessment practice in a general way in the United States. Endpoints used conventionally in ecological risk assessment, derived directly from the state of the ecosystem (e.g., biophysical structure and processes), and endpoints based on ecosystem services serve different purposes. Conventional endpoints are ecologically important and susceptible entities and attributes that are protected under US laws and regulations. Ecosystem service endpoints are a conceptual and analytical step beyond conventional endpoints and are intended to complement conventional endpoints by linking and extending endpoints to goods and services with more obvious benefit to humans. Conventional endpoints can be related to ecosystem services even when the latter are not considered explicitly during problem formulation. To advance the use of ecosystem service endpoints in ecological risk assessment, the US Environmental Protection Agency's Risk Assessment Forum has added generic endpoints based on ecosystem services (ES-GEAE) to the original 2003 set of generic ecological assessment endpoints (GEAEs). Like conventional GEAEs, ES-GEAEs are defined by an entity and an attribute. Also like conventional GEAEs, ES-GEAEs are broadly described and will need to be made specific when applied to individual assessments. Adoption of ecosystem services as a type of assessment endpoint is intended to improve the value of risk assessment to environmental decision making, linking ecological risk to human well-being, and providing an improved means of communicating those risks. Integr Environ Assess Manag 2016;12:522-528. Published 2015 SETAC. This article is a US Government work and, as such, is in the public domain in the USA.

Cumulative risk assessment lessons learned: a review of case studies and issue papers.

Cumulative risk assessments (CRAs) examine potential risks posed by exposure to multiple and sometimes disparate environmental stressors. CRAs are more resource intensive than single chemical assessments, and pose additional challenges and sources of uncertainty. CRAs may examine the impact of several factors on risk, including exposure magnitude and timing, chemical mixture composition, as well as physical, biological, or psychosocial stressors. CRAs are meant to increase the relevance of risk assessments, providing decision makers with information based on real world exposure scenarios that improve the characterization of actual risks and hazards. The U.S. Environmental Protection Agency has evaluated a number of CRAs, performed by or commissioned for the Agency, to seek insight into CRA concepts, methods, and lessons learned. In this article, ten case studies and five issue papers on key CRA topics are examined and a set of lessons learned are identified for CRA implementation. The lessons address the iterative nature of CRAs, importance of considering vulnerability, need for stakeholder engagement, value of a tiered approach, new methods to assess multiroute exposures to chemical mixtures, and the impact of geographical scale on approach and purpose.

Quantification of dentine shape in anthropoid primates.

The external shape and thickness of the enamel component of primate molars have been employed extensively in phylogenetic studies of primate relationships. The dentine component of the molar crown also has been suggested to be indicative of phylogenetic relationships, but few studies have quantified dentine morphology in order to evaluate this possibility. To explore the utility of dentine shape as an indicator of phylogenetic affinity, a two-dimensional geometric morphometric analysis (EDMA-II) was performed using nine homologous landmarks on a sample of sectioned maxillary molars of extant ceboid, cercopithecoid, and hominoid primates. Results indicate that dentine shape (the configuration of the enamel-dentine junction, or EDJ) can distinguish taxa at every taxonomic level examined, including superfamilies, subfamilies, and closely related genera and species. This supports the idea that dentine morphology may be useful for phylogenetic studies. It is further suggested that the morphology of the EDJ may be more conservative than enamel morphology, and perhaps better-suited to phylogenetic studies. Among the samples studied, cercopithecoid primates have a unique dentine shape, and it is suggested that the development of bilophodont molars may be related to the distinctive EDJ configuration in cercopithecoids.

The privatization of human services: myths, social capital and civil society.

It is fashionable to point to privatization and the involvement of for-profits as the parties responsible for many, if not most, of the ills that plague the social welfare system today. This article takes a contrary point of view. Three arguments are made. First, private sector human service delivery and the use of for-profits in the United States predate privatization as a defined public policy. Second, the privatization of the human services is a world wide phenomenon that transcends politics and ideology. Third, the privatization of human services helps to promote civil society and generate social capital.

Treatment-resistant depression: definitions, review of the evidence, and algorithmic approach.

