Although there is a sizeable body of evidence regarding the nature of hostile behaviours among clinicians in the nursing workplace, what is less clear is the nature of the relationship between these behaviours and patient care. To inform the development of appropriate intervention strategies we examine the level of evidence detailing the relationships between hostile clinician behaviours and patient care.Published qualitative and quantitative studies that examined hostile clinician behaviours and patient care were included. Quality assessment, data extraction and analysis were undertaken on all included studies. The search strategy was undertaken in July and August 2011 and comprised eight electronic databases , Medline (Ovid), Ovid Nursing Full Text, Proquest Health and Medicine, PsycInfo, Pubmed and Cochrane library) as well as hand searching of reference lists.physician-nurse relations and patient care, nurse-nurse bullying, intimidation and patient care, reduced nurse performance related to exposure to hostile clinician behaviours, and nurses and physicians directly implicating patients in hostile clinician behaviours.The search strategy yielded 30 appropriate publications. Employing content analysis four themes were refined: Our results document evidence of various forms of hostile clinician behaviours which implicate nursing care and patient care. By identifying the place of nurse-nurse hostility in undermining patient care, we focus attention upon the limitations of policy and intervention strategies that have to date largely focused upon the disruptive behaviour of physicians. We conclude that the paucity of robustly designed studies indicates the problem is a comparatively under researched area warranting further examination. Internationally, various studies and reports have raised concern regarding hostile behaviours in the nursing workplace -3. AlthoIt is widely held that the various forms of hostile behaviour exhibited in the workplace threaten patient safety by impacting negatively upon the nature of the work environment, including eroding effective professional communication and professional relationships that underpin delivery of safe care -12. HostReflecting the degree of concern about hostile workplace behaviours, The Joint Commission responsible for accrediting health care organizations in the US released a Sentinel Event Alert drawing attention to the dangers of intimidation and disruptive behaviours in undermining a culture of safety . The disDespite widespread recognition of the potential impact of hostile clinician behaviours on patient care, no studies have systematically examined the available evidence on the relationships between these factors.For this review we were specifically interested in examining the relationship between the various forms of hostile clinician behaviours and patient care. The following two questions were developed to guide the systematic review and analysis. (i) Do hostile clinician behaviours negatively influence patient care? and (ii), If so, how do these behaviours impact aspects of care delivery?The various forms of behaviour included under the umbrella concept of hostile behaviours include aggression and threat of harm, physical violence, verbal abuse, bullying, horizontal violence and lateral hostility, intimidation and harassment, as well as more subtle forms of uncivil or disruptive behaviours such as refusing to co-operate, withholding information, being unavailable to give assistance, hampering another’s performance and making their work difficult ,9.Papers published during the period 1990–2011 were included in the review. This timeframe was chosen following an initial scoping review of the literature that identified the emergence of literature on hostile clinician behaviours in the nursing context from the early 1980s, with reported studies appearing after 1990. To provide more in-depth understanding into the questions the review sought to address a mixed-studies design, including qualitative, quantitative, and mixed methods studies was chosen . The iniFor the purpose of the review, patient care refers to care processes or events. It includes the influence of clinician behaviours and attitudes as well as interventions upon clinical care, safety and quality. Hostile clinician behaviour refers to various forms of rude, intimidating, hostile, aggressive, uncivil, harassing, bullying, or disruptive behaviours occurring between clinicians. In the nursing lexicon these behaviours when they occur between nurses are commonly labelled oppressed group behaviour and horizontal or lateral violence.bullying, incivility, violence, horizontal violence, lateral violence, disruptive behaviour, aggression, in combination with nurs*, physician, doctor, patient care, clinical care, adverse events, patient safety, and quality. Hand searching of reference lists was also undertaken.The search strategy included eight electronic databases , Medline (Ovid), Ovid Nursing Full Text, Proquest Health and Medicine, PsycInfo, Pubmed and Cochrane library) and was undertaken in July and August 2011. Titles, abstracts and