Mental Health

Evaluation and Management of Mental Health Disability in Post-secondary Students Abstract Purpose of Review Due to the interdisciplinary nature of mental health disability in post-secondary educational settings, there is limited information available in the general psychiatric literature. This paper aims to familiarize psychiatrists with issues surrounding mental health disability in post-secondary educational settings. In this manuscript, we review critical aspects of the evaluation and management of post-secondary students who may be entitled to academic accommodations as a result of impairment from psychiatric diagnoses. We discuss common misconceptions about mental health impairment and best practices to mitigate its burden. We review relevant legislation and literature from psychiatric, psychological, and higher education journals and include multidisciplinary expert opinions. Recent Findings Mental illness is increasingly common in the post-secondary student population. When symptoms are severe, they can lead to academic impairment or disability. Nationwide data suggests an increase in post-secondary students requesting accommodations for mental health–related impairments. Recent guidelines from the American Psychiatric Association and The Jed Foundation aim to familiarize mental health providers, evaluators, administrators, students, and their families with best practices related to evaluating and managing mental health disability in post-secondary educational settings. Summary Evaluating, accommodating, and managing mental health disability during the post-secondary years are complicated processes. Legislation and nuanced evaluations can guide evaluating psychiatrists and administrators in recommending appropriate accommodations. By being knowledgeable about relevant legislation, best practices for evaluations, and available student resources, psychiatrists will be able to collaborate effectively with all stakeholders.

Innovative Models in Mental Health Delivery Systems: Task Sharing Care with Non-specialist Providers to Close the Mental Health Treatment Gap Abstract Purpose of Review Most people do not have access to adequate mental health care, and lack of skilled human resources is a major factor. We provide a narrative review of approaches to implementing task sharing—engaging non-specialist providers—to deliver mental health care. Recent Findings There is strong evidence both for the effectiveness of task sharing as a means of delivering care for a range of conditions across settings and for the effectiveness of non-specialist providers and health workers in delivering elements of culturally adapted psychosocial and psychological interventions for common and severe mental disorders. Key approaches to facilitate task sharing of care include balanced care, collaborative care, sustained training and supervision, use of trans-diagnostic interventions based on a dimensional approach to wellness and illness, and the use of emerging digital technologies. Summary Non-specialist providers and health workers are well positioned to deliver evidence-based interventions for mental disorders, and a variety of delivery approaches can support, facilitate, and sustain this innovation. These approaches should be used, and evaluated, to increase access to mental health services.

Attention Deficit Hyperactivity Disorder (ADHD) in the Prison System Abstract Purpose of Review To examine recent advances in the understanding of attention deficit hyperactivity disorder (ADHD) among the prison population. Recent Findings Efforts have been made to develop useful tools for assessing ADHD among prisoners. Prisoners with ADHD demonstrate incremental vulnerability due to comorbid psychiatric disorders, neurodevelopmental disorders and traumatic brain injury. Compared with prisoners without ADHD, prisoners with ADHD become involved in the criminal justice system at a younger age and have higher rates of recidivism in adulthood. Recent studies demonstrate the effectiveness of extended release stimulant medication and psychological interventions. Early identification and treatment of prisoners with ADHD have the potential to demonstrate health economic benefits. Summary Our understanding of ADHD among prisoners continues to develop. However, further research is needed, particularly among neglected groups such as females. Much more attention is needed by the prison service to engender better outcomes for this at-risk population.

Predictors of Transition to Psychosis in Individuals at Clinical High Risk Abstract Purpose of Review Current research is examining predictors of the transition to psychosis in youth who are at clinical high risk based on attenuated psychotic symptoms (APS). Determining predictors of the development of psychosis is important for an improved understanding of mechanisms as well as the development of preventative strategies. The purpose is to review the most recent literature identifying predictors of the transition to psychosis in those who are already assessed as being at risk. Recent Findings Multidomain models, in particular, integrated models of symptoms, social functioning, and cognition variables, achieve better predictive performance than individual factors. There are many methodological issues; however, several solutions have now been described in the literature. Summary For youth who already have APS, predicting who may go on to later develop psychosis is possible. Several studies are underway in large consortiums that may overcome some of the methodological concerns and develop improved means of prediction.

The Relationship Between Epilepsy and Anxiety Disorders Abstract Purpose of Review The current review aims at providing an overview of relevant aspects of anxiety symptoms and anxiety disorders (AD) in adults patients with epilepsy (PWE). Recent Findings Firstly, the appropriate diagnosis of type of anxiety symptoms and AD in PWE will be presented. Anxiety symptoms are often peri-ictal and classified in relation to their temporal occurrence to seizures. Anxiety symptoms are of three types: preictal (preceding a seizure), ictal (presenting as part of the seizure symptoms and signs), and postictal (occurring within 72 h of a seizure). AD are diagnosed in the interictal period and occur independently of seizures. Four specific AD in PWE can be objectified: anticipatory anxiety of epileptic seizures (AAS), seizure phobia, epileptic social phobia, and epileptic panic disorder. Secondly, the bidirectional pathophysiological relationship between anxiety and epilepsy will be described. Anxiety is a trigger for seizures in some patients, and the notion of stress and arousal is essential to understand the relationship between anxiety and seizure. Moreover, seizures arising from the limbic network especially involving amygdala, which may express fear-related semiology, provide insight into the pathophysiology of AD comorbidities. Thirdly, the methods of screening for AD and anxiety symptoms will be detailed. Fourthly, the pharmacological and psychobehavioral management of anxiety symptoms and AD in PWE will be presented. Arousal-based approaches for preictal and ictal symptoms and anxiety-based approaches for postictal and interictal symptoms will be presented. Summary Despite lack of evidence-based approaches, it is recognized that management of epilepsy is not only about controlling seizures, but also depends heavily on detecting, correctly diagnosing, and appropriately managing anxiety symptoms and AD comorbidities, in order to maximize quality of life. Improving self-control and self-efficacy is of fundamental importance in the management of PWE. Further rigorously designed studies focusing on anxiety symptoms and AD are essential to improve the overall care of PWE.

Behavioral Responses in Youth Exposed to Natural Disasters and Political Conflict Abstract Purpose of Review The aim of this review was to focus solely on youths' behavioral responses to natural disasters and political conflicts in order to fully understand their impact and scope. Recent Findings Recent studies in the field of trauma have shown that theoretical conceptions have moved away from a narrow focus on the individual and towards wider ecological perspectives and from a narrow focus on negative responses to trauma exposure towards positive prosocial responses. Although there is a distinction between youths' behavioral responses towards natural disasters vs. towards political conflicts, in both of these adverse situations, behavioral responses exist alongside emotional responses. Summary Adolescents exposed to either type of adverse scenario are often able to turn their negative experiences into positive ones, take greater responsibility for themselves and others, contribute to recovery processes, and engage in prosocial behaviors. These responses must be investigated in the context of the trauma field's recent understandings regarding psychological, biological, environmental, and cultural factors.

