Lay support has been associated with improved breastfeeding practices, but studies of programs that engage men in breastfeeding support have shown mixed results and most are from high-income countries. The purpose of our research is to review strategies to engage men in exclusive breastfeeding (EBF) promotion or support in 28 project areas across 20 low- and middle-income countries. This information may be used to inform program implementers and policymakers seeking to increase EBF.a = 0.05) and identified project areas with a significant increase. We categorized male engagement strategies as low- and high-intensity, using information from project reports. We looked for patterns by intensity and geography and described strategies used to engage men in different places.We tested the difference between baseline and final EBF proportions using Pearson’s chi-square  were in areas where a statistically significant increase in EBF was observed between the beginning and end of the project. A variety of high- and low-intensity male engagement strategies was used in areas with an increase in EBF prevalence and in all geographic regions. High-intensity strategies engaged men directly during home or health visits by forming men’s groups and by working with male community leaders or members to promote EBF. Low-intensity strategies included large community meetings that included men, and radio messages, and other behavior change materials directed towards men.Male engagement strategies took many forms in these project areas. We did not find consistent associations between the intensities or types of male engagement strategies and increases in EBF proportions. There is a gap in understanding how gender norms might impact male involvement in women’s health behaviors. This review does not support the broad application of male engagement to improve EBF practices, and we recommend considering local gender norms when designing programs to support women to EBF. Gender factors affect maternal and child health in many ways and often manifest in terms of gender inequality through control of resources, decision-making, and access to health information, which can affect behaviors that in turn affect the mother’s and her child’s health . The relA key constraint to EBF in some lower- and middle-income countries (LMIC) is lack of knowledge and support from household members who wield authority over many household practices, including infant feeding decisions, particularly fathers and grandmothers –13. TherThe few studies conducted in LMIC showed positive EBF outcomes when men were included in interventions. An intervention in Vietnam providing fathers with breastfeeding education materials, counseling, and household visits found significantly higher EBF at 4 and 6 months, compared to mothers whose partners were not in the intervention group . SimilarSince 1985, the United States Agency for International Development’s (USAID) Child Survival and Health Grants Program (CSHGP) has supported nongovernmental organizations’ (NGO) efforts to reduce maternal and child morbidity and mortality through interventions designed to address health issues, including EBF. USAID provides technical assistance to NGOs in designing, implementing, monitoring, and evaluating these projects, and maintains a database for project information.The purpose of our research was to review strategies to engage men in supporting the practice EBF by their partner in 28 CSHGP project areas in 20 LMIC. This information may inform program implementers and policymakers seeking to increase EBF practices. Documenting and disseminating results from community-based programs in a variety of country contexts can inform strategies to reach global goals to reduce preventable child deaths.We included all CSHGP projects beginning and ending between 2003 and 2013 that (1) reported engaging men in EBF support, (2) were conducted in LMIC in sub-Saharan Africa, Southeast Asia, South and Central Asia, or Latin America/Caribbean regions, and (3) had complete survey data. We considered survey data complete if the questions included the number of infants under 6 months of age who were exclusively breastfed in the previous 24 h, and the total number of infants under 6 months of age in the survey, with no indication of data quality concerns in the final evaluation report. The University of North Carolina’s Institutional Review Board (IRB) determined that this study was not human subject research and does not require IRB approval. It is an analysis of secondary data (project reports) with no personal identifiers.a = 0.05.Each NGO conducted population-based knowledge, practice, and coverage surveys in their project areas at the beginning and end of their projects. These surveys were designed and conducted with assistance from USAID and employed a standardized methodology, including obtaining informed consent and data collection instruments designed by survey sampling and design experts . NGOs usWe extracted qualitative information about EBF promotion and support strategies from project reports and thematically analyzed it to aid interpretation of our results. Our primary search terms included men, husband(s), father(s), exclusive, breastfeeding, and LAM . If searching for men, husband(s), and father(s) yielded no results, we searched for family, partner, male, and decision-maker. Upon identification of keywords in the text, we reviewed the report and any relevant annexes to ascertain the strategies used to engage men. We populated a matrix with information extracted from the reports related to male roles, EBF promotion or support activities that engaged men, activity frequency and timing, intensity of male engagement strategy, as well as quotes about male engagement or lack of male engagement, other EBF promotion or support activities, and other project health activities that did not engage men. We then organized male engagement activities by intensity and geographic region. We categorized male engagement strategy into three levels by intensity: none, low, and high. “Low” included indirect male engagement strategies such as general mass outreach efforts such as community health fairs and mass media campaigns; “high” included male engagement strategies with direct personal contact, such as interpersonal communication through home visits or through groups such as community-based organizations.Twenty-eight projects that reported strategies to engage men to promote or support EBF were included Fig. . FifteenHigh-intensity male engagement strategies were reported by 20 projects , radio messages , or other behavior change messaging and materials . Six (75%) of the projects reporting low-intensity strategies to engage men worked where EBF prevalence significantly increased. One such project used a combination of low-intensity strategies with high frequency, including monthly community meetings and other behavior change communication materials .Eleven project reports also documented other strategies used to promote and support breastfeeding. These other strategies included training other influencers, such as mothers-in-law, strengthening community health workers’ capacities, and promoting behavior change in communities with various messages and media.This study reviewed projects that employed strategies to engage men in EBF promotion and support in several geographic settings and calculated EBF prevalence changes in project areas. No clear pattern emerged, in terms of increased EBF prevalence where certain strategies were employed or in the choice of strategies in different geographic areas. In addition, not every project area had an increase in EBF prevalence.We do not know how effective the reported male engagement strategies were in engaging men because this type of analysis was not conducted as part of the project evaluations. Several independent project evaluators commented on male engagement, or lack of male engagement, in their final evaluation reports, with most indicating approval of male engagement to promote or support EBF. Only one comment considered having male volunteers speak with mothers about breastfeeding techniques as potentially inappropriate . The final evaluator for Care’s project in Sierra Leone noted that the concerted effort during project planning to include household decision-makers (men and older women) in the project approaches contributed to the adoption of positive health behaviors among women, which was revealed by women in project focus group discussions.With increased emphasis on male involvement in the reproductive health care and decisions in global health, it is important to understand where engaging men as a social and behavior change approach, broadly speaking, may support EBF practice and if it could hinder it. This study provided a mainly descriptive review of strategies, and we conclude that, unlike peer support, professional support in the antenatal and postpartum periods, and other evidence-based strategies , engaginOne cannot consider male engagement in women’s health issues without considering the gender norms that govern relationships in households and communities. Less than one-quarter of these projects reported using formative research to inform their strategies Table . FormatiThe impact of gender norms on women’s infant feeding practices is not well understood. Meanwhile, there is some evidence that high rates of child stunting (low height for age) can co-exist with relatively high values for positive indicators of child health, such as immunization coverage . StuntinThere is evidence of male, specifically fathers’ , influence on infant feeding practices , 38. We Conceptual theory about male engagement in EBF promotion and support is not well developed, and we do not know if the reported male engagement strategies effectively engaged men. We did not attempt an advanced quantitative assessment of the association of male engagement strategies with EBF prevalence changes but merely report those associations as part of our descriptive approach to documenting efforts to engage men in EBF promotion and support in LMIC. National or local campaigns to increase EBF may have contributed to prevalence changes in project areas, although we did not find evidence of such efforts in the project final evaluation reports. Nonetheless, we were careful not to ascribe EBF prevalence increase to these projects’ efforts. All project final evaluation reports were program evaluations and not impact evaluations; therefore, the true extent of the impact of the strategies to engage men is unknown beyond the conclusions drawn in the reports. We did not specifically examine or describe how male engagement strategies could have a detrimental effect on EBF practice nor where male involvement in infant feeding decisions reinforces gender inequality, but these questions merit further research.If considering implementation on a national scale, it would be important to evaluate the effectiveness of male engagement strategies and conduct multiple tests in different areas to determine if strategies are scalable. More comparative studies and impact evaluations are needed within countries to determine which strategies are most effective at promoting and supporting EBF with different populations. Contextual information about societal dynamics can indicate where and with whom interventions are most efficiently targeted . SpecifiIt is important to understand the association between gender norms, male engagement strategies, and EBF prevalence in different contexts. This study augments the literature on this topic by reviewing an array of strategies that have been used in different LMIC. Together, these studies point to the importance of formative research about local gender norms and power structures to inform interventions. With increased emphasis on male involvement in reproductive health care and decisions in different settings, the question of for whom to focus promotion messages and supportive skills merits further research in order to determine the most appropriate and effective way to support EBF.


