Despite the recognition of stunting as a public health priority, nutritional and nonnutritional interventions to reduce or prevent linear growth failure have demonstrated minimal impact. Investigators and policymakers face several challenges that limit their ability to assess the potential benefits of combining available interventions into a linear growth promotion package. We use two common but very different interventions, deworming and multiple micronutrient supplements, to illustrate barriers to recommending an optimal linear growth promotion package based on the currently available literature. These challenges suggest that combining individual- and population-based as well as model-based approaches would complement existing research using systematic review, meta-analysis, and factorial randomized trials, and help integrate existing fields of research to inform the development of optimal linear growth promotion packages for children living in resource-limited settings. Estimates suggest that if available growth-promoting interventions reached 90% of their target population, stunting incidence would only be reduced by one-fifth.3 The combination of proximal etiologic causes of stunting, including lack of adequate nutrition, hormonal dysregulation, repeated infections, environmental enteric dysfunction, and chronic systemic inflammation, occurs within a complex network of more distal factors that underlie stunting.2 As a result of the multifactorial etiologies of stunting, successful prevention or treatment may require combined packages of interventions targeting multiple pathophysiologic pathways leading to stunting. The failure to prevent or reverse stunting may result from the complex interactions between prenatal and early childhood health insults that result in linear growth failure.More than 165 million children worldwide are stunted  is administered to more than 100 million children annually, often in mass drug administration (MDA) programs, and there is some evidence to suggest a potential linear growth benefit from deworming.6 However, results from a recent Cochrane review of randomized trials assessing the growth benefits of deworming interventions are mixed. Although some individual trials demonstrate beneficial effects of deworming on childhood growth, the results of pooled analyses demonstrate no statistically significant effects .6 Interpreting and applying these results requires a careful understanding of the distinction between efficacy and effectiveness in the context of clinical trial design.Soil-transmitted helminths are among the world’s most common infections, affecting more than 25% of the world’s population.N = 136) were conducted under these conditions and measured linear growth as an outcome . Best available estimates of the efficacy of deworming should rely on studies that first screen for helminth infection and treat only those who are infected.6Efficacy trials assess how well an intervention can work under ideal circumstances. To determine the potential efficacy of deworming interventions, initial trials need to be conducted among children who are known to have helminth infection at baseline, to assess the effect of treatment in an infected population. Among the 42 trials in children included in the Cochrane review, few trials  the benefit expected among infected children and how that benefit is likely to translate to population level growth outcomes and 2) interaction effects of package contents.Effectiveness trials, also known as pragmatic trials, assess an intervention’s effect in real world conditions and can be challenging to interpret. Effectiveness trials of deworming use MDA to treat populations independent of individual helminth infection status because it is less expensive and more readily delivered than implementing a screen and treat program. Thus, the measured effectiveness of MDA programs, the most common deworming intervention, to promote linear growth, depends on the prevalence of helminth infection in the population as any improvement in growth would only be expected to occur in children infected with helminths. Conversely, uninfected individuals are not likely to benefit from deworming and will attenuate the population effect size observed in that study. As a result, studies testing MDA deworming interventions conducted in high prevalence settings demonstrate greater growth benefit than studies in lower prevalence populations .8 The chief aim of trialing multiple interventions is assessing whether the combination offers an added benefit over the single intervention, often referred to as additive effects. Additive effects assume that if treatment A has an effect EA over a control and treatment B has an effect EB over that same control, then the combination of A and B would have an effect EA+ EB.9 Additive effects assume that the interventions work via independent pathways. For example, it would be reasonable to assume that a handwashing intervention and a nutritional intervention do not use the same pathway and therefore, should not interact. However, many interventions have complex or uncertain mechanisms of action, and so it is advisable to test for interactions between combined interventions using factorial randomized trials. Guidance for the assumptions of additive effects have been previously reported.9 In rare circumstances, interactions can lead to a greater-than-expected treatment effect , referred to as synergy. When an interaction leads to a treatment effect less than the sum of the combined treatments  it is termed as antagonism. A common cause of antagonistic interactions is class effect. This occurs when interventions using similar pathways have comparable individual effect sizes but negligible additive effects, because the therapeutic utility of the shared pathway is already fully exploited by a single therapeutic.Results from trials of childhood multiple micronutrient interventions provide insight into the potential multiplicative or additive benefits provided by combining interventions into a package. However, although the methodological principles of evaluating the combined effects of interventions are well established, determining how combined interventions interact is complex.12 In theory, by addressing several stunting-associated deficiencies, childhood micronutrient supplementation should have additive benefits. However, demonstrating additive or synergistic benefit is more challenging than proving a single intervention efficacy.13 There may be a maximum threshold of benefit provided by micronutrient supplementation that limits the total linear growth impact achievable. In addition, individual micronutrients may compete for intestinal or hematological transport mechanisms, potentially prohibiting the full effect of each individual intervention.16Intra-package interactions are extremely relevant in the context of micronutrient interventions which often do not target a single nutrient, but rather try to tackle multiple nutritional deficiencies.17 However, results of individual factorial design studies testing zinc in combination with other micronutrients such as vitamin A or iron are inconsistent and do not demonstrate a clear additive benefit.22 It is possible that the micronutrients exert a class effect or that they compete to exert an effect through a single biological pathway. The difficulty in demonstrating the biological benefit of combining multiple individual micronutrients into a single treatment reinforces the need for careful consideration of potential interactions between constituent interventions of a package when designing any growth promotion package.For example, a published meta-analysis of zinc supplementation in children suggests a modest but statistically significant benefit on linear growth, particularly among children who are zinc deficient.To directly extract efficacy and effectiveness knowledge and quantitatively delineate the complex interaction between proximal and distal determinants on growth outcomes, a large knowledgebase combining novel modeling techniques beyond systematic review, meta-analysis, and factorial randomized trials may be helpful to increase learning and knowledge generation.Anthelmintics and multiple micronutrient interventions serve as examples to highlight the complexity of assessing interventions targeting linear growth and of determining optimal combinations of interventions to achieve maximum potential benefit. Many interventions have not been evaluated for growth benefit in well-designed efficacy trials, and many trials of combined interventions were not designed to evaluate additive effects or antagonism. In addition, the diversity of interventions suggested for inclusion in a possible package targeting linear growth promotion may require delivery through a combination of delivery platforms. Therefore, recommending an optimal linear growth promotion package based on the currently available published literature with any certainty of its beneficial effect is challenging. This, in turn, limits the ability of policymakers to set guidelines for packages of interventions. Single intervention-based recommendations may be a missed opportunity to optimize childhood health.It may be possible to use novel modeling techniques to integrate existing datasets and find commonalities that are not apparent through systematic review and meta-analysis. However, although using meta-analysis to pool or compare results from the diverse fields of research contributing to the stunting discourse may not always be methodologically appropriate, it may be possible to use nontraditional methods specifically designed to test the integration of different interventions. For example, nonlinear effect models, Markov models, piecewise linear models, principal components models, and machine-learning decision models can be used to evaluate longitudinal growth outcomes in pooled data and explore alternative treatment strategies via clinical trial simulation.23 Select examples of models developed through this initiative are summarized in 24 Although a careful understanding of efficacy versus effectiveness and potential interactions in the current literature is still required, a combination of these methods applied to pooled datasets could offer new insight into the interactions between, and importance of, growth-promoting interventions. Ultimately, these innovative techniques could be used to inform the design of growth-package interventions before clinical trial testing.The Healthy Birth, Growth, and Development knowledge integration initiative at the Bill & Melinda Gates foundation is using a variety of analytic methods to model longitudinal growth outcomes and test the effect of interventions using clinical trial data.It is clear that high-quality data from interventional trials are needed to inform the development of optimal intervention packages to improve growth in children living in resource-limited settings. However, using systematic review and meta-analysis of the current evidence base to design intervention packages is likely to expend valuable resources testing packages of interventions that are not optimized. New approaches to designing linear growth promotion packages are required.