subject descriptors were searched using the keywords - Following review, abstracts were selected if they met the following inclusion criteria: 1) peer reviewed research, (2) manuscripts published in English (3) unpublished masters or doctoral thesis, (4) substantive reviews, (5) studies that examined the relation between one or more forms of hostile clinician behaviour experienced by nurses and patient care, (6) studies that examined the relation between hostile clinician behaviours and features of the nursing work environment and patient care. Through the initial screening process 106 manuscripts were identified for scrutiny. Excluded from this pool were studies of faculty incivility and cross sectional survey studies that did not specifically identify the relations between hostile clinician behaviours and patient care. Following this initial process 95 manuscripts were retrieved for full reading. Of these 95 the majority of those excluded reported the impact of hostile clinician behaviours upon nurses or the nursing work environment without evidence of any association with patient care (n = 36) or did not specifically examine hostile clinician behaviours n = 19), with two further studies of workplace violence excluded as pooled data in the samples meant it was not possible to isolate the effect of clinician behaviours from other sources of violence i.e. patients and visitors. Additional reasons for exclusion included: duplication of data presented in another paper included in the review (n = 2); abstract reported findings that were not included in the paper (n = 5); poor or incomplete descriptions of the methodology (n = 2); and, reported abuse of patients which did not involve hostile behaviour between clinicians (n = 1). The search strategy , Australia (n = 7) and Canada (n = 3). The majority of the studies involved investigating the experiences of nurses employed in hospitals or large health centres (n = 16) or nurses in specific states or regions (n = 3), while two studies investigated students enrolled in nursing programs. Eighteen studies focused upon investigating various forms of hostile clinician behaviours categorised as disruptive behaviours, intimidation, horizontal violence and bullying, aggression, and verbal abuse. Six studies examined features of the nursing workplace, including nurse-physician collaboration and teamwork and associations with standards of care or specific adverse events. The remaining studies examined issues such as intention to leave, ethical and legal frameworks informing practice and factors that influence nurses self-esteem, agency and clinical reasoning.A meta-analysis of the quantitative data was not feasible due to the heterogeneity of behaviours and outcome measures investigated. The JBI-MAStari appraisal instrument for descriptive and case study designs guided the appraisal of quantitative studies. During this appraisal studies were excluded from the review on the basis of poor methodological quality if they scored less than 4 using the MAStari checklist. Based on assessed points, each reviewed study fell into one of three categories: low (score = 4–5), moderate (scores = 6–7) or high (scores = 8 or >). To assess the quality of studies reporting qualitative data the ten item JBI-QARI checklist from the Joanna Briggs Institute  was emplAll studies involving human subjects had obtained institutional ethics approval. The most common limitation of the quantitative studies related to sampling and study design. The majority employed non-random samples and are rated at risk of selection bias and limited inference on causality. The limited use of randomisation in dealing with confounding factors reduces the generalisability of findings. Of the two studies that employed randomisation, this was not reported in sufficient detail to be rated as adequate to establish control of selection bias. A further limitation of the majority of the correlational studies was the use of nurses’ self-reported perceptions on quality of care and exposure to hostile behaviours, with the recall period varying from the preceding year or for an undefined period. Distinguishing features between the high and medium rated quantiative studies was the detail on inclusion criteria for the sample and the reliability of measuring effects in the higher rated studies. Quantitative studies investigating features of the nursing work environment employed measures with established construct validity; in contrast few of the studies specifically examining hostile behaviours employed validated measures of these consturcts. Of note, six of the quantitative studies assessed to be of low quality reported little or no detail on the survey method. Descriptive statistics, correlation and regression analysis were the more common statistical analysis. Response rates in the quantitative studies varied from 37.0% to 80.3%. Of the survey studies reporting qualitative data, one was rated moderate quality; the majority of these studies provide little detail on the process for refining categories and themes for the open-ended responses. The absence of this information