The NIMH Research Domain Criteria (RDoC) Initiative and Its Implications for Research on Personality Disorder Abstract Purpose of Review We discuss the implications of the Research Domain Criteria (RDoC) initiative for neuroscience research on personality disorder (PD). To organize our review, we construct a preliminary conceptual mapping of PD symptom criteria onto RDoC constructs. We then highlight recent neuroscience research, often built around concepts that correspond to RDoC elements, and discuss the findings in reference to the constructs we consider most pertinent to PD. Recent Findings PD symptoms were strongly conceptually tied to RDoC constructs within the Social Processes domain, implicating brain systems involved in interpersonal rejection, facial emotion perception, and self-referential processes. Negative and Positive Valence Systems were conceptually associated with many PD symptoms, with particular relevance ascribed to the latter's Reward Valuation construct, which could reflect a more widespread disruption of computational processes involved in estimating the probability and benefits of a future outcome. Within the Cognitive Systems domain, the Cognitive Control construct mainly related to PD symptoms associated with impulse control, suggesting a connection to neural circuits that underlie goal selection and behavioral control. Arousal and Regulatory Systems could only be conceptually mapped onto PD symptoms through the Arousal construct, with different symptoms reflecting either a higher or lower biological sensitivity to internal and external stimuli. Summary The RDoC framework has promise to advance neuroscience research on PD. The Social Processes domain is especially relevant to PD, although constructs falling within the other RDoC domains could also yield important insights into the neurobiology of PD and its connections with other forms of psychopathology. Identifying RDoC constructs (e.g., habit formation) that subserve more fundamental processes relevant to personality functioning warrants further investigation.

Cannabinoid Regulation of Fear and Anxiety: an Update Abstract Purpose of Review Anxiety- and trauma-related disorders are prevalent and debilitating mental illnesses associated with a significant socioeconomic burden. Current treatment approaches often have inadequate therapeutic responses, leading to symptom relapse. Here we review recent preclinical and clinical findings on the potential of cannabinoids as novel therapeutics for regulating fear and anxiety. Recent Findings Evidence from preclinical studies has shown that the non-psychotropic phytocannabinoid cannabidiol and the endocannabinoid anandamide have acute anxiolytic effects and also regulate learned fear by dampening its expression, enhancing its extinction and disrupting its reconsolidation. The findings from the relevant clinical literature are still very preliminary but are nonetheless encouraging. Summary Based on this preclinical evidence, larger-scale placebo-controlled clinical studies are warranted to investigate the effects of cannabidiol in particular as an adjunct to psychological therapy or medication to determine its potential utility for treating anxiety-related disorders in the future.

Epidemiological and Clinical Gender Differences in OCD Abstract Purpose of Review This review highlights recent research regarding gender differences in OCD, with a focus on prevalence, course of illness, symptom presentation, comorbidity, and treatment response. Recent Findings Overall, findings remain mixed. OCD may be more common among males in childhood, but is more common among females in adolescence and adulthood. Males tend to report an earlier age of onset and present with symptoms related to blasphemous thoughts. Females often describe symptom onset as occurring during or after puberty or pregnancy and present with symptoms related to contamination and/or aggressive obsessions. Females also tend to report significantly higher depression and anxiety. There are no reported gender differences in treatment outcome. Summary Gender may play a role in the onset, presentation, and impact of OCD symptoms. However, more work is needed to account for differences across studies, with one promising future direction being the study of reproductive hormones.

Community Interventions to Promote Mental Health and Social Equity Abstract Purpose of Review We review recent community interventions to promote mental health and social equity. We define community interventions as those that involve multi-sector partnerships, emphasize community members as integral to the intervention, and/or deliver services in community settings. We examine literature in seven topic areas: collaborative care, early psychosis, school-based interventions, homelessness, criminal justice, global mental health, and mental health promotion/prevention. We adapt the social-ecological model for health promotion and provide a framework for understanding the actions of community interventions. Recent Findings There are recent examples of effective interventions in each topic area. The majority of interventions focus on individual, family/interpersonal, and program/institutional social-ecological levels, with few intervening on whole communities or involving multiple non-healthcare sectors. Findings from many studies reinforce the interplay among mental health, interpersonal relationships, and social determinants of health. Summary There is evidence for the effectiveness of community interventions for improving mental health and some social outcomes across social-ecological levels. Studies indicate the importance of ongoing resources and training to maintain long-term outcomes, explicit attention to ethics and processes to foster equitable partnerships, and policy reform to support sustainable healthcare-community collaborations.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Pharmacology

What We Can Learn from Current Inflammatory Bowel Disease (IBD) Biological Therapy—Dose Regimen and Others Abstract Purpose of Review Inflammatory bowel disease (IBD), such as Crohn's disease (CD) and ulcerative colitis (UC), is an unmet need as indicated by less than ideal remission rates with current treatments. Understanding the clinical development of approved IBD biological therapy, particularly dose selection, may help improve future biologic development. Recent Findings Seven biologics have been approved for CD and/or UC in the last two decades (as of January 2019), including anti-tumor necrosis factors (anti-TNFs) (infliximab, adalimumab, certolizumab, and golimumab), anti-integrins (natalizumab and vedolizumab), and anti-interleukin (IL)-12/IL-23 (ustekinumab). These agents demonstrate effectiveness in inducing sustained clinical remission despite the high and variable "placebo" response. Side effects such as infections and malignancies can occur for biologics partly due to the long-term immunosuppression. IBD biologics typically employ an intensive induction followed by maintenance therapy. Approved dose regimen (especially induction) tends to be the same or close to the highest doses that have been evaluated in clinical development, indicating a limited dose range tested. Biologics approved for CD and UC use the same dose regimen though a given drug may not work equally effectively for both indications. Summary Lessons learned from current IBD biological therapy may help enhance the clinical development efficiency of future biologics, e.g., test a wide dose range; characterize full dose-response for desirable and untoward effects; understand influencing factors to the treatment (and placebo) effect; and leverage dose-ranging learning between CD and UC.