BACKGROUND: Most adults with major depressive disorder (MDD) fail to achieve remission with index pharmacological treatment. Moreover, at least half will not achieve and sustain remission following multiple pharmacological approaches. Herein, we succinctly review treatment modalities proven effective in treatment-resistant depression (TRD). METHODS: We conducted a review of computerized databases (PubMed, Google Scholar) from 1980 to April 2013. Articles selected for review were based on author consensus, adequacy of sample size, the use of a standardized experimental procedure, validated assessment measures and overall manuscript quality. RESULTS: The evidence base supporting augmentation of conventional antidepressants with atypical antipsychotics (i.e., aripiprazole, quetiapine, and olanzapine) is the most extensive and rigorous of all pharmacological approaches in TRD. Emerging evidence supports the use of some psychostimulants (i.e., lisdexamfetamine) as well as aerobic exercise. In addition, treatments informed by pathogenetic disease models provide preliminary evidence for the efficacy of immune-inflammatory based therapies and metabolic interventions. Manual based psychotherapies remain a treatment option, with the most compelling evidence for cognitive behavioral therapy. Disparate neurostimulation strategies are also available for individuals insufficiently responsive to pharmacotherapy and/or psychosocial interventions. LIMITATIONS: Compared to non-treatment-resistant depression, TRD has been less studied. Most clinical studies on TRD have focused on pharmacotherapy-resistant depression, with relatively fewer studies evaluating "next choice" treatments in individuals who do not initially respond to psychosocial and/or neurostimulatory treatments. CONCLUSION: The pathoetiological heterogeneity of MDD/TRD invites the need for mechanistically dissimilar, and empirically validated, treatment approaches for TRD.

Antidepressant monotherapy vs sequential pharmacotherapy and mindfulness-based cognitive therapy, or placebo, for relapse prophylaxis in recurrent depression.

CONTEXT: Mindfulness-based cognitive therapy (MBCT) is a group-based psychosocial intervention designed to enhance self-management of prodromal symptoms associated with depressive relapse. OBJECTIVE: To compare rates of relapse in depressed patients in remission receiving MBCT against maintenance antidepressant pharmacotherapy, the current standard of care. DESIGN: Patients who met remission criteria after 8 months of algorithm-informed antidepressant treatment were randomized to receive maintenance antidepressant medication, MBCT, or placebo and were followed up for 18 months. SETTING: Outpatient clinics at the Centre for Addiction and Mental Health, Toronto, Ontario, Canada, and St Joseph's Healthcare, Hamilton, Ontario. PARTICIPANTS: One hundred sixty patients aged 18 to 65 years meeting DSM-IV criteria for major depressive disorder with a minimum of 2 past episodes. Of these, 84 achieved remission (52.5%) and were assigned to 1 of the 3 study conditions. INTERVENTIONS: Patients in remission discontinued their antidepressants and attended 8 weekly group sessions of MBCT, continued taking their therapeutic dose of antidepressant medication, or discontinued active medication and were switched to placebo. MAIN OUTCOME MEASURE: Relapse was defined as a return, for at least 2 weeks, of symptoms sufficient to meet the criteria for major depression on module A of the Structured Clinical Interview for DSM-IV. RESULTS: Intention-to-treat analyses showed a significant interaction between the quality of acute-phase remission and subsequent prevention of relapse in randomized patients (P = .03). Among unstable remitters (1 or more Hamilton Rating Scale for Depression score >7 during remission), patients in both MBCT and maintenance treatment showed a 73% decrease in hazard compared with placebo (P = .03), whereas for stable remitters (all Hamilton Rating Scale for Depression scores ≤7 during remission) there were no group differences in survival. CONCLUSIONS: For depressed patients achieving stable or unstable clinical remission, MBCT offers protection against relapse/recurrence on a par with that of maintenance antidepressant pharmacotherapy. Our data also highlight the importance of maintaining at least 1 long-term active treatment in unstable remitters.

Three-dimensional primate molar enamel thickness.

Molar enamel thickness has played an important role in the taxonomic, phylogenetic, and dietary assessments of fossil primate teeth for nearly 90 years. Despite the frequency with which enamel thickness is discussed in paleoanthropological discourse, methods used to attain information about enamel thickness are destructive and record information from only a single plane of section. Such semidestructive planar methods limit sample sizes and ignore dimensional data that may be culled from the entire length of a tooth. In light of recently developed techniques to investigate enamel thickness in 3D and the frequent use of enamel thickness in dietary and phylogenetic interpretations of living and fossil primates, the study presented here aims to produce and make available to other researchers a database of 3D enamel thickness measurements of primate molars (n=182 molars). The 3D enamel thickness measurements reported here generally agree with 2D studies. Hominoids show a broad range of relative enamel thicknesses, and cercopithecoids have relatively thicker enamel than ceboids, which in turn have relatively thicker enamel than strepsirrhine primates, on average. Past studies performed using 2D sections appear to have accurately diagnosed the 3D relative enamel thickness condition in great apes and humans: Gorilla has the relatively thinnest enamel, Pan has relatively thinner enamel than Pongo, and Homo has the relatively thickest enamel. Although the data set presented here has some taxonomic gaps, it may serve as a useful reference for researchers investigating enamel thickness in fossil taxa and studies of primate gnathic biology.