Nicotiana tabacum, Arabidopsis, Lilium longiflorum), which have been studied far more extensively and grow much faster than structurally strikingly different gymnosperm pollen tubes. Only major transport pathways are considered, which substantially contribute to the mass-flow of membrane material at the pollen tube tip. Growth oscillation, which may be displayed in particular by fast-growing pollen tubes, are not discussed as their influence on the spatial organization of apical membrane traffic is not understood.Pollen tube tip growth is a widely used model ideally suited to study cellular processes underlying polarized cell expansion. Local secretion supplying material for plasma membrane (PM) and cell wall extension is essential for this process. Cell wall biogenesis requires fusion of secretory vesicles with the PM at an about 10× higher rate than PM extension. Excess material is therefore incorporated into the PM, which needs to be reinternalized through endocytosis. The classical model of tip growth proposes that exocytosis occurs at the apex and that newly incorporated PM material is transported to adjacent lateral regions, where excess material is endocytically recycled. This model was recently challenged based on studies indicating that lateral exocytosis may be balanced by apical endocytosis. This review provides an overview of published data pertaining to exocytosis, endocytosis and vesicular trafficking in pollen tubes. Its key aim is to present classical and alternative models of tip growth in the light of available experimental data. By necessity, the review focusses on pollen tubes of angiosperm models ( Figure 1; Pollen tubes have a crucial function in the fertilization of higher plants during which they act as a conduit to deliver genetic material from the site of pollination through the transmitting tract of the style to ovules. Formed as a highly elongated outgrowth upon germination of a pollen grain, pollen tubes rapidly expand exclusively in one direction. This extreme form of polarized cell expansion, which is commonly called tip growth, is based on massive secretion taking place at the tip  pollen tubes using evanescent wave microscopy in fact strongly supported complete incorporation and did not provided any evidence for kiss-and-run temporary fusion  strongly accumulates in the vesicle rich inverted cone-shaped region at the apex, before it can eventually (after 12 h) be detected in vacuoles , which in plant cells not only generates secretory vesicles but also serves as early endosome , were concentrated in a lateral region spanning from 6 to 15 μm behind the extreme apex . According to the alternative model , in addition to lateral endocytosis, which is also supported by the classical model , endocytosis also takes place at the apex while secretion is confined to a lateral region immediately adjacent to the flanks of the apex. Membrane material newly inserted into the PM at this site is proposed to enable PM extension by traveling in anterograde direction toward the apex, where excess material is endocytically internalized  microscopy as well as FRAP analysis of FM1-43 stained endomembrane compartments. Based on the observed patterns, the authors also suggested that during pollen tube tip growth, endocytosis may occur not only laterally but also apically, whereas secretion may be focused on a lateral region.Evidence for the alternative model is largely based on time-lapse fluorescence microscopic analysis of the internalization of red fluorescent FM4-64 into rescence . Minutesrescence . To supprescence . Bove etN. tabacum pollen tubes. By contrast to positively charged particles, which appeared to be endocytosed laterally (see previous chapter), negatively charged particles were described to be detected in the lumen of vesicles in the inverted cone-shaped zone at early time points after application, and within vacuoles at later time points. Based on these observations, the authors proposed that endocytosis is also occurring at the pollen tube apex and serves to transport material to the vacuole for degradation.Additional evidence supporting endocytic membrane internalization at the pollen tube apex was provided by A large amount of evidence is supporting the classical model of pollen tube tip growth proposing apical secretion and lateral endocytosis. However, with the introduction of an alternative model suggesting that lateral secretion may be balanced by apical endocytic membrane recycling, tip growth must be reinvestigated with respect to the exact location of sites of exocytosis and endocytosis. To this end, the dynamic behavior of membrane trafficking markers such as transmembrane proteins fused to a fluorescent protein, FM4-64 and fluorescently labeled membrane lipids needs to be further characterized in growing pollen tubes using advanced fluorescence microscopy methods (FRAP and photoactivation/photoconversion experiments) in conjunction with pharmacological analysis (application of exocytosis or endocytosis inhibitors).BK and GG developed the concept of this review. GG wrote the text with the support of BK. MN contributed ideas and critical revision.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 declared a shared affiliation, though no other collaboration, with the authors and states that the process nevertheless met the standards of a fair and objective review.


Magnetic resonance imaging (MRI) is a valuable translational tool that can be used to investigate alterations in brain structure and function in both patients and animal models of disease. Regional changes in brain structure, functional connectivity, and metabolite concentrations have been reported in depressed patients, giving insight into the networks and brain regions involved, however preclinical models are less well characterized. The development of more effective treatments depends upon animal models that best translate to the human condition and animal models may be exploited to assess the molecular and cellular alterations that accompany neuroimaging changes. Recent advances in preclinical imaging have facilitated significant developments within the field, particularly relating to high resolution structural imaging and resting-state functional imaging which are emerging techniques in clinical research. This review aims to bring together the current literature on preclinical neuroimaging in animal models of stress and depression, highlighting promising avenues of research toward understanding the pathological basis of this hugely prevalent disorder. Major depressive disorder (MDD) is a chronic, heterogeneous disorder with a diverse range of risk factors including genetic predisposition, stress, early life experiences, and environmental factors. MDD often presents with co-morbid anxiety and is linked to several somatic disorders including pain, insomnia, cardiovascular disease, and gastritis. Current antidepressant treatments are inadequate with a delayed onset and a large proportion of patients being treatment resistant. The pathophysiology of MDD remains to be fully elucidated and the development of more effective therapeutics depends on a better understanding of the molecular underpinnings of the disorder. Magnetic resonance imaging (MRI) is a safe, non-invasive technique that can provide valuable information on structural and functional changes in the human brain. MRI is commonly used in patients with MDD to assess changes in brain structure and function relating to symptom severity and treatment response. Alterations in the morphology of brain structures, particularly the hippocampus, have been frequently reported, in addition to differences in microstructural integrity, network connectivity, cerebral blood flow, and metabolite concentrations , have some relevance to the etiological basis of the disorder  and finally respond similarly to treatments . Animal models can therefore be a useful tool to investigate the underlying pathophysiology or potential of novel therapeutics.1A-R KO) mouse, although not considered a model of depression, is one such manipulation used to investigate the neural circuits affected by altered serotonin transmission.Several techniques have been used to induce depressive-like symptoms in animals including acute exposure to stressors as well as more chronic interventions that reflect aspects of depression etiology such as stress or genetic manipulation. The forced swim test (FST) is a paradigm based on the observation that animals who are faced with an inescapable stressor will desist from attempting to escape after a period of time. Once a rodent is placed in a large container of water from which they cannot escape they will initially vigorously attempt to escape, but will then cease escape orientated behaviors and the immobility seen in the FST has been reported to reflect “behavioral despair.” Antidepressant treatments have been shown to reduce immobility time and therefore the FST has been used as a rapid screen for antidepressant activity in novel compounds. The FST test however has very little construct validity for depression as it does not have any etiological relevance to the disorder. Therefore, more relevant interventions have been developed to induce a depressive-like phenotype in animals and the FST is used as a behavioral measure in these. A well characterized model for depression is the olfactory bulbectomized (OB) rat which involves bilateral removal of the olfactory bulbs, resulting in retrograde degeneration of neurons that project from the olfactory bulbs and loss of efferent connections to sub-cortical brain structures. This, combined with loss of olfaction which may constitute a profound stressor, produces a depressive-like and highly agitated behavioral phenotype which is associated with alterations in endocrine and neurotransmitter levels similar to those reported in depressed human patients  rat is an inbred rat strain with an inherent anxiety- and depressive-like behavioral phenotype. Reduced hippocampal volume has also been linked to anxiety-like behavior, with mice bred for high anxiety showing reduced hippocampal volume compared to those bred for low anxiety traits , bed nucleus of the stria terminalis (BNST) and the dorsal raphe nucleus (DRN) positively correlate with social avoidance scores in animals, indicating that these areas may be linked to stress vulnerability  diet (KD) during pregnancy. Whilst small structural changes were observed at weaning (PND 21.5), KD offspring showed increased frontal cortical and cerebellar volume, but interestingly, decreased volume of the hippocampus, striatum, and some cortical areas in adulthood  allows for an assessment of Currently, tractography studies show that first episode depressed patients exhibit increased cortico-limbic structural connectivity  which attempts to account for biological variation in water diffusion and provide a more accurate model of diffusion, have both identified alterations in microstructural integrity in animal models of depression. Common metrics reported in DTI and DKI studies are mean diffusion or kurtosis across all directions (MD or MK), radial diffusion or kurtosis  and axial diffusion or kurtosis . Although, interpretation of diffusion imaging has not been fully explored, microstructural organization of the brain, including cellular membranes, myelinated axons, intracellular organelles, and dendritic architecture, affects the orientation of water diffusion.DTI and DKI studies have identified alterations in the microstructural integrity of gray matter regions in rats exposed to CMS. Increased mean diffusion values in the bilateral frontal cortex, hippocampus, hypothalamus, caudate putamen and corpus callosum were reported in rats exposed to CMS compared to control animals, which may relate to reduced membrane density or tissue degeneration  decreased glutamate MR signal in the right hippocampus  of cLH rats  on metabolite concentrations, however no difference between MS animals and controls was observed however both environmental enrichment and escitalopram treatment increased NAA levels in the  levels can be indicative of glial cell function or proliferation and it has been considered a proxy marker of inflammation , a marker commonly used to indicate neuronal integrity have also been reported, with decreased hippocampal NAA levels following both mild and unpredictable chronic stress paradigms  provides a tool to map regional changes in cerebral blood flow at resting state, i.e., in the absence of task execution. Depressed patients have been