A Small Green Red-Ox Carries a Bright Medical Future for Sub-Saharan Africa Abstract Purpose of Review Redox-related diseases are prevalent globally. Given the cost of allopathic medicines, "green preparations" are often relied on in economically developing countries. This review sought to identify medicinal plants of sub-Saharan Africa which have scientifically validated antioxidant properties, the compounds responsible for these properties, and to highlight the role of nanosizing of such plant materials in the medical future for the region. Recent Findings Eighteen plants (from 13 families) with reported antioxidant properties were identified. The Euphorbiaceae (3 plants) and Capparaceae (2 plants) were the most represented families. Most of the plants were reported to be used in folk medicine for the treatment of infections and inflammation, and water and methanol were the most widely used solvents for preparing the bioactive extracts. In vitro studies (13 cases) predominated. Forty-six different bioactive compounds were reported in the 18 plants identified. Catechin/epicatechin (13 plants), gallic acid (7 plants), caffeic acid, chlorogenic acid, and vitexin/isovitexin (5 plants each) were the most widely reported antioxidant phytochemicals. Given that synergism can occur to enhance the antioxidant activities of phytochemicals, nanosizing the plant leaves identified may open new vistas of opportunities in the development of redox active green pharmaceuticals. Summary Given the abundance of antioxidant phenolics in the plants of sub-Saharan Africa, and the challenges of solvent extraction techniques (with respect to upscaling), nanosizing presents an eco-friendly means of sustainably exploiting these plant resources for medicinal purposes. Therefore, it appears that "a small green red-ox carries a bright medical future for sub-Saharan Africa."

Electrochemical Potential-Biological Activity Relationships of Cyclic Sulfur-Containing Molecules Against Steinernema feltiae , Botrytis cinerea , and Neuro 2a Cell Line Abstract Purpose of Review This article provides a brief overview of electrochemical potential-biological activity relationships of natural and synthetic cyclic sulfur-containing molecules against Steinernema feltiae, Botrytis cinerea, and Neuro 2a cell line (from murine neuroblastoma). Recent Findings This article finds natural cyclic sulfur-containing molecules and their synthetic analogues were more reducing than glutathione (GSH) and therefore apparently did not react with GSH. The nematicidal assay indicated that cyclic disulfide compound of 1 (3-vinyl-4H-1,2-dithiin, 1,2-VDT) was more active against Steinernema feltiae with the LD50 value 151.93 ± 1.3 μM, while dithiole thione group compounds showed moderate activity against this nematode. The article also finds compound 7 (3H-1,2-dithiole-3-thione or dithiolethione, DT) has a strong activity against all different strains of Botrytis cinerea in the range concentration of 0.1–0.5 mM. This article also finds that compounds 3 (1,2-dithiane, 1,2-DT), 4 (1,5-dithiacyclooctane, 1,5-DTCO), and 7 (3H-1,2-dithiole-3-thione or dithiolethione, DT) possess some moderate activity on Neuro 2a cell lines. Summary Antinematode, antifungal, and anticancer activity of cyclic sulfur-containing molecules indicated that they could be promising candidates for "green pesticides" or phytoprotectans and for cancer prevention.

Focusing on the Pharmacological Effects of Iridoids and Crocetin and Its Ester Derivatives of Gardenia jasminoides Abstract Gardenia jasminoides (G. jasminoides), grown in multiple regions in China, was commonly used as a natural yellow dye but has been one of the popular traditional Chinese medicines since the discovery of its biological property few decades ago. It has been reported that G. jasminoides possesses multiple bioactivities, such as anti-oxidant property, hypoglycemic effect, and inhibition of inflammation, anti-depression, and improving sleeping quality. In this review, we aimed to have a comprehensive summary of its phytochemistry including the extraction, isolation, and characterization of volatiles and bioactive molecules in G. jasminoides, focusing on the two major phytochemicals, iridoids and crocetin, and its ester derivatives, which exhibit potential medicinal properties. Furthermore, this work attempted to establish a structure activity relationship (SAR) between the two major series of derivatives with different molecular skeletons and their biological activities, which would serve further exploration of the health-promoting potentials of phyto-compounds in G. jasminoides as dietary supplements or functional ingredients in medical foods. Graphical Abstract .

Selenoneine: a Unique Reactive Selenium Species From the Blood of Tuna With Implications for Human Diseases Abstract Purpose of Review The trace element selenium is found in many dietary components, from grains to Brazil nuts. In humans, this chalcogen is essential for many physiological processes. A couple of years ago, selenoneine, a rather unusual seleno-histidine derivative, has been isolated from tuna. Recent Findings Whilst there is a limited number of other naturally occurring small selenium compounds, large quantities of selenoneine can be generated in genetically engineered microorganisms and via chemical synthesis. Due to a rare selenol/selenone tautomerism, this compound exhibits unique redox properties and promising biological activities, which range of traditional antioxidant action to the interaction and subsequent protection of metal ions. Summary Selenoneine may indeed provide a promising lead for a new generation of selenium supplements and chemopreventive agents.

Protection from DNA Damage by Use of an Aronia Food Supplement—Results from a Pilot Human Intervention Study Abstract Purpose of Review Polyphenols from fruits and other plant sources exhibit protective effects against DNA damage and markers of oxidative stress. Meanwhile, previous investigations tested rather large volumes of polyphenol-rich fruit juices; hence, there is a lack of information on the efficacy of small-volume supplementation concepts suitable for daily routine. We designed a 6-week pilot study on the use of such a food supplement (aronia+) including ten healthy male volunteers and tested for effects on DNA integrity, oxidation-related parameters (Nrf2, SOD, GPx, CAT, and oxidized LDL), and blood lipids. Recent Findings Tendencies towards a decrease were observed for both total and background DNA strand breaks but were not significant after 4-week consumption of the food supplement. Transcription levels of Nrf2 were elevated; meanwhile, Nrf2/ARE-related enzymes were not affected (GPx) or even slightly decreased (SOD, CAT). Marginal reduction was observed for total and LDL cholesterol, whereas other parameters remained almost unchanged. Summary This explorative study yields first indications on protective effects on DNA damage after intake of even small volumes of polyphenol-rich food supplements. These observations must be confirmed in a follow-up study with a higher number of included volunteers and an integration of a control group in order to clearly assess the effect of the intervention.

Polymethoxyflavones: Chemistry and Molecular Mechanisms for Cancer Prevention and Treatment Abstract Polymethoxyflavones (PMFs) are one group of the flavonoid compounds, with tangeretin (Tan) and nobiletin (Nob) being the most abundant PMFs in citrus peel. Numerous biological activities of PMFs have been intensively studied, including anti-inflammatory and anticancer activities. Because of their methoxy groups, PMFs are more lipophilic than hydroxyl flavones, which may affect their biological activities. In addition, researchers found that hydroxylated PMFs (HPMFs) are one of the major metabolites of PMFs in animal urine and feces. Although PMF and HPMFs do show anticancer activity against different types of cancers, but their low hydrophilicity is still a crucial factor that may affect their biological effectiveness. Therefore, from the pharmaceutical aspect, chemical modifications of PMFs have been carried out to obtain acetylated PMFs (Ac-PMFs) for enhancing their biological effects. From the past centuries to the present, cancer is still a critical disease that needs to be solved. Carcinogenesis can be simply divided into three stages: initiation, promotion, and progression. These three stages involve different biological events, such as DNA mutation, cell proliferation, cell growth, and metastasis. In this paper, we aim to illustrate the biological effects of different PMFs, HPMFs, PMF derivatives, and metabolites against different types of cancer and related molecular mechanisms.