made it impossible to evaluate the presence or extent of reporting bias in the qualitative data presented from the majority of these studies.The more common limitation of qualitative studies was related to the congruence between the study methodology and representation and interpretation of data. Although the majority of qualitative studies reported several methods to increase trustworthiness of the analysis, including full transcription of audio taped interviews and member checking, little detail was provided in a number of studies. Three qualitative studies were rated low. These studies demonstrated little congruence between the methodology and analysis and interpretation of data. The authors also provided little detail on analysis methodology and it was not possible to determine concepts such as trustworthiness of the analysis.Using content analysis  the careThrough aggregating the data in this way, four themes emerged: (1) Physician-nurse relations and patient care, (2) Nurse-nurse bullying, intimidation and patient care, (3) Reduced nurse performance related to exposure to hostile clinician behaviours, and (4) Nurses and physicians directly implicating patients in hostile clinician behaviours. The details of each of these themes are presented below.Physician behaviours and physician-nurse relations were specifically examined in fourteen studies in this review ,36,39-41., [Particular care of interest in these studies was the degree to which satisfaction with nurse-physician relations were associated with nurse reported quality of care and the occurrence of adverse events. McCusker et al.  reported.,  reportedOther studies reported that physician intimidation played a role in medication errors and contributed to nurses’ failure to clarify medication orders for which they held concerns ,27,36. AP < .01) [Nine of the studies examining nurse-physician relations and patient care employed either the Practice Environment Scale of the Nursing Work Index (PES-NWI) ,24, the P < .01) . In examP < .01)  reportedP < .01)  nurse seP < .01) ,24,30.Four qualitative studies ,29,41,43Nurse-nurse bullying and intimidation and its relation with care was specifically reported in ten studies ,36,38,39In three survey studies ,31,38 anAn additional focus in a number of studies reviewed was the extent to which hostile clinician behaviours impacted features of staff performance with the potential to influence patient care. In the survey study by Strauss  respondeIn addition, in five survey studies that included analysis of narrative responses, nurse avoidance and delayed communication was described to place patients at increased risk or delay treatment by impacting negatively upon the flow of clinical information and patient care ,36-38. Ir = 211, p ≤ 0.01). The study did not examine the nature of these relations in any detail.The study by the Institute of Safe Medication Practices  was one Five studies reported the ways in which patients were directly implicated in hostile clinician behaviours ,34,36,39The findings of this review lend support to the claims that hostile clinician behaviours can impact unfavourably upon patient care. Importantly, understanding the nature of this relationship in any detail is made difficult due to the variability in study designs and the small number of studies identified to be of high quality. Overall, we found little robust evidence detailing the nature and extent of the relationship between hostile clinician behaviours and patient care, the evidence is mostly small in size and weak to moderate in quality. It is perhaps important to note that studies rated as low in this review ,38,39,51It is important to note that while a small group of highly rated survey studies employed valid and reliable instruments, and a few included reliable secondary data sources to identify the association between nurse-physician relations and patient care ,24,30, nThe findings from our review indicate that both nurse-nurse and nurse-physician hostile behaviours have the potential to impact on patient care and care. The types of hostile behaviours reported ranged from isolating a colleague and refusing them assistance through to directly involving patients in the abuse. Importantly, while hostile clinician behaviours experienced by nurses are widely recognised to include behaviours such as overt aggression and intimidation, this review has drawn attention to the place of more subtle behaviours and their potential to impact on patient care. An important contradiction was evidenced through the review, the majority of survey studies focused upon examining nurse-physician hostile relationships at the exclusion of nurse-nurse relationships. We found no rigorously designed and executed studies that examined nurse initiated hostile behaviours and their relationship with patient care. This is remarkable, particularly given the extensive evidence regarding the prevalence and nature of nurse-nurse hostile behaviours.Although there is evidence that nurse-assessed quality of care measures when validated against independent measures of patient mortality have been found to