reported to have decreased dorsolateral prefrontal cortex activation  signal is commonly used as surrogate marker of neuronal activation. Recent studies have shown altered BOLD signal intensity in several brain regions involved in mood regulation following exposure to early-life adversity or stress. Hui et al.  and the hippocampus . Similarly, reduced functional correlations were observed between the dorsomedial thalamus and both the cortex and hippocampus  is an emerging neuroimaging technique that exploits the capability of manganese (Mn) ions to enter excitable cells through voltage-gated calcium channels. As Mn ions decrease water longitudinal relaxation time this uptake can be visualized by MRI and as such MEMRI is being increasingly used in preclinical studies to investigate alterations in functional networks. Daducci et al.  showed tHigh resolution MRI has revealed discrete reductions in regional cerebral blood volume (rCBV) in the left habenula, particularly the lateral area, and increased rCBV in the bed nucleus of the stria terminalis (BNST) in the congenital learned helplessness (cLH) model of depression  reuptake inhibitor (SSRI) fluoxetine  in rats , and although progress is being made (Ioanas et al., Finally, it is worth highlighting that one of the benefits of animal models is the ability to use invasive techniques and given the limitations described above, preclinical MRI may not always be the best tool for delineating certain aspects of the pathophysiology. Tools such as optogenetics (Touriño et al., This review describes the recent findings in preclinical neuroimaging in animal models of stress and depression and highlights modalities that are particularly promising in translating results from animal models to clinical studies. Advances in preclinical models of depression with MRI-related changes reflecting the human condition, will further our understanding of the pathophysiology of MDD, and potentially uncover novel opportunities for drug development. Furthermore, this review emphasizes the potential for multi-modal MRI as a tool to highlight detectable physiological markers which may be useful indicators or susceptibility and lead to the development of clinical strategies that allow for patient stratification and tailored therapeutic strategies.AM and SG prepared an initial draft of the animal section and LT prepared an initial draft of the clinical section of the manuscript. TF and AH contributed to writing all sections, and oversaw revisions and preparation of the final 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. The reviewer BS and handling Editor declared their shared affiliation, and the handling Editor states that the process nevertheless met the standards of a fair and objective review


Airway remodeling is generally quite broadly defined as any change in composition, distribution, thickness, mass or volume and/or number of structural components observed in the airway wall of patients relative to healthy individuals. However, two types of airway remodeling should be distinguished more clearly: (1) physiological airway remodeling, which encompasses structural changes that occur regularly during normal lung development and growth leading to a normal mature airway wall or as an acute and transient response to injury and/or inflammation, which ultimately results in restoration of a normal airway structures; and (2) pathological airway remodeling, which comprises those structural alterations that occur as a result of either disturbed lung development or as a response to chronic injury and/or inflammation leading to persistently altered airway wall structures and function. This review will address a few major aspects: (1) what are reliable quantitative approaches to assess airway remodeling? (2) Are there any indications supporting the notion that airway remodeling can occur as a primary event, i.e., before any inflammatory process was initiated? (3) What is known about airway remodeling being a secondary event to inflammation? And (4), what can we learn from the different animal models ranging from invertebrate to primate models in the study of airway remodeling? Future studies are required addressing particularly pheno-/endotype-specific aspects of airway remodeling using both endotype-specific animal models and “endotyped” human asthmatics. Hopefully, novel in vivo imaging techniques will be further advanced to allow monitoring development, growth and inflammation of the airways already at a very early stage in life. On the basis of disability-adjusted life years, the impact of asthma is estimated being similar to other major chronic diseases such as diabetes or Alzheimer disease ” revealed that, in 1993, the first two papers falling into this category were published and that numbers slowly increased to 203 in 2007. Since then, the number of papers per year are on a relatively constant level of between 200 and 240, which represent only approx. 15% of all publications on “asthma AND airway”. Notably, among these publications, about 50–60 per year are review papers, i.e., 20–40% of all publications. To avoid carrying coals to Newcastle, in the present review we will not try to review everything already well reviewed by others Elias . InsteadThe perception of bronchial asthma has fundamentally changed during the last decade. Consequently, the Global Initiative for Asthma (GINA) suggested a new definition of asthma: “Asthma is a heterogeneous disease, usually characterized by chronic airway inflammation. It is defined by the history of respiratory symptoms such as wheeze, shortness of breath, chest tightness and cough that vary over time and in intensity, together with variable expiratory airflow limitation”  asthmatics  and the European Respiratory Society (ERS) published an Official Research Policy Statement paper that critically reviewed the state-of-the-art stereological methods in lung morphometry and defined standards to promote comparability of morphometric studies in pulmonary research  of airway smooth muscle cells in the pathogenesis of asthma symptoms, in particular with regard to airway hyperresponsiveness, has been comprehensively reviewed by others   exposures to various stressors increase the risk of children to develop deficits in lung function, which in the long run may lead to chronic respiratory diseases such as bronchial asthma  or to clinically more relevant allergens such as house dust mite (HDM), ragweed or cockroach. Once the animal has been sensitized and develop an adaptive Th2 cell-dominated immune response, allergic airway inflammation is directed to the airways by short-term allergen aerosol inhalation or local application of an allergen containing solution. Such short-term models include allergic airway inflammation with infiltration of eosinophils and Th2 cells, increased mucus production and airway hyperresponsiveness (AHR) and thus display key hallmarks of human allergic asthma. However, these models are limited by their short-term nature and, thus, fail to reflect signs of chronicity like chronic airway inflammation, intra-epithelial eosinophils and airway remodeling.Mus musculus) to an OVA-aerosol for 20 min twice a week for 12 weeks and recorded a change of the inflammatory pattern in the airways as well as signs of airway remodeling  or a sensitization protocol that has been used to indicate that once the animal has been sensitized structural changes of the lung are induced by perseverative allergen provocation  to asthma pathogenesis. Consequently, the role of Th2-type cytokines has been investigated in detail by subjecting genetically modified animals to the protocol for the induction of chronic experimental asthma. Thus, allergen-sensitized animals lacking either IL-5 or IL-13 developed significantly less airway remodeling compared to wild-type animals after chronic allergen challenge  in the lung also produced marked airway remodeling. Hence, conditional overexpression of TFG-β in airway epithelium using a tetracycline-controlled suppressor and reverse tetracycline transactivator system led to profound inflammation of the airways associated with increased collagen deposition, enhanced numbers of myofibroblasts and myocytes in the airway wall and elevated apoptosis of epithelial cells. Lung-targeted VEGF transgenic mice showed an asthma-like phenotype characterized by airway inflammation and AHR together with goblet cell hyperplasia, edema, smooth muscle cell hyperplasia and parenchymal and vascular remodeling  that were systemically sensitized to OVA using alum and Bordetella pertussis vaccine as adjuvants, an increased airway smooth muscle mass in intrapulmonary airways was already observed after three OVA aerosol challenges at day 24  and horse . Thus, approximately 1% of the feline population develops a disease characterized by episodes of coughing, mucus hypersecretion and broncho-obstruction and displays AHR as well as airway eosinophilia (Padrid Ascaris suum (AS) allergen and induced allergic airway inflammation by AS for aerosol inhalations. The authors found increased activity of matrix-metalloprotease (MMP) 9 and a significant age-related increase in interstitial and total radiographic score as assessed by radiography suggesting ongoing airway remodeling processes.Particularly interesting animals for modeling human bronchial asthma are species that spontaneously develop idiopathic forms of asthma such as cat  offer the advantage that monoclonal antibodies against human gene products display considerable cross-reactivity with primate antigens. Furthermore, one can argue that lung anatomy and physiology of the rhesus monkey is even closer to humans then that of quadrupeds like cats, dogs, sheep and horses. Thus, rhesus monkeys have also been utilized to establish models of allergic bronchial asthma and represent an important part of pre-clinical drug testing. The group of Plopper and Hyde at UC Davis sensitized rhesus monkeys to HDM allergen by subcutaneous and intra-muscular injections with alum and Bordetella pertussis as adjuvants followed by two intra-nasal applications of HDM solutions and exposure to HDM aerosol for 11 weeks with three exposures a week. Besides allergic airway inflammation, Th2-type cytokine production and development of AHR, this protocol also resulted in airway remodeling with goblet cell hyperplasia, increased thickening of the basement membrane zone, smooth muscle hypertrophy, enhanced subepithelial vascular density and VEGF expression in the airways as well as elevated density of epithelial nerves , which is the most crucial signaling pathway in mediating epithelial immune responses in the fruit fly  in the airway epithelium by crossing a fly line tagging the airway epithelium specifically to a line carrying the gene of interest. Thus, this simple non-vertebrate model exhibits a very promising potential to decipher, e.g., the functional relevance of novel candidate genes suggested to be implicated in airway epithelial remodeling.Evidence has increased that asthma can no longer be considered as a single disease entity but rather as a syndrome comprising several pheno-/endotypes, which are characterized by distinct underlying molecular mechanisms. Whether distinct features of airway remodeling are linked specifically to certain pheno-/endotypes awaits future investigation. Hopefully, such studies will implement design-based stereology, which has challenged some traditional views deduced from assumption-based methods, for a reliable assessment of airway remodeling. A plethora of data was collected from both human and animal studies supporting the notion that airway remodeling can be the result of an inflammatory process. However, more and more studies suggest that airway remodeling may alternatively evolve as a primary event initiated very early in life in the absence of any symptoms or of any detectable inflammation. With the advancement of novel in vivo imaging techniques, monitoring of the development and growth of the airways as well as of airway inflammation will be feasible so that our present knowledge on the initiation of airway remodeling can be expected to be significantly expanded. The broad range of animal models presently available from invertebrate to primate species shall be considered as an extraordinary armamentarium giving us the opportunity to select the appropriate model in the context of the specific question to be answered rather than trying to identify “the one-and-only asthma model”, which in an asthma pheno-/endotype world appears to be quite out-dated.