Dyslipidemia: Contemporary Therapy Options in Terms of Worldwide Guidelines Abstract Purpose of Review Statins represent a golden standard for treating patients with dyslipidemia. At half of the treated patients, the targeted level of LDL cholesterol is not achieved. Numerous studies which promote new medications have been published in the past several years. Therefore, the objective of this paper is to consider the new possibilities of treating dyslipidemia in terms of various dyslipidemia guidelines. Recent Findings Randomized clinical trials have shown that most positive effects are achieved by lowering the level of LDL cholesterol, and thus the guidelines define the target LDL value. Numerous guidelines in the field of dyslipidemia have been published, but there are some differences which will be analyzed in this review paper. Even if the target LDL cholesterol level is reached, there is still a residual lipid risk for the occurrence of cardiovascular diseases. Therefore, lipid factors, such as high level of triglycerides, low HDL cholesterol, LP(a), etc., play a very important role. Nowadays, there are numerous potent medications which are used in statin and non-statin therapies. PCSK9 inhibitors, which are in the special focus of this paper, have been tested in the past few years. The paper offers an overview of traditionally used medications, as well as new experimental medications. Moreover, the paper emphasizes the importance of non-adherence to antilipemic medications, which is an important issue which reduces the favorable effects of the treatment. Summary Nowadays, there are drugs which, combined with statins, may reduce HDL-C level to very low values. The studies have shown inconsistent results in terms of solving the issue of residual lipid risk. Research in this field may significantly reduce lipid risk for cardiovascular events.

Role of Reactive Oxygen Species in Cancer Progression Abstract Purpose of Review Although there are significant improvements in diagnosis and therapeutics tools, cancer remained a major cause of deaths in developing and developed countries. Among others, endogenously or exogenously generating reactive oxygen species (ROSs) are considered a crucial cause for tumor initiation, development, and survival. Unhealthy lifestyle, exposure to various carcinogens, ionizing radiations, and chemotherapy drugs are the main factors for ROS production. Recent Findings Reactive oxygen species cause genetic instability due to DNA damage or mutation load. Exposer to ROS also modulates the expression of various transcription factors such as Sp1, AP1, and NF-κβ implicated in proliferation, metastasis, and cancer stem cell maintenance. It is suggested that ROSs are involved in various cancer-related process including apoptosis, angiogenesis, metastasis, and inflammation. Numerous data from several studies suggest ROS as one of the therapeutic targets for cancer prevention and cure. Summary The current review summarizing the interactions of ROSs with various cellular molecules involved in angiogenesis, metastasis, and inflammation.

Role of Histone Acetylation and Methylation in Obesity Abstract Purpose of Review This review gives an overview of the roles of histone acetylation and methylation in obesity and related metabolic diseases. Recent Findings Nutrition can change gene expression via epigenetics such as DNA methylation and post-translational modifications of histones. A growing number of both experimental and clinical studies suggested that histone modifications are very sensitive to changes in nutritional availability and potentially impact the development and progression of metabolic disorders. Recent advances in proteomic studies provided evidence linking histone modifications to over-nutrition and metabolic dysregulation. In this review, we will summarize the recent findings on two classical histone modifications, i.e., acetylation and methylation and the related findings from clinical studies and potential applications. Summary The involvement of histone modifications in the progression of metabolic diseases is now widely appreciated. Over the recent years, mass spectrometry-based proteomics approaches discovered and mapped different kind of histone modifications linking obesity and metabolic diseases. The list of these modifications is evergrowing; however, their functions and roles in obesity are not well understood. Same as for the most well studied histone modifications, namely acetylation and methylation. Although much has been learnt from these two modifications, their contributions in regulation of metabolism are still largely unknown. It will be necessary to carry out more studies to further dissect the importance of the availability of substrates and activities of the enzymes for histone acetylation and methylation in the metabolic tissues.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Molecular Biology

Extracellular Vesicles: How to Shuttle the Metastatic Programme Abstract Purpose of Review This review has the meaning of providing a state-of-the-art in the role of tumour-derived EVs in educating the host microenvironment during the metastatic process. Recent Findings Extracellular vesicles (EVs) now represent another piece in the complex puzzle that is tumorigenesis and metastasis. The indication that EVs are more than just a way for cells to dispose of waste and actually work as active and dynamic structures packaging molecular signals arose in the late '60s, when EV-like structures were involved in the function of coagulation. Since then, a huge amount of information has been collected, and we are now aware that EVs are crucially involved in paracrine and distant cell-cell communication under physiologic and pathologic conditions, such as cancer metastasis to bone. Summary We will focus on the EV-mediated mechanisms regulating bone homeostasis, and we will describe the way these mechanisms are dysregulated by osteotropic cancer cell-derived EVs.

Interplay Between FGF23, Phosphate, and Molecules Involved in Phosphate Sensing Abstract Purpose of Review Despite the important progress made in understanding the regulation of phosphate (Pi) homeostasis over the past 20 years, the mechanisms underlying the very early step leading to the regulating cascade involving multiple hormones (PTH, vitamin D, FGF23) and organs (kidney, intestine, bone, parathyroid glands) are not deciphered. Particularly, knowledge on the Pi-sensing mechanism present within or on the surface of the cell that is able to detect changes in serum or local Pi concentrations and trigger an appropriate FGF23 synthesis/secretion is limited or absent. Recent Findings Several molecular actors have recently been involved as potential key players in Pi sensing and Pi-dependent control of FGF23 secretion. Among them, the PiT1/Slc20a1 and PiT2/Slc20a2 proteins are standing out. Summary We are just beginning to accumulate in vitro and in vivo data that will provide invaluable molecular tools to explore and understand the integrated response of the body to variations of Pi concentration.

Novel and Conventional Preclinical Models to Investigate Bone Metastasis Abstract Purpose of Review The purpose of this review is to emphasize the use of bone metastasis models in preclinical research. As classical models have been thoroughly discussed in recent reviews, we here highlight the most important aspects from these papers with a special focus on novel models developed during the past 5 years. Recent Findings Preclinical mouse models to study bone metastasis can be divided by cancer cell inoculation techniques (spontaneous, systemic, or local) or by immunological background of the mice (immunodeficient, syngeneic, or humanized). Additionally, novel computational, in vitro co-culture, and humanized bone models have been established. Summary Various models can be used to approach distinct research questions. Understanding limitations of the models is essential when planning a study and interpreting the results. Development of novel models will increase understanding of the complex biology and advance the discovery of new therapies targeting bone metastases.