Ixodes scapularis, because of ecologic and entomologic factors, the risk for human infection is low, and no confirmed Lyme disease cases were reported in Arkansas during 2008–2014  did not meet the Council of State and Territorial Epidemiologists surveillance criteria for Lyme disease.* Eleven (3.7%) met the probable (three reports) or suspected (eight) Lyme disease surveillance case definition, and two reports (0.7%) met the confirmed case definition. Further investigation of the two confirmed cases revealed that both patients were likely infected in high-incidence states. One patient had signs of arthritis soon after moving to Arkansas from the northeastern United States, but did not receive a diagnosis of and treatment for Lyme disease until nearly 1 year later, underscoring the fact that even where Lyme disease is rare, providers need to obtain a travel history and consider the diagnosis in patients with compatible symptoms who have lived in or visited states where Lyme disease is common.Borrelia burgdorferi sensu stricto and the recently discovered Borrelia mayonii (I. scapularis ticks are much less abundant, less prone to biting humans, rarely infected with B. burgdorferi, and prefer feeding on nonreservoir hosts (Lyme disease is the most common vectorborne disease in the United States, caused by the spirochete ,Of the hundreds of Lyme disease reports submitted to ADH during 2015–2016, many had incomplete information or negative laboratory results; however, the ADH Lyme disease surveillance system did identify two confirmed, travel-associated infections. The absence of similarly confirmed, locally acquired cases supports the view that autochthonous transmission of Lyme disease is either exceedingly rare or has not occurred in Arkansas. The risk for other tickborne diseases in Arkansas results in frequent requests for Lyme disease testing as part of a general tickborne disease serologic panel, even when Lyme disease is not suspected by the clinician. Strong clinical evidence supported by positive two-tiered serologic testing is essential to securing a diagnosis of Lyme disease in low-incidence states (For reporting Lyme disease to public health authorities, health care providers should follow infectious disease testing recommendations and reporting guidelines set forth by state health departments and only submit reports for cases that have complete and positive test results and associated clinical information. Given that multiple laboratory tests, potentially performed and reported by different laboratories, might be necessary to determine Lyme disease case status, health departments need an efficient process to manage and interpret incoming laboratory reports.


In dry savannas, the increased water-use efficiency in plants relaxes precipitation-driven constraints and increases woody growth. In wet savannas, the increase of carbon allocation to tree roots results in faster recovery rates after disturbance and a greater likelihood of reaching sexual maturity. Our proposed framework can be tested using a mixture of experimental and earth observational techniques. At a local level, changes in precipitation, burning regimes or herbivory could be driving woody encroachment, but are unlikely to be the explanation of this continent-wide phenomenon.Savanna ecosystems are an integral part of the African landscape and sustain the livelihoods of millions of people. Woody encroachment in savannas is a widespread phenomenon but its causes are widely debated. We review the extensive literature on woody encroachment to help improve understanding of the possible causes and to highlight where and how future scientific efforts to fully understand these causes should be focused. Rainfall is the most important determinant of maximum woody cover across Africa, but fire and herbivory interact to reduce woody cover below the maximum at many locations. We postulate that woody encroachment is most likely driven by COThe online version of this article (doi:10.1007/s00442-017-3807-6) contains supplementary material, which is available to authorized users. Over the past 60 years, growing evidence suggests that savannas throughout the world are being altered by a phenomenon known as ‘woody encroachment’  and unstable (wet) states has been questioned. Staver et al. , b showe2 would increase tree growth and encourage a closed forest system. This in turn would lower grass fuel loads and increase humidity, which lowers the flammability of the landscape, creating a positive feedback system in maintaining a forest. In contrast, in areas where fire occurs more frequently, tree maturity rates decrease due to top-killing, which prevents canopy closure and allows C4 grasses to thrive  experiments shows an increase under elevated CO2, it is lower than expected due to the effects of rising temperatures  and wet (unstable) savannas, particularly with regards to the role that water plays in altering the tree–grass competition  and dry (stable) savannas are caused by two separate mechanisms Below is the link to the electronic supplementary material.


Our relationships are such stuff as emotions are made of.” Within our relationships, emotions express our needs and desires. When problems happen in our relationships, emotions arise to help us fixing such problems . Parallels are made with the psychoanalytic concept of defense mechanisms as a form of implicit emotion regulation. Another aspect explored in this part is the role of empathy in mediating the association between difficulties in emotion regulation and hostility . Cai et al. explore how sex and extraversion modulate self-reported emotional experience in an ERP experiment. The authors suggest that there is a male advantage for using expressive suppression for emotion regulation in non-extraverted, ambivert individuals. Deficits in the regulation of interpersonal emotions have been linked to severe psychiatric disorders. Understanding how patients experience and fail to regulate such emotions is of fundamental importance . People with anxiety disorders suffer from severe emotion dysregulation and subsequent cognitive biases. Cui et al. explore how the emotional context affects successful and unsuccessful source retrieval amongst high-trait-anxiety college students by using event-related potentials (ERPs).Individuals with marked autistic traits display several features of social and emotion dysregulation. Imageability ratings of word classes denoting proprioceptive, emotional, and theoretical words predict whether people have low or high autistic traits, or, to put it differently, whether they have more or less marked empathic inclinations , an evidence-based treatment that integrates contemporary psychotherapy modalities with basic and translational affective science to offer a framework for improving emotion regulation in patients. Strategies, technique and clinical examples are provided to illustrate principles of ERT. Another promising approach, namely Schema Therapy  is presented for its potential to foster emotion regulation in severely disturbed patients . The relevance for therapy of motor behavior, with its connection to proprioceptive and interoceptive mechanisms, is also discussed (Shafir). Another paper explores the possibility of improving parenting programs for behavioral disorders in children using the Rational Positive Parenting Program (rPPP), a program with a special focus on parent emotion-regulation functional reappraisal strategies, which has recently received consistent support for reducing child externalizing and internalizing disorder . Dingle et al. present evidence of Tuned In, a new emotion regulation intervention that uses dedicated music to evoke emotions in session and teaches participants emotional awareness and regulation skills. The special issue ends with reflections on synchrony and psychotherapy, illustrating the Interpersonal Synchrony (In-Sync) model of psychotherapy (Koole and Tschacher). This model considers the alliance between patient and client as grounded in the coupling of the patient's and therapist's brains. Because brains do not interact directly, movement synchrony may help to establish inter-brain coupling.The ability to regulate emotions is essential for healthy psychological functioning and is a key focus of psychotherapy. Working actively with emotion has been empirically shown to be of central importance in psychotherapy. Different therapeutic models from different theoretical orientations have incorporated principles and techniques to work on dysregulated emotions. In this section, we present novel models of treatments to regulate emotions that therapists can use in clinical practice. We start by presenting Emotion Regulation Therapy (ERT) . An alternative emerging model, known as Experiential-Dynamic Emotion Regulation (EDER)  model of Gross , followiRenna et al.) rely mainly on extinction to foster emotion regulation through the use of new cognitive strategies. However, extinction based approaches suffer from relapse over time. Luckily, in 1997 evidence of a complete erasure of emotional learning was experimentally provided , psychodynamic therapy (Rice), and Schema Therapy  foster Memory Reconsolidation. Research is needed to understand the roles of extinction and memory consolidation in emotion regulation and how to foster them in therapeutic settings.Before the 1990s, neuroscientists agreed that once an emotional learning took place, it was “forever” (LeDoux et al., AG wrote this editorial, RJ and JF corrected it and added some observations.