Science (2015), 347(6225)] we find that mutations that facilitate cross-talk between pathways can contribute to gene network evolution, but that such mutations come with severe pleiotropic costs. Arising from this work are a number of questions surrounding how this phenomenon occurs.Bacteria have evolved complex regulatory networks that enable integration of multiple intracellular and extracellular signals to coordinate responses to environmental changes. However, our knowledge of how regulatory systems function and evolve is still relatively limited. There is often extensive homology between components of different networks, due to past cycles of gene duplication, divergence, and horizontal gene transfer, raising the possibility of cross-talk or redundancy. Consequently, evolutionary resilience is built into gene networks - homology between regulators can potentially allow rapid rescue of lost regulatory function across distant regions of the genome. In our recent study [Taylor,  Pseudomonas fluorescens, a peptide synthase (viscB), which is involved in making a surfactant and enabling sliding motility, and the master regulator (fleQ) required for flagellum biosynthesis and swarming motility, produced a strain that was immotile on the surface of soft agar despite a perfectly functional flagellum regulon existing in the cell. According to our current knowledge of the flagellum regulatory system, the removal of FleQ from the regulatory system should be a mutation that is catastrophic and irrecoverable in an environment where motility is essential to reach nutrients, like the surface of agar; the mutant should go extinct as it starves to death at the site of inoculation. However, we observed a remarkable outcome: the restoration of motility due to the resurrection of the flagellum. We showed that the evolution of motility followed a rapid and repeatable two-step trajectory in two independent P. fluorescens strains by rewiring their nitrogen regulation system to repurpose regulatory activity towards the flagellum regulon . In multiple independent replicates, we found that step 1 mutations could occur in one of three nitrogen genes, ntrB, glnA or glnK. These mutations caused a slow spreading phenotype. A second, faster spreading, mutant then emerged, carrying one of these initial mutations plus an additional mutation in ntrC; seven different ntrC mutations were found. Our model predicts that each of the step 1 mutations would have increased intracellular levels of phosphorylated NtrC, which then starts activating flagellum genes ; the step 2 mutation then shifted NtrC specificity away from its cognate ntr targets and restores flg gene expression to wild type levels.Mutational inactivation of two key genes in 54) to activate transcription from certain promoters. The specificity of EBPs for their targets probably occurs through the enhancer binding HTH domain and in one sense it is perhaps no surprise that NtrC can be co-opted to fill in for the deficiency in the fleQ mutant. However, there are numerous other RpoN-dependent EBPs in P. fluorescens, some of which show closer structural homology to FleQ than NtrC . Why, then, was NtrC the only RpoN-dependent EBP to be co-opted in this way? A likely explanation for the repeatable rewiring of the nitrogen regulatory system in our study is because this adaptive trajectory is influenced by the ecological context. Under the conditions we tested, the immotile cells begin to starve, which we can predict causes intracellular nitrogen levels to fall and triggers increased phosphoryl transfer through the Ntr system. The cell is therefore primed with an active Ntr system.Both FleQ and NtrC are enhancer binding proteins (EBPs) and interact with RpoN  arising from the slow moving mutant. The transcriptome data show that the flg genes in these strains are upregulated even further, to wild type levels of expression, while the ntr genes are tuned downwards. This confers faster motility affording reduced competition and improved access to unexploited resources, but may have an additional benefit; selection will favour mutants that are still able to move, but have reduced toxic effects of higher levels of nitrogen on the cell. A number of biochemical, genetic and ecological experiments are required to test these hypotheses.Intriguingly, our transcriptome data do not show activation of other RpoN-dependent genes outside of the flg genes in the slow and fast moving mutants. We propose two potential mechanisms that may be underpinning this switch in specificity: 1. NtrC-P binds onto flg enhancer sites; 2. NtrC-P activates flg genes by direct binding to RpoN. Although either or both mechanisms may be operating, our structural modelling of the proteins found that the ntrC mutations in the fast spreaders were located in, or close to, the DNA-binding HTH domain. The same point mutation (N454S) arose in four independent lines, suggesting that selection favoured a particular, precise alteration of binding specificity. However, one mutant had a gene deletion resulting in loss of the HTH domain; it is likely that in this case, the activated NtrC-P protein binds directly to RpoN at flg promoters. This raises the intriguing possibility that mutations in the same domain of the same protein could still potentially represent disparate evolutionary pathways to novel network function.An interesting question this raises is how NtrC-P is able to activate the Finally, a further exciting question is to determine the evolutionary fate of the newly evolved fast mutant. Now that this strain lacks a key regulator but has evolved a dual functioning EBP, albeit without any environmental control, suggests that this strain should experience selective pressure to reinstate environmental control and perhaps evolve orthologous duplication to re-establish independent regulatory control.bricolage), but this term has connotations of haphazard stochasticity that may be misleading, as evolutionary trajectories can be remarkably repeatable. It remains to be seen whether there will be continuing consistency in the longer-term trajectory of compensatory mutations, as NtrC further adapts to its dual roles following this major rewiring, or duplicates and specialises anew.Our knowledge of how regulatory systems function and adapt has been greatly improved by this discovery and this system can be used to examine how complex regulatory networks evolve. Francoise Jacob famously described evolution as a process of tinkering (P. fluorescens strains are often touted as highly promising biocontrol agents for various diseases, including, among others, fire blight, Pythium spp. and Phytophthora spp. diseases and take-all of wheat, as well as potent plant growth promoters. This evidence of a reproducible evolutionary capability to restore lost functions by adaptation shows promise for these bacteria as resilient biocontrol or biofertilizer treatments, able to adapt and maintain populations in changing conditions. A better understanding of how environmental and genetic factors affect motility in P. fluorescens could also increase knowledge of how and why soil colonization by these bacteria, and consequently biological activity, are often inconsistent during field application. This could lead to the improvement of efficiency and consistency of plant colonization by P. fluorescens treatments, ultimately leading to the reduced use of agrochemicals.Further studies on the downstream physiological effects of this evolution will include analyses to determine how the adapted strain performs in different environments, particularly with regards to its modified capacity for nitrogen uptake, and especially under other ecological conditions and more complex environments. Verification of the immotile double mutants’ flagellar restoration ability under natural soil conditions will also be of interest to determine if such mutants can surmount the physiological disadvantage of losing regulatory control of flagella and nitrogen systems, to ensure better persistence when exposed to competing soil microorganisms and fluctuating nitrogen and carbon sources. Different


A number of new drugs are moving through the osteoporosis therapy pipeline. Some show great promise for patients while one has fallen by the wayside at the last hurdle. New, effective therapies are warmly welcomed but there are still uncertainties around management of osteoporosis with currently available drugs that are contributing to what is commonly being referred to as the ‘treatment gap’; a differential between those patients who would benefit from treatment versus those who actually are receiving it. Furthermore, in parallel to the common public health disease of osteoporosis, there have been tangible developments in therapies available for some rare bone and calcium diseases. Teriparatide is the only currently licensed anabolic bone drug and has been used clinically for around 15 years,2 Risk of non-vertebral fractures was reduced by 43%. Compared with teriparatide, bone density changes and anti-fracture effect was similar although there was a lower incidence of hypercalcaemia with abaloparatide.Abaloparatide is a 34 amino acid peptide that selectively activates the parathyroid hormone type I receptor. A daily subcutaneous injection of abaloparatide over 18 months showed a reduction in new vertebral fractures of 86% compared with placebo.3 Clinical vertebral fractures were reduced by 36%. There was a non-significant reduction in non-vertebral fractures after 12 months of treatment. Adverse event profile was good. When compared with teriparatide, romosozumab caused greater gains in bone mineral content at the spine and the hip. Studies using sequential romosozumab with denosumab over a 2-year study period have revealed optimistic results but the exact future position of romosozumab in osteoporosis therapy remains to be determined.Romosozumab is a humanised monoclonal antibody to sclerostin, an osteocyte-derived factor that blocks the canonical Wnt signalling pathway in bone. Romosozumab blocks sclerostin, which in turn enhances Wnt signalling, resulting in an increase in bone formation and bone mineral density. Data reveal substantial gains in bone density during romosozumab treatment and after 12 months of treatment there was a 73% reduction in new vertebral fractures compared to placebo.4 that inhibits osteoclast function (but not viability) via inhibition of cathepsin K. Fracture prevention data were encouraging although due to a negative adverse event profile, largely around cardiovascular risk, odanacatib was pulled from further development.In addition to the development of the two bone anabolic agents above, 2016 saw the demise of another promising anti-fracture agent called odanacatib5While novel therapies continue to add to the therapeutic possibilities in the management of osteoporosis, it is of concern that there appears to be an ever widening treatment gap between those individuals who would benefit from therapy versus those who actually receive such therapies. This creates concern by creating a growing population of individuals at risk of fracture who are not receiving optimal care. The treatment gap has been highlighted internationally.One of the main factors in creating the treatment gap, is professional concern by physicians, as well as patient concerns relating to side effects of drugs and lack of clarity regarding long-term interventions and management of osteoporosis. Atypical femoral fractures (AFFs) and osteonecrosis of the jaw have played a centre-stage role in the lay media and professional publications that are probably responsible for over-exaggerated causes for concern. It is likely that improved education and contextualisation of information will be required to ensure that the treatment gap does not widen, but in fact, constricts. There is an onus upon us all to risk stratify with respect to potential long-term complications of antiresorptive therapy, including extended femur scans during dual-energy X-ray absorptiometry (DXA) scanning in patients being monitored with antiresorptive therapy, better identification of high-risk patients based on geometrical parameters on DXA scanning, as well as better education of patients and professionals related to prodromal symptoms, and also better research understanding of AFFs and risk factors for development.We have developed sophisticated tools to risk stratify and identify individuals who will benefit from treatments and services, such as fracture liaison services that are in place across the globe to identify those most at risk. However, if we cannot manage the treatment gap and perceptions of risk-versus-benefit, many of these developments will not be delivered in full to the benefit of patients.6 there was an increased rate of bisphosphonate prescriptions between 1990 and 2006 and then a plateau; however, in the last 3 years, there has been a 12% decrease in new prescriptions.7 These marked secular changes over the last two decades are probably revealing a change in understanding and societal views. Although, it is important to recognise that treatments, in addition to oral bisphosphonates, have become available and this is likely in small part to explain some of the more recent reductions in oral bisphosphonate prescribing.Looking at the UK Clinical Research Practice Datalink (CPRD),8 Its potential value on a larger scale in adults with less apparent symptomatology remains to be determined.As well as the population impact of osteoporosis in an ageing society, rare diseases have also made developments in terms of specific therapies. Hypophosphatasia is a very rare condition that has variable expression. In childhood this can be a very severe, life-threatening condition and the introduction of asfotase alfa as a recombinant mineral-targeted form of alkaline phosphatase, has revolutionised the severe end of the spectrum of disease.9Finally, understanding of the aetiopathogenesis of hypophosphataemic rickets involving fibroblast growth factor (FGF) 23 signalling has allowed the evolution of anti-FGF receptor monoclonal antibodies that have been shown to improve phosphate regulation and improvement in both paediatric and adult X-linked hypophosphatemia (XLH).The field of bone and mineral metabolism is exciting and rapidly progressive. Common public health diseases continue to challenge in terms of practical management of patients, but pipeline development of new drugs continues to allow refinement and personalisation of management. In parallel, a number of the fascinating rare diseases that have been managed on an ad hoc basis to date are now starting to be managed in a targeted, disease-specific manner allowing much improved outcomes, particularly in severe disease expressed in early childhood.