be a good predictor of actual nursing outcomes , confirmOf note, we failed to find survey studies that employed instrumentation sufficiently refined to capture the breadth of hostile behaviours between clinicians reported in the qualitative studies reviewed. This is a notable observation and may reflect the country of origin of the studies; the majority of qualitative studies were undertaken in Europe and Australia while instrumentation and survey studies largely emanated from North America. Drawing upon our findings, future research may modify existing instruments or develop new measures to more specifically explore the relations between hostile clinician behaviours and clinical outcomes. To strengthen study designs, future research can utilise more probability sampling and analysis of secondary data sources for clinical outcomes. The application of higher level multivariate statistical analysis, such as structural equation modelling can be utilised to understand the relationships between hostile behaviours, other workplace factors and clinical outcomes. These studies might usefully shed light on potential intervention strategies.An important limitation identified through this review is that no studies have specifically examined hostile behaviours and reliable secondary sources of outcome data. Furthermore, the variability in the conceptualisations of hostile clinician behaviours and the associated measurement instruments may limit the validity of the findings.It is evident from this review that the implications of hostile clinician behaviours upon patient care and patient care processes are potentially profound and more complex than often postulated. The paucity of robustly designed studies indicates that this is a comparatively under researched area and findings from this review suggest this may be a significant omission in our understanding of the factors that influence nurses work environment and patient care. The findings from the review provide the basis for further investigation or the development of conceptual models and working hypothesis to extend understanding of this phenomenon and guide the further development of intervention strategies.The authors declare that they have no competing interests.MH and JD participated in design of the study, MH undertook the literature search, MH and DJ participated in manuscript reviews, MH and JD drafted manuscript. Both authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1472-6955/12/25/prepub


Epileptic seizures are characterized dynamically on multiple scales in space and time. Understanding the relations between components within and across those scales is among the fundamental goals of computational neuroscience ,2, togetThrough this framework, we investigate plausible biological causation of epileptic dynamics such as electrical and chemical synaptic connectivity, excitation/inhibition ratios, and combine them to experimental data recorded from rodent hippocampus. This multiscale architecture allows to (i) perform automatic dynamical analysis of a particular neural system, (ii) characterize the level of biological accuracy required to portray epi-phenomena, and (iii) design new experiments to comprehend seizure mechanisms. We discuss the validity of our results with regard to both biologically and computationally oriented investigations that have been performed on the topic to provide a line of thoughts for future research.


Sex is an important factor in the prevalence, incidence, progression, and response to treatment of many medical conditions, including autoimmune and cardiovascular diseases and psychiatric conditions. Identification of molecular differences between typical males and females can provide a valuable basis for exploring conditions differentially affected by sex.Using multiplexed immunoassays, we analyzed 174 serum molecules in 9 independent cohorts of typical individuals, comprising 196 males and 196 females. Sex differences in analyte levels were quantified using a meta-analysis approach and put into biological context using k-means to generate clusters of analytes with distinct biological functions. Natural sex differences were established in these analyte groups and these were applied to illustrate sexually dimorphic analyte expression in a cohort of 22 males and 22 females with Asperger syndrome. Reproducible sex differences were found in the levels of 77 analytes in serum of typical controls, and these comprised clusters of molecules enriched with distinct biological functions. Analytes involved in fatty acid oxidation/hormone regulation, immune cell growth and activation, and cell death were found at higher levels in females, and analytes involved in immune cell chemotaxis and other indistinct functions were higher in males. Comparison of these naturally occurring sex differences against a cohort of people with Asperger syndrome indicated that a cluster of analytes that had functions related to fatty acid oxidation/hormone regulation was associated with sex and the occurrence of this condition.Sex-specific molecular differences were detected in serum of typical