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Intervention studies in animals suggest molecular changes underlying age-related disease and disability can be slowed or reversed. To speed translation of these so-called “geroprotective” therapies to prevent age-related disease and disability in humans, biomarkers are needed that can track changes in the rate of human aging over the course of intervention trials. Algorithm methods that measure biological processes of aging from combinations of DNA methylation marks or clinical biomarkers show promise. To identify next steps for establishing utility of these algorithm-based measures of biological aging for geroprotector trials, we considered the history a candidate biomarker of aging that has received substantial research attention, telomere length. Although telomere length possesses compelling biology to recommend it as a biomarker of aging, mixed research findings have impeded clinical and epidemiologic translation. Strengths of telomeres that should be established for algorithm biomarkers of aging are correlation with chronological age across the lifespan, prediction of disease, disability, and early death, and responsiveness to risk and protective exposures. Key challenges in telomere research that algorithm biomarkers of aging must address are measurement precision and reliability, establishing links between longitudinal rates of change across repeated measurements and aging outcomes, and clarity over whether the biomarker is a causal mechanism of aging. These strengths and challenges suggest a research agenda to advance translation of algorithm-based aging biomarkers: establish validity in young-adult and midlife individuals; test responsiveness to exposures that shorten or extend healthy lifespan; and conduct repeated-measures longitudinal studies to test differential rates of change. Biomarkers of aging are needed to advance translation of new therapies to slow aging and extend healthy lifespan or “healthspan.” Accumulating evidence suggests molecular changes that occur with aging are among the root causes of age-related disease and disability . ExperimUnlike worms, flies, and mice, humans live too long to observe complete lifespans within individual studies. Age-related disease and disability typically develop over a period of decades spanning the second half of the human life course. Preventive interventions are therefore needed relatively early, before age-related disease becomes established . True teMeasurement of aging biomarkers before, during, and after administration of therapy in treatment and control groups would allow for a simple test of whether the therapy showed promise to slow aging and extend healthspan. Such aging biomarkers may be within reach from new algorithms that combine information from multiple clinical parameters and dozens or hundreds of gene expression or DNA methylation measurements . InitialTelomeric DNA functions as a cellular biological clock and a proximate cause of cellular senescence. Telomeres are repetitive nucleoprotein regions (TTAGGG in humans) at chromosome ends which prevent end to end fusions and protect against DNA degradation. Each time a cell divides, 12–30 base-pairs of telomeric DNA are lost due to inefficiency in DNA replication machinery, a phenomena known as the “end-replication problem” Establish validity across the lifespan. A primary strength of telomeres as a biomarker of aging is that age-related telomere shortening occurs across the life course. This matches theoretical models of aging as a lifelong process . Epigene(2)Test responsiveness to exposures known to shorten or extend healthy lifespan. A second strength of telomeres as an aging biomarker is that exposures that predict shorter healthspan are associated with shorter telomeres well before onset of age-related disease, although this finding needs further confirmation from longitudinal studies . There i(3)Conduct longitudinal repeated measures studies to test differential rates of change. Longitudinal repeated measures studies are needed to determine if cross-sectional measurements suggesting accelerated biological aging in fact reflect differential rates of change or instead differences established early in development. Just as critical, as 1 is a model to be emulated. Because of variation in assay technology, it is unclear if the same kind of standardization is possible for transcriptomic, proteomic, or metabolomic clocks. But for clinical biomarker algorithms, an automated system is possible, e.g., the aging.ai tool2 (Standardization of measurement technology for algorithm-based biomarkers of aging can help to achieve these objectives. In telomere research, lack of comparability of measurements across labs has slowed progress. Differences in assay technology and analysis methods are both issues. As an example of the benefits of standardization, epigenetic clock research achieved rapid progress partly because many different labs used the same assay technology and investigators publicly disseminated software to implement analysis. The Horvath lab’s website interface to aid researchers in computing epigenetic clocks in their own dataai tool2 . ScalingAs algorithm-based biomarkers of aging accumulate evidence, comparative studies should be done to establish whether different measures quantify the same aging processes . RelatedAlgorithm-based biomarkers of aging have the potential to advance translation of geroprotective therapies by providing clinical trials with surrogate endpoints for healthspan extension. But there is still much work to be done. Algorithm-based biomarkers of aging by construction lack specificity about the mechanism or mechanisms of aging they reflect. Instead, they seek to capture information from multiple sources to provide a summary of the organism’s rate of aging. Because of this lack of specificity regarding mechanism, algorithm-based biomarkers are only as useful as the predictions they make about healthspan. The primary empirical criterion laid out by DB and IS conceived the article, drafted sections of the manuscript, and critically revised the manuscript. WH conducted primary literature reviews, drafted sections of the manuscript, and critically revised the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Three recent studies analyzing large-scale collections of human induced pluripotent stem cell lines provide valuable insight into how genetic regulatory variation affects cellular and molecular traits. Induced pluripotent stem cells (iPSCs) have been widely used as an important model system for human development and disease. They provide a potentially unlimited cell source for regenerative medicine, as well as a system in which to model patient-specific disease and test drug toxicity and effectiveness –3. HowevNow, three recent studies have undertaken large-scale genomic analysis of iPSCs from hundreds of individuals  and all iPSC lines and accompanying data are available to the scientific community –7. TheseThe combinatorial approaches utilized by each of these three studies have the distinct benefit of being able to correlate specific genotypes to variations in gene expression levels and provide a resource that allows the prediction of the consequences of genetic changes on phenotype variation . All thrThe data provided in these three large-scale studies represent the highest resolution map of common regulatory variations in human iPSCs. Since Kilpinen et al.  and CarcTERT expression and telomerase activity, which they showed has significant effects in pluripotent or stem-like cells, but likely exerts little effect in differentiated cells, where TERT expression is usually silenced. However, cancer cells reactivate telomerase activity, meaning that this particular genomic variant, and others like it, may be useful to study diseases that affect cells only in limited states of cell growth and differentiation [The correlations between genomic variation and functional consequences are of particular interest in iPSCs. Since these cells can theoretically be differentiated into any cell type, they allow for the analysis of specific genomic changes that may have significantly different effects dependent on cell type. For example, Kilpinen et al.  identifyntiation . DeBoeventiation  showed tntiation . These rntiation , but arentiation . Thus, tOverall, these collective findings provide a valuable resource for understanding the genomic and phenotypic variation in iPSCs, and the drivers of this variation that are directly relevant to the use of these cells in understanding disease. This work serves as an important foundation for utilizing iPSCs to test variants identified by genome-wide association studies, as iPSCs can be readily used to interrogate variations that have functional consequences which may be driving disease phenotypes . In addi


The tumor microenvironment contains not only cancer cells but also non-cancerous cells and extracellular matrices (ECMs). These cell types interact through chemical and mechanical stimuli and as a result, regulate tumor progression. While many studies have identified chemical stimuli that are critical for cancer progression, the role of mechanical stimuli is less defined. It has been recently shown that mechanical stimuli, especially the stiffness of ECMs, contribute to tumor progression in some specific cancers including breast, colorectal, and lung , 2, 3. IMesenchymal stem cells (MSCs) are multi- potent cells existing in major types of connective tissue which have recently been shown to migrate to tumor sites and mediate tumor growth and progression . In respin vitro and in vivo. However, we found that prosaposin secreted from MSCs inhibited lung metastasis, while prosaposin knockdown in MSCs increased metastasis. Thus, prosaposin secreted from MSCs has contradicting roles for cancer progression: promoting cancer progression by enhancement of proliferation and survival whereas preventing cancer progression by inhibition of metastasis (Figure Recently we reported that MSCs respond to both chemical and mechanical stimuli in the mammary tumor microenvironment by promoting tumor progression . Treatins Figure .Interestingly, soluble factors such as vascular endothelial growth factor, hepatocyte growth factor, and TGFβ, reported to be secreted from CAFs , were noTo our knowledge, this is the first report to demonstrate that the mechanical stimulus of ECM stiffness and the chemical cue of TGFβ both play a critical role in the activation of MSCs and the promotion of cancer progression. These findings are critical for the field because they provide evidence that the stiffness and composition of the tumor microenvironment are critical determinants of cancer progression. In fact, the stiffness of the extracellular matrix may be the driving factor of chemical secretion that is necessary to differentiate and advance tumors toward metastasis.These results are consistent with previous reports which showed that prosaposin drives tumor growth  and prev