How oncology practitioners communicate with patients has a strong impact on quality health care. Good communication facilitates positive experiences for both practitioners and patients alike, yet many practitioners report they are inadequately prepared for delivering bad news to cancer patients and often have negative experiences due to poor communication. Using a qualitative exploratory descriptive design this study sought to understand the experiences of nurse practitioners (NPs) when communicating bad news to cancer patients. Methodology consisted of two steps. First, five Florida-licensed NPs with at least 2 years of oncology experience were educated on the use of the SPIKES protocol and utilized it in clinical practice for 30 days. Second, semistructured individual interviews were conducted to record their perceptions of using the SPIKES protocol. Thematic analysis results support the concept that "the experiences of the nurse practitioner when delivering bad news to cancer patients are shaped by their own communication skills." Educating oncology NPs in using the SPIKES protocol when delivering bad news has the potential to positively impact the experiences of both NPs and patients.In 1995, Breaking Bad News Consensus Guidelines were published . They caThe SPIKES protocol is one such step-wise framework for delivering bad news that can support discussions, improve communication, enhance practitioner confidence, support patient-centered care, and facilitate a shared decision-making model in patient care. This tool is an acronym for the steps in which to deliver bad news see . Since tResearch has shown that when poor communication is used to deliver bad news, cancer patients often suffer significant emotional and psychological trauma and are at risk of receiving less-than-optimal quality of care . ResearcMore recently, research in this important area has expanded to evaluate the way in which formal communication skills training impacts not only patients, but also the "deliverer" of the bad news, such as the medical student ; nursingHowever, although research on the "deliverer" is beginning to be amassed, it appears that few studies have examined nurse practitioners as a separate entity , and forHistorically, physicians may have uncertainty in deciding the best way in which to share difficult news with patients . Like thTo reiterate, research with medical students and physicians demonstrates that the skill of communicating bad news can be taught through communication skills training. Therefore, formal communication skills training is beginning to be standardized in medical provider curricula but has not traditionally been a routine part of NP education. However, many NPs currently in practice have often learned by observing physicians, who may also have limited communication skills training themselves before this was standard in their medical education .Literature review reveals that implementing education may not be enough to enhance the feeling of confidence with the skill and that continued practice in the clinical setting is warranted, as it can be more challenging in the clinical setting than in practice . FurtherTo meet the communication needs of patients, NPs must learn to communicate in a manner that delivers bad news in a supportive fashion while at the same time allowing patients to be a vital part of their cancer treatment plan , a conceAlthough the position paper by the NCI  recommenNCI’s Framework for Patient-Centered Communication in Cancer CareImprovement in the delivery of patient-centered communication has been identified as a priority in the NCI’s plan for research to reduce the pain and suffering of cancer patients. To deal with these issues, the NCI developed a conceptual framework built on six core functions to support both the provider and patient as a communication template for patient-centered cancer care . These fDesign and ProceduresAfter institutional review board approval was obtained, a flier announcing the research study was distributed to two professional groups: the Central Florida Chapter of the Oncology Nursing Society (CFONS) and the Greater Orlando Hematology Oncology Physician Extenders (GO HOPE).Five NPs volunteered to participate in this two-part study utilizing a qualitative exploratory descriptive. In step one, a meeting with each NP was conducted to obtain informed consent and provide education on the use of the SPIKES Six-Step Protocol for Delivering Bad News to Patients . ParticiThirty days later in step two, individual one-on-one interviews were conducted and recorded. Interview questions consisted of five scripted, open-ended, qualitative discussion questions, which were developed based on the NCI’s Conceptual Framework for patient-centered communication in cancer care, and are listed here .Nurse practitioners were asked to share their perceptions, experiences, and insights on the changes or differences the protocol made in their relationships with patients. Additionally, participants were questioned about the tool’s usefulness in helping patients in problem-solving and decision-making. To maintain patient privacy, the researcher discouraged all discussion regarding specific patients, and no data were collected on any specific patient.SampleParticipants were female, with an average age of 33.8 years, and had 2 to 10 years of professional experience. All worked in private practice, with three reporting associated acute care duties. Two participants had Doctorate of Nursing Practice degrees (DNP) and three had Masters of Science in Nursing degrees (MSN). Three participants were certified as "Advanced Oncology Certified Nurse Practitioners," and two were certified as "Adult Nurse Practitioners."Data AnalysisInterviews were transcribed by the investigator, and a six-step process conducting thematic network analysis was utilized to extract common themes from individual interviews; they were used to evaluate and understand each study objective See . ValiditResults and Discussion of ThemesAs part of the individual interviews, participants were asked five questions regarding their use of the SPIKES protocol when delivering bad news to cancer patients in practice.Question 1: Did the SPIKES protocol foster a healing, compassionate relationship between you and your patient when bad news was communicated?Themes that arose from participants’ responses supported the concept that the SPIKES protocol helped to establish a relationship between patient and NP by providing a supportive relationship. Subthemes that arose included (1) being deliberate; (2) developing a sense of compassion; (3) becoming more personable; (4) limiting misunderstanding; and (5) giving it time.Question 2: Did the SPIKES protocol help you to respond to the emotions exhibited by your patients in a sensitive manner, allowing for their cultural and spiritual beliefs?Themes that arose from participants’ responses supported the concept that the SPIKES protocol builds understanding that promotes emotional support. Participant subthemes related to this question included promoting emotional support through (1) understanding; (2) watching emotions; (3) recognizing and respecting; and (4) creating space consideration.Question 3: Did the SPIKES protocol help to support your patients in problem-solving and encourage them to participate in decision-making related to their care?Themes that arose from participants’ responses supported the concept that the SPIKES protocol supports patient understanding, leading to patient problem-solving and decision-making. Subthemes related to this question included (1) patient problem-solving; (2) patient decision-making; and (3) patient understanding.Question 4: What are the facilitators provided by the SPIKES protocol when trying to create a healing environment for your patients that respects their human dignity when giving them bad news?Themes that arose from participants’ responses supported the concept that the SPIKES protocol promotes a positive environment when delivering bad news. Subthemes that arose included (1) promoting a quiet environment; (2) creating a private environment; and (3) intentionally arranging the best setting for difficult conversations.An additional theme that arose from participants’ responses to this question supported the concept that the SPIKES protocol supports a respectful environment that provides human dignity, and subthemes included (1) not rushing; (2) respect; and (3) intentionally supportive body language.Question 5: What elements of the SPIKES protocol helped you to promote patients’ self-management while meeting their basic physical, emotional, and spiritual needs?Themes that arose from participants’ responses supported the concept that the SPIKES protocol allows for information giving that supports self-management and decision-making. Subthemes included (1) understanding; (2) self-management; (3) decision-making; (4) partnering; and (5) giving information.A second concept that emerged from participants’ responses to this question was the concept that the SPIKES protocol promotes holistic patient care. Subthemes that arose from participants’ responses included (1) physical; (2) emotional; (3) spiritual; and (4) cultural.Finally, results from this study revealed there were common global themes among participants when utilizing the SPIKES protocol. Utilizing Terry’s  thematicHelps to establish a relationship between patients and NPsBuilds understanding that promotes emotional supportSupports patient understanding, leading to patient problem-solving and decision-makingPromotes a positive environment when delivering bad newsSupports a respectful environment that promotes human dignityAllows for information giving that supports self-management and decision-makingPromotes holistic patient care.Based on the thematic analysis of the study objectives and their supporting global themes, results support the overarching concept that "the experiences of the nurse practitioner when delivering bad news to cancer patients are shaped by their own communication skills."This type of qualitative research is of great value in generating an understanding of how utilizing the SPIKES protocol positively impacts how NPs deliver bad news to patients. The resulting themes suggest this tool is as useful for MDs as it is for NPs. These findings support that communication training and using a standardized tool play an important part in improving not only patient experiences but also provider experiences. Although PAs were not included in this research sample, it is reasonable to conclude they too would benefit from additional communication training and use of a protocol to help them compassionately deliver bad news.Communication training should be included in all providers’ educational programs and often is now standard; however, since providers shape their own experiences, this research implies that repeat education and training in communication  may be necessary to hone providers’ skills and facilitate holistic patient care. Limitations of this study include the following: (1) its small sample size; (2) participants consisted of only female NPs; (3) it is from one geographic area; (4) it focused on private practice; (5) the ages of the participants is similar; thus, the findings may not be generalizable to other practitioners, genders, and practice settings. Additionally, there may be a bias, as participants may have wanted to please the researchers. Future research should replicate this study with physician assistants as well as represent a more diverse mix of gender, ages, and geographic areas. Examining whether the use of this tool improved confidence for all health-care providers, the relationship of provider burnout, and occupational commitment to communication skills training are other areas of opportunity for new research.Delivering bad news is an unavoidable part of an oncology practitioner’s role. Promoting emotional support of patients while improving the experience for practitioners is essential. As self-reported, all five participants indicated they would continue to use the protocol, teach its methods to their peers in practice, and recommend it to others.