controls and these were reproducible across independent cohorts. This study extends current knowledge of sex differences in biological functions involved in metabolism and immune function. Deviations from typical sex differences were found in a cluster of molecules in Asperger syndrome. These findings illustrate the importance of investigating the influence of sex on medical conditions. Sexual dimorphism in underlying processes in medical conditions are numerous and diverse, occurring in diseases ranging from autoimmune and cardiovascular conditions to neurological conditions Physiological and molecular mechanisms causing sex dimorphisms have also been investigated in the context of cardiovascular diseases. Myocardial infarctions in women result in a higher mortality rate and poorer prognosis compared to men An increased understanding of sex dimorphisms in biological regulation may also help to elucidate potential differences in treatment response. For example, growth hormone, which has been used to treat a variety of irregularities associated with cardiovascular, immune, metabolic, psychological and other biological functions, is less effective in women than men http://myriadrbm.com/. Accessed 2012 May 18). The applied multiplexed immunoassay platform has been used previously to explore molecular changes in cancer and autoimmune, cardiovascular, gastrointestinal, neurological, and various other diseases, many of which show sex differences Studies measuring sex differences at the molecular level have so far been limited to the investigation of only a few molecules and specific disease and inflammation processes Protocols for the study were approved by ethical committees at all involved university hospitals (see below) and carried out in accordance with the Declaration of Helsinki. Informed written consent was obtained from all participants. Individuals with a family history of mental illness or medical conditions like hypertension, type II diabetes, cardiovascular, or autoimmune diseases were excluded from the study. Pregnant females were also excluded from the study. A total of nine cohorts of typical individuals were used in this investigation. Cohort 1 was from the Autism Research Centre, University of Cambridge, Department of Psychiatry, UK; cohorts 2 and 3 were from University of Cologne Department of Psychiatry, Germany; cohorts 4 to 6 were from the University of Muenster, Germany; cohorts 7 and 8 were from the University of Magdeburg, Germany; and cohort 9 was from Erasmus Medical Centre in the Netherlands. In addition, a separate cohort of adults with Asperger syndrome (Cohort 10) was obtained from the Autism Research Centre, University of Cambridge, Department of Psychiatry, UK. Diagnosis of Asperger syndrome by psychiatrists was based on the Structured Clinical Interview for the Diagnostic and Statistic Manual-IV-Text Review Disorders and the DSM-IV-TR. Biological sex was used to classify males and females. Females were not excluded for contraceptive use and were at variable times in the menstrual cycle. Blood was collected in the morning after overnight fasting, serum prepared and 181–247 analytes measured using multiplexed immunoassay analyses in a CLIA-certified laboratory at Myriad-RBM , as described previously The statistical programming software R was used to match controls, replace missing analyte values, remove outliers, and to perform meta-analysis. For each of the nine cohorts, typical males and females were matched according to age, BMI, waist circumference, smoking, and cannabis consumption. Demographic details including available metadata used for matching in all nine cohorts are shown in 2 test Meta-analysis was carried out using the non-parametric Cliff’s delta as a measure of effect size All determined p-values were adjusted for the false discovery rate according to the method of Benjamini and Hochberg To assign molecules to biological pathways, we first employed a clustering approach to group analytes with similar concentration patterns. For this purpose, k-means clustering was performed on standardized analyte levels measured in the largest cohort (cohort 7). To avoid the influence of outlying observations on the clustering, such values were replaced with a uniform random number between the minimum and maximum analyte values. The number of clusters was pre-specified to 6, but different qualitatively similar results were obtained by using other cluster numbers.http://www.ingenuity.com/. Accessed 2012 April 18). Main biological functions were determined by identifying overrepresented functions of the molecules in the cluster. These biological functions were verified using the Database for Annotation, Visualization and Integrated Discovery (DAVID ) version 6.7 (DAVID website. Available: http://david.abcc.ncifcrf.gov/. Accessed 2012 Oct 16) The main biological functions for the analytes in each cluster of related molecules were identified using Ingenuity Pathway Knowledgebase (IPA) software with all measured molecules as the reference dataset . Principal components were used to create a single composite variable summarizing the