Molecular Control of Growth-Related Sodium-Phosphate Co-transporter (SLC34A3) Abstract The type IIa sodium-dependent inorganic phosphate transporter (NaPi-IIa) has a central regulatory role in inorganic phosphate (Pi) homeostasis. Many studies have reported on the functions and regulatory mechanisms of NaPi-IIa. NaPi-IIc, however, was initially identified as a NaPi transporter required for growth in rodents. The gene encoding NaPi-IIc is causative for hereditary hypophosphatemic rickets with hypercalciuria and considered to be a critical NaPi transporter in the human kidney. However, the physiological roles and regulatory mechanisms of NaPi-IIc are not sufficiently elucidated. Recent studies show that NaPi-IIc is tightly regulated by a variety of agonists and physiological conditions via partially defined molecular mechanisms, including transcriptional and posttranscriptional regulation, protein phosphorylation, trafficking (endocytosis, exocytosis, and recycling), and the association of NaPi-IIc with interacting protein complexes. These data provide further information about understanding of human renal Pi handling. Here, we review recent findings regarding the molecular control of NaPi-IIc transporters.

Animal Models of Phosphorus Homeostasis Abstract Purpose of Review Phosphate homeostasis is a complex process that involves many regulators and multiple organs. In vivo models have been used extensively to study the pathophysiological mechanisms of phosphate disorders. This review focuses on evaluating mouse models generated for the study of disorders of phosphate metabolism. Recent Findings Over the years, several mouse models have been generated by strategies that knockin or knockout one or more genes that encode for the phosphate transporters or other regulatory factors that directly or indirectly influence phosphate homeostasis. These models have shed light on the pathways involved in phosphate metabolism and the mechanisms that lead to phosphate dysregulation in human diseases. Summary Animal models are essential tools to study multisystem disorders that affect multiple organs and cell types. In particular, mouse models generated by a variety of genetic approaches have become the preferred mammalian models to study human diseases. Mouse models of phosphate homeostasis have provided valuable insights and enhanced our understanding of the cross talk between bone, kidney, and intestine and the relationships between the key phosphate regulators FGF23, 1,25(OH)2-vitamin D3, and PTH.

MicroRNAs Are Critical Regulators of Osteoclast Differentiation Abstract Purpose of Review Our goal is to comprehensively review the most recent reports of microRNA (miRNA) regulation of osteoclastogenesis. We highlight validated miRNA-target interactions and their place in the signaling networks controlling osteoclast differentiation and function. Recent Findings Using unbiased approaches to identify miRNAs of interest and reporter-3′UTR assays to validate interactions, recent studies have elucidated the impact of specific miRNA-mRNA interactions during in vitro osteoclastogenesis. There has been a focus on signaling mediators downstream of the RANK and CSF1R signaling, and genes essential for differentiation and function. For example, several miRNAs directly and indirectly target the master osteoclast transcription factor, Nfatc1 (e.g., miR-124 and miR-214) and Rho-GTPases, Cdc42, and Rac1 (e.g., miR-29 family). Summary Validating miRNA expression patterns, targets, and impact in osteoclasts and other skeletal cells is critical for understanding basic bone biology and for fulfilling the therapeutic potential of miRNA-based strategies in the treatment bone diseases.

FGF23 Synthesis and Activity Abstract Purpose of Review The phosphaturic hormone FGF23 is produced primarily in osteoblasts/osteocytes and is known to respond to increases in serum phosphate and 1,25(OH)2 vitamin D (1,25D). Novel regulators of FGF23 were recently identified and may help explain the pathophysiologies of several diseases. This review will focus on recent studies examining the synthesis and actions of FGF23. Recent Findings The synthesis of FGF23 in response to 1,25D is similar to other steroid hormone targets, but the cellular responses to phosphate remain largely unknown. The activity of intracellular processing genes control FGF23 glycosylation and phosphorylation, providing critical functions in determining the serum levels of bioactive FGF23. The actions of FGF23 largely occur through its co-receptor αKlotho (KL) under normal circumstances, but FGF23 has KL-independent activity during situations of high concentrations. Summary Recent work regarding FGF23 synthesis and bioactivity, as well as considerations for diseases of altered phosphate balance, will be reviewed.

MICROmanagement of Runx2 Function in Skeletal Cells Abstract Purpose of Review Precise and temporal expression of Runx2 and its regulatory transcriptional network is a key determinant for the intricate cellular and developmental processes in adult bone tissue formation. This review analyzes how microRNA functions to regulate this network, and how dysregulation results in bone disorders. Recent Findings Similar to other biologic processes, microRNA (miRNA/miR) regulation is undeniably indispensable to bone synthesis and maintenance. There exists a miRNA–RUNX2 network where RUNX2 regulates the transcription of miRs or is post-transcriptionally regulated by a class of miRs, forming a variety of miR-RUNX2 regulatory pathways which regulate osteogenesis. Summary The current review provides insights to understand transcriptional–post-transcriptional regulatory network governed by Runx2 and osteogenic miRs, and is based largely from in vitro and in vivo studies. When taken together, this article discusses a new regulatory layer of bone tissue-specific gene expression by RUNX2 influenced via miRNA.

Regulation of Fibroblast Growth Factor 23 by Iron, EPO, and HIF Abstract Purpose of Review Fibroblast growth factor-23 (FGF23) is the key hormone produced in bone critical for phosphate homeostasis. Elevated serum phosphorus and 1,25-dihydroxyvitamin D stimulates FGF23 production to promote renal phosphate excretion and decrease 1,25-dihydroxyvitamin D synthesis, thus completing the feedback loop and suppressing FGF23. Unexpectedly, studies of common and rare heritable disorders of phosphate handling identified links between iron and FGF23 demonstrating novel regulation outside the phosphate pathway. Recent Findings Iron deficiency combined with an FGF23 cleavage mutation was found to induce the autosomal dominant hypophosphatemic rickets phenotype. Physiological responses to iron deficiency, such as erythropoietin production as well as hypoxia inducible factor activation, have been indicated in regulating FGF23. Additionally, specific iron formulations, used to treat iron deficiency, alter post-translational processing thereby shifting FGF23 protein secretion. Summary Molecular and clinical studies revealed that iron deficiency, through several mechanisms, alters FGF23 at the transcriptional and post-translational level. This review will focus upon the novel discoveries elucidated between iron, its regulators, and their influence on FGF23 bioactivity.

Epigenetics of Multiple Myeloma Bone Disease Abstract Purpose of Review Multiple myeloma bone disease (MMDB) is a devastating clinical manifestation of multiple myeloma associated with excessive bone osteolysis, which results from enhanced osteoclastogenesis and suppression of bone marrow stromal cell (BMSC) differentiation into osteoblasts. Impaired osteogenesis and functional alterations of myeloma-exposed BMSCs (MM-BMSCs) during the course of disease evolution significantly contribute to myeloma growth, metastasis, and chemoresistance. This review highlights new studies demonstrating that epigenetic modalities including chromatin-mediated gene silencing and non-coding RNA contribute to pathogenesis of MM-BMSCs. Recent Findings Inhibitors targeting histone-modifying enzymes EZH2, JMJD3, HDACs, and BET proteins have been successfully used to revert osteogenic suppression of MM-BMSCs. Aberrant expression of non-coding RNA cause functional changes associated with senescence, osteogenic suppression, and tumor-promoting phenotype of MM-BMSCs. Summary Epigenetic events guiding transformations of the surrounding BMSC compartments are ultimately linked to disease onset and progression and open new therapeutic opportunity to target dissemination of MM tumors and reliably repair bone lesions.