Precision medicine has been announced as a new health revolution. The term precision implies more accuracy in healthcare and prevention of diseases, which could yield substantial cost savings. However, scientific debate about precision medicine is needed to avoid wasting economic resources and hype. In this commentary, we express the reasons why precision medicine cannot be a health revolution for population health. Advocates of precision medicine neglect the limitations of individual-centred, high-risk strategies  and the current crisis of evidence-based medicine. Overrated “precision medicine” promises may be serving vested interests, by dictating priorities in the research agenda and justifying the exorbitant healthcare expenditure in our finance-based medicine. If societies aspire to address strong risk factors for non-communicable diseases , they need less medicine and more investment in population prevention strategies. For example, some projections indicate that cardiovascular disease rates will rise in USA by 10% between 2010 and 2030Here, we call for greater recognition of the social determinants of health in the biomedical community and we suggest some solutions that could help to mitigate the burden of non-communicable diseases worldwide.It is well established that social disadvantaged groups have a lower life expectancy and quality of life (disability-free life expectancy) in both high-income and low- to middleincome countriesAdvocates of precision medicine claim that advances and implementation of new technologies will optimize prevention strategiesAn excessive emphasis in technological solutions to prevent or treat diseases diverts our attention from the root of the problem: health relies on favourable social circumstancesIn addition, clinical medicine and “precision” prevention have become an industry advertisement toolThe argument that technologies may help us make more sustainable healthy choices should be subject to scrutiny given the over simplistic approach of behavioural change behind such claims. For example, in a recent randomized controlled trial, the provision of one physical activity wearable monitor to increase weight loss by higher physical activity did not offer advantages compared with standard weight lost approaches without these devicesIn summary, precision medicine seems to be a secondary route to a healthier world. The XXI century is becoming a turning point for life on Earth – human-made climate disruption, chaotic urbanization, forced migration, pollution, degradation, and depletion of natural resources are all examples of challenges


We generalize specifically from research on discrimination against LGBT employees, because they have received little legal protection until recently, as well as on best practices for providing support to these employees and propose that initiatives used recently by both unions and universities can provide insights into the effectiveness of allies in creating organizational climate change.Workplace discrimination, harassment, exclusion, and incivility incidents are often subtle in nature but can nonetheless have deleterious impacts on targets  that signal to LGBT employees to stay in the closet. Additionally, a lack of inclusive organizational policies and the presence of heterosexist norms and language  can serve as subtle cues illustrating an unsupportive climate even if a particular employee is not directly targeted  provide informative feedback that can influence a perpetrator to rethink displays of subtle bias.We want to emphasize the risk of ignoring mistreatment. At a minimum, silent bystanders can intentionally or unintentionally add to targets' feelings of ostracism  provides resources related to workplace discrimination laws and applications to union issues such as suggestions for LGBT-inclusive contract language. Another example of effective union advocacy is a recent collaboration between the International Brotherhood of Electrical Workers, the Communications Workers Association, and Verizon that trained male allies to combat domestic violence against women by focusing on changes in workplace climate  acts as a task force to foster inclusiveness by investigating complaints related to hate or bias reported by university community members. The ICRT includes representatives from campus police, the Dean of Students office, the university housing office, and student counseling services; it uses expertise from various domains of campus life to determine if bias-based violations of the Student Code of Conduct or criminal acts have occurred, as well as broader concerns about campus climate and accessibility for all students. Other campus initiatives, such as the Triangle Association, focus on improving the retention of LGBT faculty and staff. If such campus initiatives are highly visible and demonstrate their effectiveness in creating change, individuals predisposed to engage in subtle discrimination likely receive cues that such behavior is unacceptable. Such initiatives may also increase a general feeling of inclusion for members of marginalized groups.Organizational leaders can also draw from university-based advocacy efforts. As noted earlier, at many universities, “affinity groups (employees linked by a common interest) in order to facilitate networks of supportive individuals with diverse identities and backgrounds. These groups provide opportunities for intergroup interaction that highlight similarities among members on the basis of their shared interest, a solution that is known to improve empathy. However, we argue that simple social contact, although a useful strategy, works best when individuals have opportunities to demonstrate their expertise and move beyond simple interactions. For instance, unfamiliarity is not likely to be the main driver of gender-based discrimination; in some workplaces, the same could be said for race-based, sexual orientation, or religious-based subtle discrimination. Additionally, even in affinity groups, it is difficult to eliminate pre-existing group status and power differences that often limit what is gained from intergroup contact. Workplace strategies focusing on intergroup interactions should be paired with other approaches that reduce status and power differences and allow task- and skill-based demonstrations of diverse group members' expertise.Organizational leaders may also create Organizational leaders can increase both the inclusivity of their workplaces and the wellbeing of their employees. However, allies' effectiveness may be limited based on their perceived motives. A supervisor may be perceived as completing ally training or confronting bias for self-serving motives, rather than out of concern for equality. Worse, allies' behavior may be perceived as paternalistic or they may be resented as “outsiders” (Duhigg et al., Organizations should assess potential barriers before implementing ally programs, such as the time and resources it may take to change organizational culture. Leaders should be prepared to address backlash if ally programs are perceived negatively by majority group members or if affinity groups are perceived as exclusionary. Ally training should also prepare trainees for potential backlash (Ashburn-Nardo et al., Little research has assessed ally training, but general diversity training assessments indicate medium-to-large effects on cognitive-based and skill-based outcomes, and small-to-medium effects on affective outcomes (Kalinoski et al., There is a clear need for additional empirical studies within organizations that directly examine the processes by which allies can change intolerant climates. Effective ally strategies may depend on the specific group targeted for mistreatment, along with the perpetrator's and ally's demographic characteristics, status, or power (Ashburn-Nardo et al., All authors listed have made substantial, direct and intellectual contribution to the work, and approved it for publication.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.