Thyroid hormones are crucial in normal brain development. Transient and mild thyroid hormone insufficiency in pregnancy is also associated with impaired neurodevelopment in the offspring . While inadequate iodine intake remains the most common underlying cause of mild thyroid hormone insufficiency in vulnerable populations including pregnant women, other factors such as exposure to environmental contaminants have recently attracted increasing attention, in particular in interaction with iodine deficiency. Endocrine-disrupting chemicals (EDCs) are natural and synthetic substances with ubiquitous exposure in children and adults including pregnant women. EDCs interfere, temporarily or permanently, with hormonal signaling pathways in the endocrine system by binding to hormone receptors and modifying gene expression. Other mechanisms involve alterations in production, metabolism, and transfer of hormones. Experimental studies have shown that exposures to EDCs affect various brain processes such as neurogenesis, neural differentiation and migration, as well as neural connectivity. Neuroimaging studies confirm brain morphological abnormalities  consistent with neurodevelopmental impairments as a result of EDC exposures at standard use levels. In this review, we provide an overview of present findings from toxicological and human studies on the anti-thyroid effect of EDCs with a specific attention to fetal and early childhood exposure. This brief overview highlights the need for additional multidisciplinary studies with a focus on thyroid disruption as an underlying mechanism for developmental neurotoxicity of EDC, which can provide insight into modifiable risk factors of developmental delays in children. Observations of children born with cretinism in iodine deficient areas prompted scientists to discuss the impact of early thyroid function on brain development . DecadesWhile inadequate iodine intake remains the most common cause of thyroid insufficiency worldwide , other fPolychlorinated biphenyls and polychlorinated dibenzodioxins (PCDD) are persistent organic pollutants, which are no longer produced due to their carcinogenic effects , but areSubstantial evidence from epidemiological studies has shown associations between PCB or PCDD exposures and abnormal thyroid parameters. Cross-sectional examination of serum PCB and dioxin levels and thyroid parameters have shown positive associations between serum thyroid-stimulating hormone (TSH) and PCB congeners and PCDD and negative associations between PCBs and T3 and thyroxine (T4), with stronger associations among women –29. In cPolybrominated diphenyl ethers are organic compounds that are used as flame retardants in building materials, electronics, furnishing, and textiles. The usage of some PBDE congeners is increasingly being controlled; however, due to their high resistance to degradation processes, people are still exposed to PBDEs. PBDEs have a similar chemical structure to thyroid hormones. Experimental studies have shown that PBDEs, at environmentally relevant doses, bind to receptors, and inhibit binding of T3 to TRs, and suppress T3 actions , 41. OthIndividuals are widely exposed to pesticides. Several pesticides are currently banned; however, they are still detectible in the environment from previous use . Chlorpyn-pentanoic acid has been positively associated with cord blood TT4 (n-pentanoic acid and perfluorohexane sulfonic acid was associated with increased T4 and T3 levels (in the cord blood), while PFNA was associated with decreased TSH concentration in newborn girls  and by suppressing its transcriptional activity in a dose-dependent manner  are no longer used in baby toys; yet phthalates metabolites remain detectible in individuals across age groups , 112. UrDespite data suggesting thyroid dysregulation resulting from phthalate exposure, specific underlying mechanisms are poorly understood. A recent experimental study in rats has shown that DEHP can downregulate the thyroid-releasing hormone (TRH) receptor in the hypothalamus, upregulate the protein and mRNA levels of TRH receptor in the pituitary, and downregulate mRNA expression of TSH receptors in the thyroid . In zebrConcern is growing regarding the long-lasting effect of chemicals, routinely found in the environment, on the fetal and child brain through anti-thyroid capacities. Thyroid disruption is of particular interest because several EDCs interfere with thyroid function in a sex-specific manner, which might explain the sexual dimorphism in the brain effect of EDCs. EDCs comprise of various compounds with different mechanisms of anti-thyroid effects. This might explain a heterogeneous neurodevelopmental outcomes associated with EDCs. Thyroid disruptive effects of chemicals in combination with or independent of iodine deficiency is another topic which has been sparsely considered in epidemiological settings.Additional multidisciplinary studies with a focus on thyroid disruption as an underlying mechanism can strengthen the existing knowledge on the neurotoxicity EDC. Two such interdisciplinary efforts have been started in Europe and in the US. The LifeCycle Project is a European network of population-based birth cohorts which aims to examine the impact of early life stressors on health and development using a life course approach. In the US, the Environmental Influences on Child Health Outcomes (ECHO) program uses information from 50,000 children and their families from across the US “to enhance the health of children for generations to come” . This inAG and LT drafted the manuscript and reviewed the final draft for submission.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling Editor and reviewer BD declared their involvement as co-editors in the Research Topic, and confirm the absence of any other collaboration.


Easily identifiable risk factors including: obesity and ethnicity at high risk of diabetes are commonly used to indicate which women should be offered the oral glucose tolerance test (OGTT) to diagnose gestational diabetes (GDM). Evidence regarding these risk factors is limited however. We conducted a systematic review (SR) and meta-analysis and individual participant data (IPD) analysis to evaluate the performance of risk factors in identifying women with GDM.We searched MEDLINE, Medline in Process, Embase, Maternity and Infant Care and the Cochrane Central Register of Controlled Trials (CENTRAL) up to August 2016 and conducted additional reference checking. We included observational, cohort, case-control and cross-sectional studies reporting the performance characteristics of risk factors used to identify women at high risk of GDM. We had access to IPD from the Born in Bradford and Atlantic Diabetes in Pregnancy cohorts, all pregnant women in the two cohorts with data on risk factors and OGTT results were included.Twenty nine published studies with 211,698 women for the SR and a further 14,103 women from two birth cohorts (Born in Bradford and the Atlantic Diabetes in Pregnancy study) for the IPD analysis were included. Six studies assessed the screening performance of guidelines; six examined combinations of risk factors; eight evaluated the number of risk factors and nine examined prediction models or scores. Meta-analysis using data from published studies suggests that irrespective of the method used, risk factors do not identify women with GDM well.Using IPD and combining risk factors to produce the highest sensitivities, results in low specificities . Strategies that use the risk factors of age (>25 or >30) and BMI (>25 or 30) perform as well as other strategies with additional risk factors included.2 or more is as good as more complex risk prediction models. Research to identify more accurate (bio)markers is needed.Risk factor screening methods are poor predictors of which pregnant women will be diagnosed with GDM. A simple approach of offering an OGTT to women 25 years or older and/or with a BMI of 25kg/mSystematic Review Registration: PROSPERO CRD42013004608 Gestational diabetes mellitus (GDM) is hyperglycaemia of variable severity first identified in pregnancy. GDM is associated with an increased risk of a range of adverse perinatal outcomes,,2 includTreatment of GDM improves perinatal outcomes,–8 suggesRisk factor screening involves the assessment of maternal characteristics, such as family history of diabetes; being of an ethnicity with a high prevalence of diabetes ; history of having GDM or a macrosomic infant; maternal obesity and occaSeveral healthcare agencies including the UK National Institute for Health and Care Excellence (NICE), the AmeRisk factor assessment is recommended in many populations in early pregnancy. The presence of a risk factor therefore influences early assessment of hyperglycaemia and whether mid-trimester testing in selectively tested populations is conducted. The aim of this study was to evaluate the performance of risk factors in identifying women requiring diagnostic testing for GDM, utilising published studies and available individual participant data.We conducted a systematic review and meta-analyses of published studies evaluating risk factors for the identification of women at high risk of GDM. The review was conducted in accordance with the Centre for Reviews and Dissemination’s guidance. We alsoTitle, abstract screening and then full text screening was performed in duplicate by two reviewers  with disagreements resolved by consensus or by a third reviewer.Searches were undertaken up to August 2016 in MEDLINE, MEDLINE in-process, Embase, Maternity and Infant Care and CENTRAL with no date or country restrictions . In addiAll eligible published and on-going observational, cohort, case-control or cross-sectional studies were included. Due to time and cost constraints only studies published in English were included. Studies had to report data from women in whom risk factors for GDM were recorded and who were tested for GDM using an OGTT. We included studies that evaluated readily available/routinely collected maternal characteristics: age, ethnicity, parity, previous