Gene and Genome

Consent and Autonomy in the Genomics Era Abstract Purpose of Review Genomic tests offer increased opportunity for diagnosis, but their outputs are often uncertain and complex; results may need to be revised and/or may not be relevant until some future time. We discuss the challenges that this presents for consent and autonomy. Recent Findings Popular discourse around genomic testing tends to be strongly deterministic and optimistic, yet many findings from genomic tests are uncertain or unclear. Clinical conversations need to anticipate and potentially challenge unrealistic expectations of what a genomic test can deliver in order to enhance autonomy and ensure that consent to genomic testing is valid. Summary We conclude that 'fully informed' consent is often not possible in the context of genomic testing, but that an open-ended approach is appropriate. We consider that such broad consent can only work if located within systems or organisations that are trustworthy and that have measures in place to ensure that such open-ended agreements are not abused. We suggest that a relational concept of autonomy has benefits in encouraging focus on the networks and relationships that allow decision making to flourish.

Management and Screening in Neurofibromatosis Types 1 and 2 Abstract Purpose of Review Neurofibromatosis types 1 and 2 (NF1 & NF2) are complex genetic diseases that provide challenges in diagnosis, monitoring, clinical management and genetic counselling. This review highlights these challenges and provides insight into the general and specialist management considerations. Recent Findings Multidisciplinary care with a focus on evidence based interventions and quality of life outcomes has benefited patients. Anti-VEGF therapy has recently altered the management paradigm for NF2. Other novel molecularly targeted therapies are being trialled in both NF1 and NF2. Improved understanding of associated risks and natural history has informed screening regimes. Summary Both diseases have significant associated morbidity and mortality, with the prognosis for some patients with NF2 particularly poor. A holistic and multidisciplinary approach provides the best model of care.

The Changing Role of the Genetic Counsellor in the Genomics Era Abstract Purpose of Review Rapid advances in the scope, affordability and clinical utility of genetic testing have driven significant change and expansion of the genetic counselling profession. Increasing volume, complexity and diversity of patients and their genomic data present a challenge. To manage this, examination of how genetic counsellors can adapt and thrive in the genomics era is warranted. Recent Findings Digital applications, web-based educational platforms and artificial intelligence are being harnessed to support and enhance genetic counselling delivery for patients and consumers. Genetic counsellors are also ideally placed to educate and support other healthcare professionals delivering genomic medicine. Concurrently, core genetic counselling skills in managing psychosocial, familial and ethical issues have continued relevance, and further investment in evidence-based research is needed to guide practice. A focus on improving diversity and equity of access to genetic counselling is also necessary. Summary Working in a changing and uncertain environment is not unfamiliar ground for genetic counsellors. Their specialist knowledge and core skills will continue to be highly valued in the genomics era. Genomic medicine has the potential to positively transform public health, and the genetic counselling profession has the opportunity to play a pivotal role.

GWAS and Beyond: Using Omics Approaches to Interpret SNP Associations Abstract Purpose of Review Neurodegenerative diseases, neuropsychiatric disorders, and related traits have highly complex etiologies but are also highly heritable; identifying the causal genes and biological pathways underlying these traits may advance the development of treatments and preventive strategies. While many genome-wide association studies (GWAS) have successfully identified variants contributing to polygenic neurodegenerative and neuropsychiatric phenotypes including Alzheimer's disease (AD), schizophrenia (SCZ), and bipolar disorder (BPD) among others, interpreting the biological roles of significantly associated variants in the genetic architecture of these traits remains a significant challenge. Here, we review several 'omics' approaches which attempt to bridge the gap from associated genetic variants to phenotype by helping define the functional roles of GWAS loci in the development of neuropsychiatric disorders and traits. Recent Findings Several common 'omics' approaches have been applied to examine neuropsychiatric traits, such as nearest-gene mapping, trans-ethnic fine mapping, annotation enrichment analysis, transcriptomic analysis, and pathway analysis, and each of these approaches has strengths and limitations in providing insight into biological mechanisms. One popular emerging method is the examination of tissue-specific genetically regulated gene expression (GReX), which aggregates the genetic variants' effects at the gene level. Furthermore, proteomic, metabolomic, and microbiomic studies and phenome-wide association studies will further enhance our understanding of neuropsychiatric traits. Summary GWAS has been applied to neuropsychiatric traits for a decade, but our understanding about the biological function of identified variants remains limited. Today, technological advancements have created analytical approaches for integrating transcriptomics, metabolomics, proteomics, pharmacology, and toxicology as tools for understanding the functional roles of genetic variants. These data, as well as the broader clinical information provided by electronic health records, can provide additional insight and complement genomic analyses.

Benefits and Challenges of Rare Genetic Variation in Alzheimer's Disease Abstract Purpose of Review It is well established that sporadic Alzheimer's disease (AD) is polygenic with common and rare genetic variation alongside environmental factors contributing to disease. Here, we review our current understanding of the genetic architecture of disease, paying specific attention to rare susceptibility variants, and explore some of the limitations in rare variant detection and analysis. Recent Findings Rare variation has been shown to robustly associate with disease. These include potentially damaging and loss of function mutations that are easily modelled in silico, in vitro and in vivo, and represent potentially druggable targets. A number of risk genes, including TREM2, SORL1 and ABCA7 show multiple independent associations suggesting that they may influence disease via multiple mechanisms. With transcriptional regulation, inflammatory response and modification of protein production suggested to be of primary importance. Summary We are at the beginning of our journey of rare variant detection in AD. Whole exome sequencing has been the predominant technology of choice. While fruitful, this has introduced a number of challenges with regard to data integration. Ultimately the future of disease-associated rare variant identification lies in whole genome sequencing projects that will allow the testing of the full range of genomic variation.

Sex Differences in the Genetic Architecture of Alzheimer's Disease Abstract Purpose of Review Summarize sex-specific contributors to the genetic architecture of Alzheimer's disease (AD). Recent Findings There are sex differences in the effects of apolipoprotein E (APOE), genes along the APOE pathway, and genes along the neurotrophic signaling pathway in predicting AD. Reported sex differences are largely driven by stronger associations among females. Evidence also suggests that genetic predictors of amyloidosis are largely shared across sexes, while sex-specific genetic effects emerge downstream of amyloidosis and drive the clinical manifestation of AD. Summary There is a lack of comprehensive assessments of sex differences in genome-wide analyses of AD and a need for more systematic reporting of sex-stratified genetic effects. The emerging emphasis on sex as a biological variable provides an opportunity for transdisciplinary collaborations aimed at addressing major analytical challenges that have hampered advancements in the field. Ultimately, sex-specific genetic association studies represent a logical first step towards precision medicine.