Morphology of the enamel-dentine junction in sections of anthropoid primate maxillary molars.

The shape of the enamel-dentine junction (EDJ) in primate molars is regarded as a potential indicator of phylogenetic relatedness because it may be morphologically more conservative than the outer enamel surface (OES), and it may preserve vestigial features (e.g., cuspules, accessory ridges, and remnants of cingula) that are not manifest at the OES. Qualitative accounts of dentine-horn morphology occasionally appear in character analyses, but little has been done to quantify EDJ shape in a broad taxonomic sample. In this study, we examine homologous planar sections of maxillary molars to investigate whether measurements describing EDJ morphology reliably group extant anthropoid taxa, and we extend this technique to a small sample of fossil catarrhine molars to assess the utility of these measurements in the classification of fossil teeth. Although certain aspects of the EDJ are variable within a taxon, a taxon-specific cross-sectional EDJ configuration predominates. A discriminant function analysis classified extant taxa successfully, suggesting that EDJ shape may a reliable indicator of phyletic affinity. When considered in conjunction with aspects of molar morphology, such as developmental features and enamel thickness, EDJ shape may be a useful tool for the taxonomic assessment of fossil molars.

Variation in hominoid molar enamel thickness.

Enamel thickness has figured prominently in discussions of hominid origins for nearly a century, although little is known about its intra-taxon variation. It has been suggested that enamel thickness increases from first to third molars, perhaps due to varying functional demands or developmental constraints, but this has not been tested with appropriate statistical methods. We quantified enamel cap area (c), dentine area (b), and enamel-dentine junction length (e) in coronal planes of sections through the mesial and distal cusps in 57 permanent molars of Pan and 59 of Pongo, and calculated average (c/e) and relative enamel thickness (([c/e]/ radicalb) * 100). Posteriorly increasing or decreasing trends in each variable and average (AET) and relative enamel thickness (RET) were tested among molars in the same row. Differences between maxillary and mandibular analogues and between mesial and distal sections of the same tooth were also examined. In mesial sections of both genera, enamel cap area significantly increased posteriorly, except in Pan maxillary sections. In distal sections of maxillary teeth, trends of decreasing dentine area were significant in both taxa, possibly due to hypocone reduction. Significant increases in AET and RET posteriorly were found in all comparisons, except for AET in Pongo distal maxillary sections. Several significant differences were found between maxillary and mandibular analogues in both taxa. Relative to their mesial counterparts, distal sections showed increased enamel cap area and/or decreased dentine area, and thus increased AET and RET. This study indicates that when AET and RET are calculated from samples of mixed molars, variability is exaggerated due to the lumping of tooth types. To maximize taxonomic discrimination using enamel thickness, tooth type and section plane should be taken into account. Nonetheless, previous findings that African apes have relatively thinner enamel than Pongo is supported for certain molar positions.

Residency training: challenges and opportunities in preparing trainees for the 21st century.

The future will see increased medicalization of psychiatry and will demand changes in training that better prepare residents for the realities of practice in a sustained period of physician shortage. Residency programs will need to move from the current apprenticeship model of training to competency-based programs built on the CanMEDS 2000 articulation of physician roles. Training will need to focus on evidence-based treatments, more efficient models of health care delivery, more attentive tracking of resident clinical work, and more reliable and standardized methods of evaluating resident competencies.

Enamel thickness, microstructure and development in Afropithecus turkanensis.