GDM, macrosomia, family history of diabetes, BMI and blood pressure. We did not include studies that focused solely on biochemical tests such as the 50g oral glucose challenge test, as these tests are less commonly used in universal pre-diagnostic test screening programmes and are more costly than risk factor screening. We examiNo formal quality assessment process was undertaken because of the lack of any validated quality assessment tool for studies evaluating the performance of risk factors as a screening test; however studies had to report adequate information and that information had to be in a format that allowed comparison with others .Data were extracted by three reviewers  and any disagreements resolved through discussion. Publication year, location, GDM diagnostic criteria, risk factors, cut-off levels of risk factors if appropriate and number of women included with risk factor combinations were recorded. The total number of women with and without GDM according to diagnostic test results and assessment of risk factor performance  were recorded.For each group of risk factor combinations, sensitivity (proportion of GDM cases correctly identified by the risk factor); specificity (proportion of women without GDM correctly identified) and positive rate (proportion of women who would be offered an OGTT if the risk factor combinations were present) were calculated. Statistics were plotted for each study in Receiver Operating Characteristic (ROC) space, by plotting screening performance—sensitivity against positive rate. A ‘good’Data from two birth cohorts were eligible and available. Born in Bradford (BiB)  is a proRisk factors recorded by the IPD cohorts were similar to those recorded by published studies included in the systematic review. We considered seven commonly used risk factors: age; BMI; parity ; ethnicity , family history of diabetes; previous GDM or having had a previous macrosomic infant. We grouped women into white (British/Irish), south Asian or other, as these groupings most appropriately represent the ethnicities of the women in the included cohorts, it should be noted that these groupings may not be appropriate for other populations. Data on previous GDM or having had a previous macrosomic infant were not available in the Atlantic DIP cohort.2 (kilogramme/meter2) or over, or 30kg/m2 or over; because these are the recommended thresholds for overweight and obesity.[We classified BMI using the thresholds of 25kg/m obesity.,27 We us obesity.–31 and aIn addition we also examined screening performance based on a predicted risk of GDM, similar to screening strategies used to identify those at risk of cardiovascular disease. A logistSearches identified 4272 unique citations (7858 before de-duplication). Thirteen additional publications were identified through reference checking. After title and abstract screening, 225 publications were retrieved for full-text screening. One hundred and ninety six full text papers were excluded because they did not meet eligibility criteria, leaving 29 studies , with 21All studies were observational, consisting of a mix of prospective and retrospective cohort studies, with GDM diagnosed using an OGTT, using specified diagnostic criteria. Diagnostic criteria and glucose thresholds varied between studies, which influenced estimates of GDM prevalence. Studies were diverse in their included populations .Figs Figs The odds ratios for the association between each risk factor and GDM for each cohort are shown in When considering risk factors available in both cohorts, the odds ratios were generally consistent, with the exception of non-white/Irish ethnicity, the strength of the association being more than twice that in Atlantic DIP than BiB  origin, half are white British, whereas few women in Atlantic DIP are non-white). ‘Having had GDM in a previous pregnancy’ was most strongly associated with GDM in BiB (this risk factor was not available in Atlantic DIP).The odds ratios shown in To our knowledge, this is the first systematic review and meta-analysis to assess the predictive accuracy of different combinations of risk factors to identify women at high risk of GDM. We found that universal risk factor pre-diagnostic test screening can take a variety of forms, but whatever the form, this strategy did not appear effective for accurately identifying women with GDM. Furthermore we found no evidence that complex risk screening strategies using several risk factors or risk prediction models offered significant benefit over the simpler strategy of identifying one or two risk factors. Regardless of the methods used, correctly identifying most women with GDM, requires offering an OGTT to the majority of women and therefore does not vary considerably from offering all women an OGTT. For some populations however, limiting the offer of an OGTT to high risk women may result in important cost savings.2) would identify the majority of women with GDM, but consistent with our systematic review findings, would mean inviting most women for an OGTT. Although this is as effective as more complex strategies (risk prediction models for example) it may not vary greatly from offering all women an OGTT.Our IPD analyses suggest that the risk factor combination of maternal age and BMI markers that might more accurately identify women at high and low risk of GDM. Until then and if universal offer of an OGTT is not adopted, our results suggest that using age with a cut-off of 25 years (i.e. referring women at or older than 25 years for an OGTT) or who have a BMI of ≥25 or ≥30 kg/mS1 File(PDF)Click here for additional data file.S2 File(PDF)Click here for additional data file.


Editorial on the Research TopicUpdate on the Treatment of Metastatic Non-small Cell Lung Cancer (NSCLC) in New Era of Personalised MedicineWe are honored and privileged to present 11 review articles in the context of “An Update on the Treatment of Non Squamous Non-small Cell Lung Carcinoma (NSCLC) in the era of Personalized Medicine.” Gone are the days when all lung cancers are treated the same. Treatment is now personalized for multiple biomarkers leading to major advances in survival and quality of life.Morin-Ben Abdallah and Hirsh). The benefit in treatment naïve, refractory, and squamous histology is reviewed reflecting a benefit of irreversibly inhibiting all ErbB family members. As we identify resistance mechanisms to both first- and second-generation EGFR TKI’s, the use and benefit of third-generation inhibitors has become standard of care . The treatment paradigm of ALK rearrangement is rapidly changing. This incredible journey is leading to prolonged survival in these patients. With next generation sequencing, rare oncogenic drivers are found and successful drug development has occurred (Daoud and Chu). Histology is itself a biomarker and with multiple mutations now being found, the practicing oncologist is challenged. A series of algorithms will be presented for non-squamous histology (Melosky). Squamous histology deserves its own attention and potential molecular targets and novel agents are explored (Soldera and Leighl).It has been over a decade since the IPASS trial was published showing us that patients with an EGFR mutation fare better with a first-generation EFGR TKI targeted to inhibit that mutation versus chemotherapy. In this update, results of clinical trials of the second-generation EGFR inhibitor, afatinib are explored (Iafolla and Juergens).You cannot mention advances in lung cancer without discussing the amazing story of immune-oncology. Activating one’s own immune system has led to impressive survival in thoracic malignancies. Future investigations combining PD-1/L1 with chemotherapy, targeted therapy, or other immune-oncology agents aim to improve the number of patients to benefit are ongoing (Tabchi and Blais).Targeting angiogenesis is recognized as an effective treatment strategy in a multitude of malignancies including lung cancer. Adding angiogenesis inhibitors to EGFR inhibitors has promising results. Preclinical evidence suggesting an immunosuppressive effect of pro-angiogenic factors leads also to the rationale of adding these agents to immune checkpoint inhibitors (Wong). Thoracic oncologists have had to become experts in systemic therapy of pain. The field of interventional pain management needs to be highlighted as it leads to comprehensive patient care .Addressing and maintaining quality of life has always been on the forefront goal of lung oncologists. Because of this and impact on lifespan, brain metastases have been an important issue to address. Both targeted therapy and immunotherapy have changed the natural history and our treatment in this important metastatic site (Melosky).Finally, carcinoid and atypical carcinoid tumors of lung origin are reviewed as new treatment options exist and education in these rare tumors is lacking (As far as we have come in the past few years, we still have to strive for improvement in patients with advanced disease. Molecular testing for should be standardized. Patients with non-squamous histology and never smokers should have molecular testing to include at least EGFR, ALK, ROS 1, and BRAF. In addition, genes that could and should be tested include RET, HER2, NTRK, and C MET Exon 14 Skip. Driver mutations continue to be discovered and therapeutics directed toward them continue to be developed. We should not stop trying to inhibit KRAS, the most prevalent mutation in adenocarcinoma. Patients with advanced disease squamous histology should also be tested with molecular panels. CMET Exon 14 Skip is just one example of a driver in squamous histology that when identified may be treated appropriately. PD-L1 testing should be done reflexively on all patients. Although immuno-oncology has changed the treatment landscape, many still do not benefit or respond. Combination therapy may be the answer but toxicity must be low. Our goal for our patients it to prolong their survival duration while maintaining a high quality of their life.We welcome you to read this issue. The treatment has become complex but the winner is our patients who are now living longer and sustaining a higher quality of life as their treatment is now focused on their tumor