A better understanding of the neural substrates that underlie motor recovery after stroke has led to the development of innovative rehabilitation strategies and tools that incorporate key elements of motor skill relearning, that is, intensive motor training involving goal-oriented repeated movements. Robotic devices for the upper limb are increasingly used in rehabilitation. Studies have demonstrated the effectiveness of these devices in reducing motor impairments, but less so for the improvement of upper limb function. Other studies have begun to investigate the benefits of combined approaches that target muscle function , modulate neural activity (noninvasive brain stimulation), and enhance motivation  in an attempt to potentialize the benefits of robot-mediated training. The aim of this paper is to overview the current status of such combined treatments and to analyze the rationale behind them. Significant advances have been made in the management of stroke ; however cerebrovascular diseases remain the third most common cause of death and the first cause of disability worldwide –6. StrokRobotic systems for upper limb rehabilitation have two main designs: (i) exoskeletons, generally based on torque actuators that control each joint of the affected limb to be treated and (ii) end-effectors systems that guide only the most distal part of the affected limb –30.During the last 2 decades, a growing number of robotic devices have been developed  to offer intensive training based on repeated movements and challenging task-specific exercises . These dSeveral systematic reviews and meta-analyses have been carried out on the numerous studies of robotic rehabilitation to assess the effects in patients with stroke with a growing interest in the latest years –37.Despite significant heterogeneity in the types of system evaluated  as well as the clinical research paradigms used , there iMost reviews concluded that robotic therapy does not provide any functional benefit and so does not improve activities of daily living due to the lack of generalization of improvement to untreated joints . However the latest update of the review conducted by Mehrholz et al.  found thThe effect of robotic therapy on muscle tone remains uncertain as only two reviews included this outcome; Bertani et al.  found noOne raised question is that of the effect of the robotic system itself on improvements in motor outcomes versus simply the provision of highly repetitive treatment. Current evidence suggests it is the large number of repetitions that is effective since there are no differences in outcome between robot-assisted therapy and dose-matched conventional therapy . In the Thus two decades after the pioneering study by Aisen et al. , a suffiRobotic systems should therefore be considered as vehicles that enable delivery of evidence-based, impairment-oriented treatment, providing highly repetitive, intensive, and interactive treatment that is not possible in usual care. Further improvements in function might come from combining treatments that target different impairments  and other components of the neural disorder  or are based on a more functional approach .The effects of functional electrical stimulation (FES) on upper limb recovery in individuals with stroke have been extensively investigated during the last 30 years. FES activates muscles in a pattern that produces a functionally useful movement . Most FEThe effects of FES on motor function are mixed in the literature. A meta-analysis of 10 randomized controlled trials (RCT) concluded that the addition of FES to conventional therapy did not further improve motor function . In contThese results stimulated the development of hybrid robotic systems combining FES with robotic systems . This isTranscranial magnetic stimulation (TMS) is a 25-year-old noninvasive technique used to characterize the physiological processes involved in functional consequences of stroke . The useAlong with clinical evaluation, functional magnetic resonance imaging (fMRI), and diffusion tensor imaging, rTMS can be used as a predictor of upper limb motor recovery after stroke . MoreoveA study of six patients with chronic stroke highlighted the need to adapt rTMS to the patient's lesions since rTMS may have different effects on motor reorganization depending on the location of the lesions . A groupA growing number of studies have investigated the effects of combining various upper limb rehabilitation techniques with rTMS –71, withHowever, despite these mixed results, it seems likely that the association of the relative normalization of cortical excitability by rTMS, with repetitive active robotic training, would potentiate the effects of each treatment, resulting in greater motor recovery . CurrentTranscranial Direct Current Stimulation (tDCS) is a noninvasive, painless neural modulation technique. It involves cortical stimulation by a constant and low intensity current delivered via two electrodes placed over the head. Anodal and cathodal tDCS have different effects on the motor cortex. The former has an excitatory effect while the latter inhibits or reduces neuronal activity. Knowledge of these effects is useful as general rule; however numerous other factors also affect inhibition and excitation , such asThe application of cathodal tDCS over the unaffected motor cortex has been shown to improve the motor control of the proximal upper limb in the case of mild impairment and to worsen control in the case of moderate to severe impairment. It is likely that difference in effect is related to the level of spasticity . MoreoveSeveral studies have investigated the effects of combining tDCS with robot therapy. Edwards et al.  showed tThe timing of the application of tDCS may be important. One study showed that movement smoothness improved only when anodal tDCS was delivered prior to robotic training, rather than during or after robotic training . The phaIt appears that the effects of anodal tDCS (on the affected hemisphere) and cathodal tDCS (on the unaffected hemisphere) combined with robot-assisted arm training are similar. A comparative study in patients with severe impairment found that spasticity and motor function (upper limb section of the Fugl-Meyer Assessment (FMA) scale) improved to a similar extent with both modalities .Virtual reality (VR) is an innovative, interactive, and adaptive treatment modality. It can be used to provide sensorimotor training in complex, enriched environments, which would be impossible to design in the real world. VR optimizes patient engagement and can provide mass practice tailored to the individual . VR is cThe results of several meta-analyses and systematic reviews suggest that the use of virtual reality as an adjunct to usual care can lead to substantial improvements in upper limb motor function and in activities of daily living when compared with the same dose of conventional care in patients with stroke , 96. A rSeveral groups have developed systems that combine VR with robotic devices , 99. TheBotulinum neurotoxin (BoNT) is a microbial protein that blocks acetylcholine release at the neuromuscular junction. It is used to reduce dystonia, spasticity, and related disorders. Over the last 2 decades, two BoNT serotypes (A and B) have become widely used in neurorehabilitation. BoNT has been demonstrated to be safe and effective for the treatment of spasticity in adults and children, including upper limb spastic paresis due to stroke and traumatic brain injury (TBI) –110.BoNT injected in upper limb muscles reduces muscle tone, with perceived functional benefits . Some stBoNT and robotic rehabilitation appear to be a natural, synergistic combination since several studies have demonstrated that repetitive movement-based robot therapy can reduce muscle tone as well as motor impairment –120. ThiOver the last two decades, neurorehabilitation has evolved from being empirically based towards a more evidence-based form of practice, transferring the scientific concepts of neuroplasticity and motor relearning as well as advanced knowledge from clinical studies, into clinical practice. A growing body of evidence has demonstrated that stroke induced-changes in cortical neuronal activity and neural circuits can be influenced by physical interventions that target functional deficits and/or impairments such as weakness and spasticity. A growing number of treatment methods and devices are becoming available to facilitate plastic-reorganization of the central nervous system. However, the optimization of treatment effectiveness might require combined approaches with complementary actions. The following section discusses the rationale for combining robotic therapy with other innovative approaches.Motor recovery and/or improvements in motor performance after stroke are driven by motor skill leaning that can be mediated by movement-based rehabilitation paradigms. Robotic rehabilitation systems fully meet the requirements for motor learning, since they facilitate practice-dependent improvements in motor performance that persist over time. Although robust evidence for neurorehabilitation-induced plasticity is lacking, it has been suggested that robot-mediated treatment using adaptive algorithms (assistance or perturbation) might have the potential to enhance neuroplasticity .Noninvasive brain stimulation (NIBS) techniques can transiently modulate brain excitability. An obvious application is to prime motor networks , increasOne of the aims of combining virtual reality environments with robotic rehabilitation is to enhance patient motivation and engagement in movement-based practice. The association of VR with robot therapy adds a “recreational” component to rehabilitation that distracts patients from fatigue and pain and motivates them to improve their performance . As suchAlthough BoNT injections have been shown to reduce muscle spasticity, studies have failed to find a concomitant improvement in motor function and disability. It is likely that patients “learn” new patterns of movement in order to function as effectively as possible in the presence of spasticity. Once these new patterns are established, they may not change, even if spasticity is reduced. Repetitive, goal-directed movements using robotic devices may change these patterns, facilitating more normal movement and improving functional capacity, particularly since robot-mediated training has been shown to change muscle synergies . HoweverFES has obvious applications to facilitate appropriate muscle recruitment, and its use with assist-as needed robotic rehabilitation appears to be an interesting combination. Although studies suggest that robot-mediated therapy should focus more on movement coordination than on muscle activation to be effective , EMG driCurrently available robotic devices are mostly single or bijoint-based modules that carry out training of only proximal or distal segments, with a single goal to improve either reaching or grasping ability. Hybrid systems combining FES with robot training can train both proximal and distal segments simultaneously, combining impairment-based therapy with functional-oriented tasks (reach-to-grasp). Although some studies have suggested there are no additional advantages when shoulder/elbow robot-assisted training is combined with functional tasks , this apEngagement in rehabilitation is essential to promote learning . VR and One advantage of robotic devices is their ability to provide a simple and affordable measurement of motion kinematics in standardized conditions, complementing clinical scales of motor function, with a high resolution and specific metrics –22. AdvaThere is currently some evidence to suggest that combination-therapies may be more effective than individual treatment techniques.This paper highlights the potential benefits of combining upper limb movement-based robotic therapy with other approaches. Much work is, however, required to evaluate and optimize such combination-approaches as current studies have many limitations .