Afropithecus turkanensis, a 17-17.5 million year old large-bodied hominoid from Kenya, has previously been reported to be the oldest known thick-enamelled Miocene ape. Most investigations of enamel thickness in Miocene apes have been limited to opportunistic or destructive studies of small samples. Recently, more comprehensive studies of enamel thickness and microstructure in Proconsul, Lufengpithecus, and Dryopithecus, as well as extant apes and fossil humans, have provided information on rates and patterns of dental development, including crown formation time, and have begun to provide a comparative context for interpretation of the evolution of these characters throughout the past 20 million years of hominoid evolution. In this study, enamel thickness and aspects of the enamel microstructure in two A. turkanensis second molars were quantified and provide insight into rates of enamel apposition, numbers of cells actively secreting enamel, and the time required to form regions of the crown. The average value for relative enamel thickness in the two molars is 21.4, which is a lower value than a previous analysis of this species, but which is still relatively thick compared to extant apes. This value is similar to those of several Miocene hominoids, a fossil hominid, and modern humans. Certain aspects of the enamel microstructure are similar to Proconsul nyanzae, Dryopithecus laietanus, Lufengpithecus lufengensis, Graecopithecus freybergi and Pongo pygmaeus, while other features differ from extant and fossil hominoids. Crown formation times for the two teeth are 2.4-2.6 years and 2.9-3.1 years respectively. These times are similar to a number of extant and fossil hominoids, some of which appear to show additional developmental similarities, including thick enamel. Although thick enamel may be formed through several developmental pathways, most Miocene hominoids and fossil hominids with relatively thick enamel are characterized by a relatively long period of cuspal enamel formation and a rapid rate of enamel secretion throughout the whole cusp, but a shorter total crown formation time than thinner-enamelled extant apes.

Enamel thickness and microstructure in pitheciin primates, with comments on dietary adaptations of the middle Miocene hominoid Kenyapithecus.

Many living primates that feed on hard food have been observed to have thick-enameled molars. Among platyrrhine primates, members of the tribe Pitheciini (Cacajao, Chiropotes, and Pithecia) are the most specialized seed and nut predators, and Cebus apella also includes exceptionally hard foods in its diet. To examine the hypothesized relationship between thick enamel and hard-object feeding, we sectioned small samples of molars from the platyrrhine primates Aotus trivergatus, Ateles paniscus, Callicebus moloch, Cebus apella, Cacajao calvus, Chiropotes satanas, Pithecia monachus, and Pithecia pithecia. We measured relative enamel thickness and examined enamel microstructure, paying special attention to the development of prism decussation and its optical manifestation, Hunter-Schreger Bands (HSB). Cebus apella has thick enamel with well-defined but sinuous HSB overlain by a substantial layer of radial prisms. Aotus and Callicebus have thin enamel consisting primarily of radial enamel with no HSB, Ateles has thin enamel with moderately developed HSB and an outer layer of radial prisms, and the thin enamel of the pitheciins (Cacajao, Chiropotes, and Pithecia) has extremely well-defined HSB. Among platyrrhines, two groups that feed on hard objects process these hard foods in different ways. Cebus apella masticates hard and brittle seeds with its thick-enameled cheek teeth. Pitheciin sclerocarpic foragers open hard husks with their canines but chew relatively soft and pliable seeds with their molars. These results reveal that thick enamel per se is not a prerequisite for hard object feeding. The Miocene hominoid Kenyapithecus may have included hard objects in its diet, but its thick-enameled molars indicate that its feeding adaptations differed from those of the pitheciins. The morphology of both the anterior and posterior dentition, including enamel thickness and microstructure, should be taken into consideration when inferring the dietary regime of fossil species.

An examination of dental development in Graecopithecus freybergi (=Ouranopithecus macedoniensis).

This study examined enamel thickness and dental development in Graecopithecus freybergi (=Ouranopithecus macedoniensis), a late Miocene hominoid from Greece. Comparative emphasis was placed on Proconsul, Afropithecus, Dryopithecus, Lufengpithecus, and Gigantopithecus, fossil apes that vary in enamel thickness and patterns of development. In addition, comparisons were made with Paranthropus to investigate reported similarities in enamel thickness. Several sections of a right lower third molar were generated, from which enamel thickness and aspects of the enamel and dentine microstructure were determined. Data from parallel sections shed light on the effects of section obliquity, which may influence determination of both enamel thickness and crown formation time. Graecopithecus has relatively thick enamel, greater than any fossil ape but less than Paranthropus, with which it does show similarity in prism path and Hunter-Schreger band morphology. Aspects of enamel microstructure, including the periodicity and daily secretion rate, are similar to most extant and fossil apes, especially Afropithecus. Total crown formation time was estimated to be 3.5 years, which is greater than published values for modern Homo, similar to Pan, and less than Gigantopithecus. Data on dentine secretion and extension rates suggest that coronal dentine formation was relatively slow, but comparative data are very limited. Graecopithecus shares a crown formation pattern with several thick-enamelled hominoids, in which cuspal enamel makes up a very large portion of crown area, is formed by a large cell cohort, and is formed in less than half of the total time of formation. In Paranthropus, this pattern appears to be even more extreme, which may result in thicker enamel formed in an even shorter time. Developmental similarities between Paranthropus and Graecopithecus are interpreted to be parallelisms due to similarities in the mechanical demands of their diets.