Polygenic Risk Scores in Neurodegenerative Diseases: a Review Abstract Purpose of the Review This review summarizes the current state of the art of polygenic risk scores (PRSs) in the assessment of risk for neurodegenerative diseases. Recent Findings Polygenic risk scores have been used to identify the shared genetic architecture between comorbid complex traits, disease presentations, and disease endophenotypes. Summary The pathological and symptomatologic overlap between neurodegenerative diseases is strikingly high. In some cases, the diagnostic decision is arbitrary depending on the first appearance of symptomatology. Genetic studies have demonstrated that the genetic architecture of each of these diseases is different, but has a high degree of overlap. The creation of polygenic risk scores has allowed a more accurate calculation of this overlap. However, the power of the PRS is dependent on the power of the genome-wide association studies (GWAS) used to describe the genetic architecture. Even though not all neurodegenerative disease GWAS have the same sample size, and thus the same power, the use of polygenic risk scores has been successful in demonstrating the genetic overlap that has been observed phenotypically.

Recent Advances in the Genetics of Frontotemporal Dementia Abstract Purpose of Review In this review, we highlight recent advances in the human genetics of frontotemporal dementia (FTD). In addition to providing a broad survey of genes implicated in FTD in the last several years, we also discuss variation in genes implicated in both hereditary leukodystrophies and risk for FTD (e.g., TREM2, TMEM106B, CSF1R, AARS2, NOTCH3). Recent Findings Over the past 5 years, genetic variation in approximately 50 genes has been confirmed or suggested to cause or influence risk for FTD and FTD-spectrum disorders. We first give background and discuss recent findings related to C9ORF72, GRN, and MAPT, the genes most commonly implicated in FTD. We then provide a broad overview of other FTD-associated genes and go on to discuss new findings in FTD genetics in East Asian populations, including pathogenic variation in CHCHD10, which may represent a frequent cause of disease in Chinese populations. Finally, we consider recent insights gleaned from genome-wide association and genetic pleiotropy studies. Summary Recent genetic discoveries highlight cellular pathways involving autophagy, the endolysosomal system, and neuroinflammation and reveal an intriguing overlap between genes that confer risk for leukodystrophy and FTD.

Protective Variants in Alzheimer's Disease Abstract Purpose of Review Over the last decade, over 40 loci have been associated with risk of Alzheimer's disease (AD). However, most studies have either focused on identifying risk loci or performing unbiased screens without a focus on protective variation in AD. Here, we provide a review of known protective variants in AD and their putative mechanisms of action. Additionally, we recommend strategies for finding new protective variants. Recent Findings Recent Genome-Wide Association Studies have identified both common and rare protective variants associated with AD. These include variants in or near APP, APOE, PLCG2, MS4A, MAPT-KANSL1, RAB10, ABCA1, CCL11, SORL1, NOCT, SCL24A4-RIN3, CASS4, EPHA1, SPPL2A, and NFIC. Summary There are very few protective variants with functional evidence and a derived allele with a frequency below 20%. Additional fine mapping and multi-omic studies are needed to further validate and characterize known variants as well as specialized genome-wide scans to identify novel variants.

Fragile Sites as Drivers of Gene and Genome Evolution Abstract Purpose of Review Although the detailed composition of the human genome is known base by base for its major part, the orchestration of and which elements exactly facilitate organization and flexibility of higher order gene and genome architecture, are poorly understood and scarcely studied. Recent Findings This review focuses on fragile sites (FSs). They are considered as regions of chromosome breakage with overlapping signatures for breakpoints observed repeatedly in tumor and constitutional rearrangements, and also in evolutionary conserved breakpoints. Thus, FSs are promising targets to study and get deeper insights into chromosome, gene, and genome evolution. Summary Here, we summarize the current knowledge on FSs and their correlation with aforementioned breakpoint categories. Based on that, we introduce a new model for FSs driven gene and genome evolution, which also can explain the recently observed spreading of (pseudo-)gene family members among the human genome. FSs therefore may provide an "infrastructure" to distribute gene copies onto different sites of the genome and may be the underlying cause for formation of gene families.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Environmental Health

Statistical Approaches for Investigating Periods of Susceptibility in Children's Environmental Health Research Abstract Purpose of Review Children's environmental health researchers are increasingly interested in identifying time intervals during which individuals are most susceptible to adverse impacts of environmental exposures. We review recent advances in methods for assessing susceptible periods. Recent Findings We identified three general classes of modeling approaches aimed at identifying susceptible periods in children's environmental health research: multiple informant models, distributed lag models, and Bayesian approaches. Benefits over traditional regression modeling include the ability to formally test period effect differences, to incorporate highly time-resolved exposure data, or to address correlation among exposure periods or exposure mixtures. Summary Several statistical approaches exist for investigating periods of susceptibility. Assessment of susceptible periods would be advanced by additional basic biological research, further development of statistical methods to assess susceptibility to complex exposure mixtures, validation studies evaluating model assumptions, replication studies in different populations, and consideration of susceptible periods from before conception to disease onset.

Biomonitoring and Nonpersistent Chemicals—Understanding and Addressing Variability and Exposure Misclassification Abstract Purpose of Review We offer here a review of intraindividual variability in urinary biomarkers for assessing exposure to nonpersistent chemicals. We provide thoughts on how to better evaluate exposure to nonpersistent chemicals. Recent Findings We summarized reported values of intraclass correlation coefficients and found that most values fall into categories that indicate only poor to good reproducibility. Even within the "good" classification, a large percentage of study participants is likely to be misclassified as to their exposure. Summary There is sufficient information to support the statement that studies using only one spot measurement of a nonpersistent chemical will be unreliable. It is unequivocal that multiple samples have to be collected over a period of toxicological relevance and with consideration of exposure patterns. Sponsors of research and researchers themselves should be vocal about ensuring that sufficient resources are made available to properly characterize exposures when studying nonpersistent chemicals. Otherwise, we will continue to see an ever-growing body of literature yielding inconsistent and/or uninterpretable results.

Understanding and Mitigating the Replication Crisis, for Environmental Epidemiologists Abstract Purpose of Review In recent years, investigators in a variety of fields have reported that most published findings can not be replicated. This review evaluates the factors contributing to lack of reproducibility, implications for environmental epidemiology, and strategies for mitigation. Recent Findings Although publication bias and other types of selective reporting may contribute substantially to irreproducible results, underpowered analyses and low prevalence of true associations likely explain most failures to replicate novel scientific results. Epidemiologists can counter these risks by ensuring that analyses are well-powered or precise, focusing on scientifically justified hypotheses, strictly controlling type I error rates, emphasizing estimation over statistical significance, avoiding practices that introduce bias, or employing bias analysis and triangulation. Avoidance of p values has no effect on reproducibility if confidence intervals excluding the null are emphasized in a similar manner. Summary Increased attention to exposure mixtures and susceptible subpopulations, and wider use of omics technologies, will likely decrease the proportion of investigated associations that are true associations, requiring greater caution in study design, analysis, and interpretation. Though well intentioned, these recent trends in environmental epidemiology will likely decrease reproducibility if no effective actions are taken to mitigate the risk of spurious findings.