Verbal short-term memory (STM) impairment is one of the most consistent associated deficits observed in developmental reading disorders such as dyslexia. Few studies have addressed the nature of this STM impairment, especially as regards the ability to temporarily store serial order information. This question is important as studies in typically developing children have shown that serial order STM abilities are predictors of oral and written language development. Associated serial order STM deficits in dyslexia may therefore further increase the learning difficulties in these populations. In this mini review, we show that specific serial order STM impairment is frequently reported in both dyslexic children and adults with a history of dyslexia. Serial order STM impairment appears to occur for the retention of both verbal and visuo-spatial sequence information. Serial order STM impairment is, however, not a characteristic of every individual dyslexic subject and is not specific to dyslexia. Future studies need to determine whether serial order STM impairment is a risk factor which, in association with phonological processing deficits, can lead to dyslexia or whether serial order STM impairment reflects associated deficits causally unrelated to dyslexia. Dyslexia is characterized by important and persisting difficulties in acquiring accurate and efficient reading abilities despite normal-range intellectual efficiency . AlthougThe nature of the link between verbal STM impairment and dyslexia is complicated by the fact that mechanisms that allow information to be maintained for a given duration are themselves dependent upon access to long-term memory (LTM) representations. These LTM representations correspond to representations stored in the language system. Several studies showed that the likelihood of an item being recalled in a verbal STM task is determined partly by the nature of underlying linguistic representations: Words lead to higher recall performance than non-words . Even foNot all aspects of verbal STM, however, depend upon access to the language system. Mainly retention of item information appears to be influenced by long-term knowledge: Linguistic variables such as word frequency and semantic similarity determine the number of items recalled in a STM task, but not the number of items recalled in correct serial order . At a thNext, we review the recent studies that have distinguished item and serial order STM abilities in dyslexia. These studies mainly involve adults with a history of dyslexia as there are currently very few studies that specifically investigated serial order STM in children with dyslexia.Table 1). The item STM task was a single non-word repetition task probing the retention of phonological item information. Serial order STM was assessed using a serial order reconstruction task for auditory sequences of familiar words. A first study making an explicit distinction between item and serial order STM was conducted by Table 1). They did not observe verbal item STM impairment, while this impairment could have been expected given that verbal item STM is considered to depend on access to underlying linguistic representations. However, the linguistic levels that are impaired in dyslexia are at the level of phonological rather than lexico-semantic representations (Table 1). Item and serial order STM deficits appeared to be statistically independent and their correlation (r = -0.07) was non-significant after controlling for verbal and non-verbal intellectual efficiency. Note that the dyslexic participants were impaired in non-word and word item recall tasks, but not in a non-word item probe recognition task, suggesting that phonological item representations were sufficient for accurate recognition but not full reproduction. The finding of specific serial order impairment is also supported by a recent study by Table 1).Studies in adults with a history of dyslexia have used similar study designs to distinguish item and serial order STM abilities. ntations ; the iteTable 1). Although at the behavioral level, item and serial order STM deficits of similar severity were observed for the verbal STM modality, they were associated with distinct neural networks. The dyslexic participants activated to a higher extent the left intraparietal cortex, the bilateral cingulate cortex and the right dorsolateral prefrontal cortex in the verbal item STM condition; this network has been associated with attentional control processes during STM tasks . Table 1). They observed difficulties in reconstructing the order of the characters, especially when they were presented in a sequential rather than a simultaneous manner. Finally, Table 1) with a strong serial order processing component, and these deficits correlated with performance on verbal STM tasks.Other studies have investigated serial order processing capacities in dyslexia using tasks that slightly differ from STM tasks. This mini-review of STM deficits in dyslexia reveals a number of important findings. First, all studies reviewed here, except for one, show verbal STM impairment in dyslexia, and these deficits persist until adulthood. Second, the verbal STM deficits cannot be explained only on the basis of underlying phonological processing impairment, given that both item STM, considered to depend most strongly on phonological processing, and serial order STM aspects appear to be impaired; importantly, serial order STM also appears to be impaired in the visuo-spatial STM domain, further ruling out the possibility that serial order STM would only be the consequence of verbal impairment.At the same time, the level to which item and serial order STM deficits are independent in the verbal domain has been questioned, some studies showing independent verbal item and serial order STM impairment, while others do not. The use of bilingual populations with an emigration background in some studies , making These observations, however, also stress the likely heterogeneity of dyslexia populations as regards the presence and severity of verbal STM impairment, and particularly serial order STM impairment. We further know that serial order STM impairment is not specific to dyslexia as it has also been observed in other developmental learning disorders such as dyscalculia . We suggA further question relates to domain-general factors that could explain serial order STM impairment. A number of studies have shown that children with dyslexia show difficulties in processing temporally organized information, at either fast or normal sequential presentation speeds . This fiAnother domain-general factor that needs to be considered is attentional impairment , 2016. SThe mechanisms linking serial order STM and reading acquisition also need further exploration. Serial order STM may support ordered storage and output of letter-to-sound conversion processes during early reading acquisition and support the matching of letter serial positions within a letter string with those of visual word forms stored in LTM during visual word identification . If seriFuture studies should focus more specifically on children populations with dyslexia, few studies exploring item and serial order STM in dyslexia having focused on children populations. Also, in order to determine the potential causal involvement of serial order STM deficits in dyslexia, longitudinal study designs need to be used, in order to determine to what extent the STM deficits are predictive of the severity of later reading impairment as opposed to simply reflecting an associated deficit. Also, whether the serial order STM impairment precedes dyslexia or whether it arises at a later age, after the diagnosis of dyslexia, remains an open question. Importantly, future studies need to shed more light on the inconsistencies regarding the status of STM functioning in dyslexia observed in some studies. Given that these inconsistencies may be related to some degree of heterogeneity in dyslexic populations, population characteristics should be reported with as much detail as possible and include information about history of diagnosis, tests used to establish the diagnosis, linguistic, and socio-economic environment as well as a comprehensive characterization of both linguistic and non-linguistic cognitive abilities.All authors listed, have made substantial, direct and intellectual contribution to the work, and approved it for publication.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.


One of the predicted consequences of climate change is a shift in body mass distributions within animal populations. Yet body mass, an important component of the physiological state of an organism, can affect key life-history traits and consequently population dynamics. Over the past decades, the wandering albatross—a pelagic seabird providing bi-parental care with marked sexual size dimorphism—has exhibited an increase in average body mass and breeding success in parallel with experiencing increasing wind speeds. To assess the impact of these changes, we examined how body mass affects five key life-history traits at the individual level: adult survival, breeding probability, breeding success, chick mass and juvenile survival. We found that male mass impacted all traits examined except breeding probability, whereas female mass affected none. Adult male survival increased with increasing mass. Increasing adult male mass increased breeding success and mass of sons but not of daughters. Juvenile male survival increased with their chick mass. These results suggest that a higher investment in sons by fathers can increase their inclusive fitness, which is not the case for daughters. Our study highlights sex-specific differences in the effect of body mass on the life history of a monogamous species with bi-parental care. Yet bodThalassarche chlororhynchos) were only slightly lighter, experienced no change in survival but substantially decreased their provisioning rate to their offspring )The strategy of wandering albatross fathers is consistent with the current theory stating that long-lived seabirds should adjust their reproductive performance to both their own body condition and the need of their offspring . We founOur results suggest that, in wandering albatrosses, investing further in sons to respond to their higher energy requirement is an efficient strategy for fathers to increase their inclusive fitness because it increased sons' juvenile survival, and it came at no cost to future breeding performance. Indeed, heavy male chicks had a higher juvenile survival than lighter ones, whereas mass had no effect on female juvenile survival. Furthermore, the breeding probability of fathers that produced sons 1 or 2 years later was not lower than that of fathers that produced daughters. This suggests that producing a son has no carry-over effect on male breeding performance in the short term. Not only do fathers adjust investment in their sons to their sons' conditions , but als5.Our results showed that among long-lived species, a relationship between body mass and survival can be present independently of environmental conditions. The survival of only one of the two sexes can be affected by body mass but not the other, probably due to sex-specific energy requirements . FurtherWhen some life-history traits are mass-dependent, variation in mass distribution is expected to have consequences at population level. Given that body mass has been reported to have changed over the past years with wind speed in both sexes , underst


Educational-based problem gambling prevention programs are important avenues in targeting at-risk behaviors among adolescents to prevent an escalation of problematic behaviors into adulthood. The aim of this review is to examine features pertinent to effective educational-based programs in the area of adolescent problem gambling prevention in hopes of providing a foundation and future suggestions for preventive efforts. A stronger understanding of this research area will be essential in ensuring that past practical and theoretical advancements are integrated into the development of future programs. Gambling disorder (GD) is defined as a continuous and recurring compulsive gambling behavior that may affect functioning at the individual, family and social level  and components  in educational programs, the evaluation of programs should be emphasized as well. Follow up evaluations on actual PG behaviour should be conducted to investigate long-term effects of prevention programs, as youths who are exposed to gambling at a young age could potentially develop PG during adulthood (Kourgiantakis et al. In summary, the current review paper outlined studies that focus on educational-based gambling prevention programs for adolescents. Emerging discussions here emphasize the need for more theoretical and evidence-based programs that examine approaches, potential risk and protective factors, program structure, delivery methods and structured long-term evaluation. All these factors should be taken into consideration by future researchers in developing and implementing programs that can effectively mitigate PG among adolescent.


Atherosclerosis is a disease characterized by inflammation in the arterial wall. Atherogenesis is dependent on the innate immune response involving activation of Toll-like receptors (TLRs) and the expression of inflammatory proteins. TLRs, which recognize various pathogen-associated molecular patterns, are expressed in various cell types within the atherosclerotic plaque. Microbial agents are associated with an increased risk of atherosclerosis and this is, in part, due to activation of TLRs. Recently considerable evidence has been provided suggesting that endogenous proteins promote atherosclerosis by binding to TLRs. In this review, we describe the role of TLRs in atherosclerosis with particular emphasis on those atherogenic endogenous proteins that have been implicated as TLR ligands.