factors. The world of lung cancer has changed dramatically with personalized medicine.The author confirms being the sole contributor of this work and approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Bacteria have evolved sophisticated mechanisms for regulation of metabolic pathways. Such regulatory circuits ensure that anabolic pathways remain repressed unless final products are in short supply and that catabolic enzymes are not produced in absence of their substrates. The precisely tuned gene activity underlying such circuits is in the purview of transcription factors that may bind pathway intermediates, which in turn modulate transcription factor function and therefore gene expression. This review focuses on the role of ligand-responsive MarR family transcription factors in controlling expression of genes encoding metabolic enzymes and the mechanisms by which such control is exerted. Prospects for exploiting these transcription factors for optimization of gene expression for metabolic engineering and for the development of biosensors are considered. In many cases, ligand- and DNA-binding functions reside in the same protein, either within a single domain as seen in members of the multiple antibiotic resistance regulator (MarR) protein family A change in the conformation or flexibility of the transcription factor is elicited upon ligand binding, and this results in altered interaction with cognate DNA and therefore a change in gene expression . Such alThe ability to sense and metabolize specific nutrients confers a fitness advantage, as it avoids costly synthesis of unnecessary enzymes and allows utilization of resources that competing species may not be able to catabolize. In addition, genes encoding enzymes that participate in a specific pathway are often encoded together in an operon, a genome organization that allows concerted regulation of all genes. While metabolic pathways are often conserved, regulatory networks vary between species. This review highlights examples of ligand-responsive MarR family transcription factors that respond to specific pathway intermediates to effect differential gene expression; a particular focus is on MarRs that respond to lignin-derived aromatics, as high resolution structural analyses have been reported that illustrate distinct mechanisms by which binding of structurally related ligands may alter association with cognate DNA. Advances towards optimizing or (re)designing MarR protein function for metabolic engineering or generation of biosensors are discussed.2Escherichia coli Multiple Antibiotic Resistance Regulator, MarR family transcription factors are ubiquitous in the bacterial kingdom Helicobacter pylori does not uncover any MarR homologs whereas the human pathogen Staphylococcus aureus, which can infect multiple ecological niches within the host environment, encodes 18 Named for the E. coli MarR MarR proteins exist as obligate homodimers in which each monomer contributes a winged helix-turn-helix (wHTH) DNA-binding motif. Recognition helices from each DNA-binding motif bind palindromic DNA sequences in consecutive major grooves, with residues in the wing contacting the adjacent minor grooves A [12]. D3Bacteria continuously monitor their environment and cellular metabolic state and modify their gene expression patterns in response to perceived cues. The ensuing changes in gene activity are the result of complex transcriptional networks that may include global regulators that control a large number of transcription units  as well as more specific transcription factors that are dedicated to particular genes 3.1Mineralization of lignin-derived aromatic compounds by soil bacteria is a key step in the terrestrial carbon cycle, and several bacterial species have been characterized that can utilize such compounds as carbon and energy sources Acinetobacter baylyi ADP1, which controls expression of the hca operon that encodes proteins involved in catabolism of the p-hydroxycinnamic acid derivatives caffeate, p-coumarate, and ferulate. Hydroxycinnamates are constituents of lignin and other plant components, and they are precursors in the synthesis of flavonoids. For A. baylyi ADP1 HcaR, the inducing metabolites were reported to be the hydroxycinnamate-CoA thioesters Neisseria NadR, which controls expression of an adhesin that mediates binding to human cells Pseudomonas aeruginosa MexR, which regulates expression of genes encoding the MexAB-OprM efflux pump, suggested that a flexible DNA-binding state is reached only transiently and that ligand-binding shifts the conformational ensemble towards a less flexible conformation that cannot bind DNA One example is the MarR protein HcaR from Rhodococcus jostii RHA1 can also grow on p-hydroxycinnamate derivatives such as p-coumarate. Catabolism requires expression of the cou genes, which are under control of CouR. CouR acts as a repressor, and gene expression is induced on binding of the inducer p-coumaroyl-CoA, but not p-coumarate. Structural analysis revealed binding of two ligand molecules per protein dimer, with no significant structural differences on ligand binding compared to apo-CouR. However, while the phenolic ligand moieties occupy equivalent hydrophobic pockets between DNA-binding and dimerization regions of the protein, the CoA parts extend down and are predicted to interfere sterically with DNA binding as well as impose a charge repulsion  represses multiple genes linked to the citric acid cycle, including the gene encoding aconitase cis-aconitate. Citrate and trans-aconitate levels may increase when the iron-sulfur cluster required for enzymatic activity is damaged by reactive oxygen species, causing accumulation of the substrate citrate and release of the intermediate cis-aconitate, which is then converted to the more stable trans isomer Metabolic pathways are frequently regulated in response to stress, as exemplified by the wide-spread repression of gene activity during the bacterial stringent response, when genes associated with growth are repressed in favor of genes linked to survival 4A thorough understanding of transcriptional regulatory networks responsible for optimizing cellular metabolism is essential, not only from the perspective of bacterial physiology but for optimization of such networks for industrial applications or for generation of biosensors. The interest in metabolic engineering in which existing metabolic fluxes are redirected to target pathways or heterologous pathways are expressed is fueled by prospects for commercial generation of value-added compounds such as biofuels and polymer precursors and by switching to sustainable “green” production. Metabolic engineering of bacteria to produce desirable products is challenging, however, as linked reactions may be adversely affected by channeling intermediates towards a specific pathway, resulting in a failure to maintain metabolic balance and leading to a reduced yield of the desired compound 4.1Hydrolysis of plant biomass is actively considered for generation of renewable energy such as biofuels and for production of aromatic precursors in plastics manufacturing 4.2Synthetic biology, the (re)design and implementation of novel biological devices or circuits, aims to create systems with predictable function. Transcription factors play a major role in biosensor design, since they can be implemented in synthetic circuits controlling gene expression in response to specific ligands. Such synthetic circuits may be designed to control downstream metabolic functions in response to changes in the environment or an imbalance of cellular metabolites. Such circuits have been successfully designed based on bacterial transcription factors with specificity for cellular metabolites. However, redesign of transcription factors to respond to new effector molecules remains a challenge, as changes in the ligand-binding residues required to accommodate novel scaffolds may disrupt allosteric communication with the DNA-binding domain Deinococcus radiodurans HucR. In D. radiodurans, the gene encoding uricase is divergently oriented from hucR; HucR binds urate with low micromolar affinity, a binding event that leads to loss of DNA binding and upregulation of the divergently oriented genes. HucR binds with high affinity and specificity to a single DNA site in the intergenic region spanning genes encoding uricase and HucR Synthetic sensor–effector gene networks may be designed to correct metabolic defects and restore metabolic homeostasis. One successful application of a ligand-responsive transcription factor for this purpose was aimed at treating tumor lysis syndrome or gouty arthritis by sensing and reducing levels of urate in the bloodstream Apergillus flavus uricase, and microencapsulated cells engineered to express this prosthetic gene network successfully reduced serum levels of urate in mice A synthetic mammalian circuit designed to maintain urate homeostasis in the bloodstream was created in which detection of urate by HucR results in derepression of a gene encoding Agrobacterium fabrum encodes a homolog of HucR, named PecS, which binds urate and xanthine with equivalent low-micromolar affinity, and both ligands effectively attenuate the specific binding of PecS to its cognate DNA site HucR binds urate in preference to xanthine, a preference ascribed to conformational changes induced only on binding of a negatively charged ligand 5As exemplified above, MarR family transcription factors frequently bind phenolic compounds. This property makes them ideally suited for regulation of genes encoding enzymes involved, for example, in degradation of lignin-derived aromatics as well as man-made environmental pollutants marR gene promoters, identification of specific ligands may be a challenge. Expanding the inventory of MarR proteins with known DNA- and ligand-specificities promises not only to further understanding of bacterial metabolism, but also to develop a larger repertoire of biosensors with clinical potential.The ability to sense metabolites as a readout of cellular metabolic state makes MarR proteins well suited for the development of biosensors. So far, such detection has relied on the native ligand-specificity, as illustrated by the successful implementation of HucR in several urate-sensing devices. Because these transcription factors are very sensitive to changes that alter the dynamics of the dimer interface, redesign of ligand-specificity may be confounded by resulting changes in communication between ligand-binding pockets and the DNA-binding wHTH motif. While identification of cognate DNA sites for MarR proteins is frequently facile due to the presence of palindromic sequences in