Transforming Our Cities: Best Practices Towards Clean Air and Active Transportation Abstract Purpose of Review By 2050, 70% of the global population will live in urban areas, exposing a greater number of people to specific city-related health risks that will only be exacerbated by climate change. Two prominent health risks are poor air quality and physical inactivity. We aim to review the literature and state the best practices for clean air and active transportation in urban areas. Recent Findings Cities have been targeting reductions in air pollution and physical inactivity to improve population health. Oslo, Paris, and Madrid plan on banning cars from their city centers to mitigate climate change, reduce vehicle emissions, and increase walking and cycling. Urban streets are being redesigned to accommodate and integrate various modes of transportation to ensure individuals can become actively mobile and healthy. Investments in pedestrian, cycling, and public transport infrastructure and services can both improve air quality and support active transportation. Emerging technologies like electric and autonomous vehicles are being developed and may reduce air pollution but have limited impact on physical activity. Green spaces too can mitigate air pollution and encourage physical activity. Summary Clean air and active transportation overlap considerably as they are both functions of mobility. The best practices of clean air and active transportation have produced impressive results, which are improved when enacted simultaneously in integrated policy packages. Further research is needed in middle- and low-income countries, using measurements from real-world interventions, tracing air pollution back to the sources responsible, and holistically addressing the entire spectrum of exposures and health outcomes related to transportation.

Mendelian Randomization and the Environmental Epigenetics of Health: a Systematic Review Abstract Purpose of Review Epigenetic modifications are environmentally responsive and may play a mechanistic role in the development of disease. Mendelian randomization uses genetic variation to assess the causal effect of modifiable exposures on health outcomes. We conducted a systematic review of Mendelian randomization studies evaluating the causal role of DNA methylation (DNAm) changes on the development of health states, emphasizing on studies that formally evaluate exposure-DNAm, in addition to DNAm-outcome, causal associations. Recent Findings We identified 15 articles, 4 of them including an environmental determinant of DNAm, including self-reported tobacco smoke exposure, in utero tobacco smoke exposure, measured vitamin B12, and glycemia. Summary Selected articles suggest a causal association of DNAm with some cardiometabolic endpoints. DNAm seemed to partly explain the association of postnatal and prenatal exposure to tobacco smoke and vitamin B12 with inflammation biomarkers, birth weight, and cognitive outcomes, respectively. However, the current evidence is not sufficient to infer causality. Additional Mendelian randomization studies from large epidemiologic samples are needed to support the causal role of environmental factors as determinants of health-related epigenetic modifications.

Planetary Health and Population Health: the Anthropocene Requires Different Thinking and Approaches in Serving Public Health

Planetary Epidemiology: Towards First Principles Abstract Purpose of Review To combine evolutionary principles of competition and co-operation with limits to growth models, generating six principles for a new sub-discipline, called "planetary epidemiology." Suggestions are made for how to quantify four principles. Recent Findings Climate change is one of a suite of threats increasingly being re-discovered by health workers as a major threat to civilization. Although "planetary health" is now in vogue, neither it nor its allied sub-disciplines have, as yet, had significant impact on epidemiology. Few if any theorists have sought to develop principles for Earth system human epidemiology, in its ecological, social, and technological milieu. Summary The principles of planetary epidemiology described here can be used to stimulate applied, quantitative work to explore past, contemporary, and future population health, at scales from local to planetary, in order to promote enduring health. It is also proposed that global well-being will decline this century, without radical reform.

The Holistic Effects of Climate Change on the Culture, Well-Being, and Health of the Saami, the Only Indigenous People in the European Union Abstract Purpose of Review (1) To develop a framework for understanding the holistic effects of climate change on the Saami people; (2) to summarize the scientific evidence about the primary, secondary, and tertiary effects of climate change on Saami culture and Sápmi region; and (3) to identify gaps in the knowledge of the effects of climate change on health and well-being of the Saami. Recent Findings The Saami health is on average similar, or slightly better compared to the health of other populations in the same area. Warming climate has already influenced Saami reindeer culture. Mental health and suicide risk partly linked to changing physical and social environments are major concerns. Summary The lifestyle, diet, and morbidity of the Saami are changing to resemble the majority populations posing threats for the health of the Saami and making them more vulnerable to the adverse effects of climate change. Climate change is a threat for the cultural way of life of Saami. Possibilities for Saami to adapt to climate change are limited.

Adverse Maternal Metabolic Intrauterine Environment and Placental Epigenetics: Implications for Fetal Metabolic Programming Abstract Purpose of Review Herein, we summarize existent epidemiological studies relating adverse maternal metabolic environments of maternal obesity and gestational diabetes and placental DNA methylation. Recent Findings Multiple studies have evaluated associations between intrauterine exposure to gestational diabetes and/or maternal glucose levels and DNA methylation at candidate metabolic genes as well as in epigenome-wide studies. Some of the genomic regions more consistently associated include lipid-related genes (LPL and PPARGC1A), the major histocompatibility complex (MHC), and imprinted genes. Studies solely focused on maternal obesity influences on the placental epigenome are scarce. Summary Understanding the placental mechanisms involved in fetal metabolic programming could lead to discovery of placental biomarkers at birth that predict later-life metabolic risk. Moving forward is important to standardize methods utilized in epigenetics research; consistent methodology can help interpret disparate findings. Larger studies with longitudinal follow-up are needed to address future challenges in fetal programming research.

Pesticides and Child's Health in France Abstract Purpose of Review The use of pesticides is predominant in agriculture, inducing environmental contamination, and has been extended to the domestic sphere. In France, > 500 pesticides were authorized for use in 2009; given their various toxicological properties, there are legitimate concerns about the possible consequences for child health. This review summarizes the recent French studies of good quality dealing with pesticides and child health. Recent Findings Three cohorts (mother–child, retrospective) and two case–control studies have been conducted in the last decade. Using various instruments for exposure assessment including biomarkers, they have suggested alterations of subclinical health parameters at birth, increased risk of otitis at age 2, and increased risk of several types of childhood cancer. However, there were no adverse neurodevelopmental outcomes at 6 years of age following prenatal exposure to pesticides. Summary Both agricultural and domestic pesticides might be involved in such adverse health outcomes. Similar studies are lacking in Europe. Studies on fungicides and child health are scarce.