This article reviews and integrates research on gender-related biological, cognitive, and social processes that take place in or between family members, resulting in a newly developed gendered family process (GFP) model. The GFP model serves as a guiding framework for research on gender in the family context, calling for the integration of biological, social, and cognitive factors. Biological factors in the model are prenatal, postnatal, and pubertal androgen levels of children and parents, and genetic effects on parent and child gendered behavior. Social factors are family sex composition  and parental gender socialization, such as modeling, gender-differentiated parenting, and gender talk. Cognitive factors are implicit and explicit gender-role cognitions of parents and children. Our review and the GFP model confirm that gender is an important organizer of family processes, but also highlight that much is still unclear about the mechanisms underlying gender-related processes within the family context. Therefore, we stress the need for (1) longitudinal studies that take into account the complex bidirectional relationship between parent and child gendered behavior and cognitions, in which within-family comparisons (comparing behavior of parents toward a boy and a girl in the same family) are made instead of between-family comparisons , (2) experimental studies on the influence of testosterone on human gender development, (3) studies examining the interplay between biology with gender socialization and gender-role cognitions in humans. Gender is one of the most important organizers of social life  levels have “organizational” and “activational” effects on the child’s gender-typed behavior as reviewed by Hines et al. , 2016b. A small number of studies have linked natural variations in prenatal T levels, measured in maternal blood during pregnancy or amniotic fluid, to variations in both girls’ and boys’ gender-role behavior  has found that these men show impaired social processing, verbal abilities, and cognitive functioning compared to normal controls  socialization and the child’s T levels. Money and Ehrhardt  were amoBiological characteristics of children might also indirectly influence parental gender socialization via child gender-typed behavior. Research on disorders of sex development (DSD)  could provide some evidence in this regard. Children with DSDs provide us with the opportunity to examine whether their hormonally/genetically induced gender-atypical behavior leads to differential treatment by parents and enable us to disentangle effects of genetic sex versus early hormonal exposure on parental socialization. However, the results of the few studies that have been conducted are mixed. Some studies found that parents did not treat their daughters with CAH differently than they treated their unaffected daughters  may expand her stereotypes about what is appropriate behavior for boys and girls , to restore congruence between her stereotypes and behavior . Even though gender roles have become more egalitarian in the past decades, the traditional homemaker–breadwinner division is still visible in current-day families. Mothers are more likely to be the primary caregivers of young children . Experimental evidence indeed supports this hypothesis, showing that children are more likely to imitate same-sex models only in situations when there was consensus within a same-sex group of models and a clear differentiation in behavior compared to a group of the other sex  are rewarded for it than when they (or others) are punished for these behaviors  to the same behaviors in boys and girls, or when parents use different parenting practices with boys and girls, children will learn that boys and girls are different and that certain behaviors are appropriate for boys, whereas other behaviors are appropriate for girls. Both Maccoby and Jacklin  and LyttThere are some unresolved issues in the literature on gender-differentiated parenting. First, it has been argued that fathers might be more involved with gender socialization than mothers  to take into account the possible influence of between-family differences . A series of studies by McHale et al. has demonstrated more gender-differentiated parenting in families with mixed-gender siblings than in families with same-gender siblings in parenting domains of warmth, involvement, and knowledge about children’s activities  and actively construct schemas on the basis of the information that is attended to. Last, GSTs hypothesize that gender schemas influence the way we perceive gendered information and provide social standards that guide behavior. Gender schemas exert their influence for example by processes such as schema-directed memory . Gender schemas also provide a motivation to act in accordance with gender norms, because gender is related to the self-concept and because of the prescriptive nature of stereotypes . From GSTs predictions, one could argue that there is a bidirectional association between gender-related behavior/experiences and gendered cognitions .In the 1970s and 1980s, several versions of gender-schema theory were developed independently from each other , whereas for controversial subjects like gender and race, implicit stereotypes that operate largely outside conscious awareness may be better predictors of behavior than explicit self-reported stereotypes  is present for the internalization of parents’ gender socialization practices into children’s gender cognitions  more favorably than a nonmembership group (the out-group)  and the parent sex configuration . Regarding parent sex configuration, data from the US Census Bureau have shown that the number of single-parent households increased in most Western countries from around 10% in the 1980s to around 30% in 2008  hold less traditional stereotypes about gender and are less traditional in their behaviors than parents in traditional families. Biblarz and Stacey  examinedIt seems reasonable to expect that children in these nontraditional families  would also hold less traditional stereotypes about gender and show less gender-typical behavior. However, meta-analytically there are no significant differences between children with heterosexual or homosexual parents, or between children from single-mother families or families with a mother and a father, with regard to sexual orientation, gender identity, satisfaction with life, and cognitive and moral development  in which the complex issue of child-to-parent and parent-to-child reciprocal effects with regard to gender-differentiated parenting could be examined appropriately. With such studies, it is also possible to empirically test the widely held assumption that parental gender socialization practices have an important impact on the development of gender-typed behavior  to conduct experiments in which T levels are externally manipulated. An opportunity to study the effects of T on parenting experimentally is provided by adolescents or adults with gender identity disorder who receive hormonal treatment to suppress puberty or to enhance cross-gender secondary sex characteristics. As the majority of gender-dysphoric adults do not have children of their own, a paradigm that can be used for this is the Leiden Infant Simulator Sensitivity Assessment . Only then can we be more sure that systematic variations in parenting boys and girls cannot be ascribed to other family variables. More within-family studies are needed to disentangle the effect of child sex on parenting practices from between-family effects. However, these studies need to be designed carefully with attention to age-matching or controlling for birth order effects.In studying gender-related processes in the family context, future researchers should move beyond investigating children’s dyadic interactions with parents or other members in the nuclear or extended family context. Triadic interactions are now widely used to investigate family dynamics, and it has been consistently found that fathers’ and mothers’ behaviors with their child differ when observed in dyads versus triads  and the actual gender socialization behaviors toward their children is scarce. The same is true for studies examining child and parent biological factors, such as testosterone, on gender cognitions. More studies  should investigate associations between gender cognitions and behavior in parents and between parent/child biological factors and gender cognitions. These studies should incorporate implicit measures or neuroscientific measures  of gender cognitions, since for controversial subjects like gender or race implicit stereotypes appear to be better predictors of behavior (Nosek et al., To conclude, our review of the literature has shown that gender is indeed an important organizer of family processes. Based on the review, pathways between gender-related biological, social, and cognitive factors at both the parent and child level have been identified and integrated in a new comprehensive explanatory model of gendered family processes. In addition, the review demonstrated that to date much is still unclear about the mechanisms underlying gender-related processes within the family context, partly due to methodological limitations of previous research. Therefore, future studies should take into account the complexity of gendered family processes, by using advanced research designs, methods, and analytic approaches, studying interactions between biological, social, and cognitive factors in relation to gender-related family processes and child gender development. These studies can draw on the GFP model for pertinent research questions and theoretical grounding of their hypotheses so that we can fully understand how gender influences family processes.


A number of new tuberculosis (TB) vaccines have been or are entering clinical trials, which include genetically modified mycobacteria, mycobacterial antigens delivered by viral vectors, or mycobacterial antigens in adjuvant. Some of these vaccines aim to replace the existing BCG vaccine but others will be given as a boosting vaccine following BCG vaccination given soon after birth. It is clear that the existing BCG vaccines provide incomplete and variable protection against pulmonary TB. This review will discuss what we have learnt over the last 20 years about how the BCG vaccine induces specific and non-specific immunity, what factors influence the immune responses induced by BCG, and progress toward identifying correlates of immunity against TB from BCG vaccination studies. There is still a lot to learn about the BCG vaccine and the insights gained can help the development of more protective vaccines. The BCG vaccine has been used since 1921 to prevent tuberculosis (TB) and is considered to be the world’s most widely used vaccine . Other countries have never given BCG, in order to retain the use of the tuberculin skin test (or the newer IGRA tests) as a means of assessing infection or because the risk of infection is low . BCG scaVaccination of young infants can, however, lead to disseminated BCGosis if the infant is HIV-infected . For thiBCG vaccination immediately or shortly after birth provides consistent protection against the disseminated forms of TB in young children , 13, 14,Mycobacterium avium) (Mycobacterium tuberculosis purified protein derivative (PPD or tuberculin) increases with age, although indurations >10 mm are less frequent in those who are BCG vaccinated  . Skin teccinated . It is wccinated , 23; howccinated .Mycobacterium bovis bacille Calmette Guerin was kept in culture for many years before it was properly conserved and seed lots were preserved by lyophilization. It was distributed to different locations worldwide where further culture resulted in what are now known as BCG Russia, Japan, Copenhagen, etc. Improved sequencing methods have shown that further genetic events have occurred in these strains, including additional genetic deletions  cultures from those vaccinated with different BCG vaccine strains . A study in West Africa found that batches of BCG showing slower growth were associated with larger BCG scars, and a higher prevalence of positive PPD skin test responses in the Mantoux skin test . Issues There has been interest in the benefits of administering BCG for reasons other than as a vaccine against TB for many years. For example, BCG vaccine can be instilled into the bladder where it is an effective immunotherapy against non-muscle invasive bladder cancer , 40. BCGStudies in West Africa have indicated that BCG vaccination may have beneficial effects on all-cause mortality in infants, although the effects were most marked in low birth weight infants . Until rin vitro have been shown to cooperate with dendritic cells to enhance antigen-specific T-cell responses  however the differences became less apparent when samples were obtained later, at 9 months of age . In contAlthough most of these studies have investigated immunogenicity rather than protection, a large study based in South Africa that recruited 5,726 BCG-vaccinated infants and followed them for 2 years, has enabled correlates of risk of disease to be investigated more directly. In this cohort, the proportion of polyfunctional T-cells in BCG stimulated cultures was not associated with reduced risk of developing TB disease . DespitePerhaps as a response to the lack of confirmed T-cell correlates of protection induced by BCG vaccination, there is renewed interest in B-cell immunity in TB, which as noted above has been under-studied. Although antibodies have not provided useful diagnostic tests for TB, expression of B-cell-associated genes are modulated during TB treatment  and the in vitro expansion of lymphocytes with relevant antigens prior to incubation with BCG-infected monocytes. PBMC previously stimulated with mycobacterial whole cell lysate or live BCG induced infected monocytes to control the growth of BCG better as did previous BCG vaccination of donors themselves  were incubated with live BCG and growth inhibition determined by Bactec MGIT analysis. The study reported that PBMC from adults who had received primary BCG did control mycobacterial growth better ex vivo than unvaccinated controls  and are unbiased in the sense that they do not focus on any given immune component. Early interest in mycobacterial growth inhibition as a surrogate marker of protection involved the emselves . In anotcontrols . In a stcontrols . Despitecontrols . The conlive BCG , 118. Suesponses .As discussed above, population differences exist in adult and infant immune response to BCG –93 howevAlthough there is opportunity in the fact that BCG vaccination demonstrates protective efficacy in infants and in adults in some geographical locations, there are clearly some host-related factors that modify immune responses to BCG and give rise to significant heterogeneity. Until we understand these factors better and take them into account, it will be difficult to identify broadly relevant correlates of protection in BCG-vaccinated cohorts.Although there has been much progress over the last 20 years, we are still unable to identify BCG-induced correlates of protection in vaccinated infants. This remains a priority area for further research, as it is possible that the development of effective boosting TB vaccines could be abandoned simply because we have yet to discover the essential aspect of BCG-induced immunity to TB that should be boosted. Similarly, a better understanding of BCG-induced correlates of protection will help novel, live mycobacterial vaccines avoid the pitfalls that have caused BCG to fail in certain settings. To date, the search for BCG-induced correlates has been far too simplistic. However, the advent of more detailed immune and memory cell phenotyping obtained using mass cytometry  and the HD and SS wrote, edited, and approved the final version of this article.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Entamoeba histolytica is a protozoan parasite and human pathogen that kills human cells in a nibbling-like process termed amebic trogocytosis. We have recently found that amebic lysosomes play a key role in amebic trogocytosis and cell killing. Impairing lysosome acidification with pharmacological inhibitors dramatically decreased amebic trogocytosis and cell killing. Our data suggest that these inhibitors do not block the ingestion of an initial fragment, but rather prevent continued trogocytosis and the ingestion of multiple fragments. These findings raise a number of interesting biological questions, notably how do lysosomes function in amebic trogocytosis? A deeper understanding of the role of lysosomes in trogocytosis could provide interesting insights into trogocytosis as a fundamental biological process.Trogocytosis, the intracellular transfer of fragments of cell material (including intact proteins but not whole cells) has been implicated in both microbial pathogenesis and the host defense against pathogens. Although trogocytosis has been observed in a number of organisms, from humans to amebae, the process remains poorly understood. Entamoeba histolytica causes potentially fatal diarrhea, dysentery and liver abscesses in humans E. histolytica infection, manifesting as massive intestinal ulceration and abscesses at other sites. This tissue destruction is likely driven by amebic trogocytosis 2+ Naegleria fowleri, a human parasite that may use this process to destroy host cells, but again the mechanism is unknown 6Plasmodium falciparum-infected red blood cells has been implicated in the pathogenesis of cerebral malaria 67Francisella tularensis Trogocytosis has been observed in a number of other organisms. In humans, trogocytosis has been observed in lymphocytes, including T-, B-, NK and dendritic cells. In lymphocytes, trogocytosis has been implicated in cell-cell communication (with ingestion of the T cell receptor complexed with HLA from antigen presenting cells implicated in sustained activation of T cells) and defense against pathogens 3E. histolytica with the less-pathogenic species Entamoeba dispar have noted that acidification of the phagosomes takes significantly longer in E. dispar and does not reach the same level of acidification, suggesting a role for lysosomes in the pathogenesis of amebiasis Early research indicated that inhibiting amebic lysosomal acidification impaired amebic killing of human cell Leishmania 11. Thus it is possible that lysosomes are crucial for continued amebic trogocytosis and cell killing because they are required for efficient degradation of the ingested host fragments.There are several possible roles that lysosomes might play in amebic trogocytosis : lysosomes might be required for efficient degradation of the ingested fragments, for rapid recycling of ingested receptors and membrane, or for the rapid formation of an acidified synapse at the site of ameba-host interaction. During amebic trogocytosis, parasites ingest numerous host cell fragments, which must be degraded. In eukaryotes, it is well established that lysosomes are crucial for the turnover of ingested material. Breakdown of material in the lysosome requires lysosomal enzymes, many of which are pH-dependent. Weak bases, such as the ammonium chloride used in our studies, raise the pH of amebic lysosomes, which would impair the function of pH-dependent lysosomal enzymes Previous work has shown that trogocytosed fragments are surrounded by amebic membrane, likely derived from the amebic plasma membrane It has been suggested that amebic lysosomes may form an acidified synapse at the site of host cell attachment similar to the synapse created by mammalian osteoclasts, which secrete lysosomes into an acidified synapse during bone matrix degradation In conclusion, this work sheds new light on an observation, first made 30 years ago, that weak bases inhibit amebic killing of human cells, by demonstrating that acid vesicle neutralization acts through the inhibition of trogocytosis. This work raises several interesting questions and further investigation will contribute to a better understanding of the nature of trogocytosis as a fundamental biological process.


In spite of the inherent difficulties in achieving a biologically meaningful definition of consciousness, recent neurophysiological studies are starting to provide some insight in fundamental mechanisms associated with impaired consciousness in neurological disorders. Generalised seizures are associated with disruption of the default state network, a functional network of discrete brain areas, which include the fronto-parietal cortices. Subcortical contribution through activation of thalamocortical structures, as well as striate nuclei are also crucial to produce impaired consciousness in generalised seizures.