information of all molecules in each cluster. For this purpose, we used the first principal component of standardized analyte concentrations in each cluster and determined sex differences. These were combined across cohorts using a random effects meta-analysis. Since principal components are indifferent with respect to sign, this was determined using the average sign of the individual standardized molecular concentrations within each cluster. The average sign was calculated from the molecules with the highest principal component loadings. Subsequently, ANOVA was used on all principal component scores to quantify sex-by-condition interactions in groups of analytes. P-values were adjusted for the false discovery rate with the Benjamini and Hochberg method  and After data pre-processing, a pooled Cliff’s delta was calculated for each of the 174 serum molecules across the nine cohorts of typical individuals. Of these, a total of 77 analytes were present at significantly different concentrations between male and female participants after adjusting for the false discovery rate   Figure 2This is the first large-scale study investigating molecular sex differences in serum of typical individuals. The present findings provide insight into biological pathways with specific differences in male and female participants, significantly extending current knowledge of sex-specific molecular profiles. These naturally occurring differences provide a baseline for comparison against diseases and may help to uncover pathways involved in disease-related sex dimorphisms. A particular strength of the present study was the multiplexed investigation of a large number of molecules covering multiple biological pathways. This allowed a comprehensive assessment of changes in these pathways at the time of sampling and circumvents problems associated with combining results from single molecular assays across studies.The most significant finding was a higher level of molecules associated with oxidation of fatty acids and hormone function in female participants. It is well known that lipid metabolism differs between males and females, and multiple studies have suggested that these differences are not only a consequence of phenotypical differences such as percentage of body fat, but also related to sex dimorphisms in metabolism itself The molecules found to be associated with higher fatty acid metabolism in females included adiponectin, leptin and apolipoprotein AI. In contrast, molecules involved in lipid transport, including most of the measured apolipoproteins, showed inconsistent sex differences. To the best of our knowledge, this is the first report showing different effects of sex on lipid metabolism and transport. Elevated lipid metabolic rate coupled with few changes in the levels of many of the apolipoproteins involved in lipid transport in females may reflect intrinsic sex differences in the handling of lipids, including metabolism, transport and storage. For example, a study investigating basal, postabsorptive very low density lipoprotein – triglyceride (VLDL-TG) kinetics identified higher female secretion rates as well as differences in production in clearance A second important finding was that higher levels of fatty acid metabolism and hormone regulation-related molecules coincided with elevated levels of immune cell chemotaxis proteins in males. This is interesting since molecules related to immune cell growth and activation showed the opposite behaviour and were increased in females.+ T cells and CD4/CD8 T cell ratios in blood, along with higher cytokine expression during infection and stronger T cell humoral immune responses It has been established that humoral and cell-mediated immune responses are generally more active and robust in females compared to males and that inflammation and production of inflammatory markers show sex differences Recruitment of immune cells to sites of infection and inflammation is necessary to coordinate immune response and is important in disease, as the type of chemokine produced in a specific condition influences inflammation Differences in cytokines and inflammatory processes have also been linked to alterations in lipid metabolism, providing further support for the co-occurrence of such differences in the present study. Adiponectin has been found previously to be elevated in females and this sex difference decreased linearly with the stage of diabetes progression. The inflammatory molecules C-reactive protein (CRP) and IL1 receptor antagonist (RA) were also increased in pre-diabetic and diabetic women, and these increased even further as the disease progressed, relative to the findings in males To evaluate sex dimorphisms deviating from the variation seen in normal controls, we investigated a cohort of participants with Asperger syndrome, which is characterised by a particularly pronounced sex difference in incidence. This analysis led to identification of an interaction in a clustered group of molecules enriched in fatty acid catabolism and hormone regulation functions, indicating a deviation from normal sex variation that affected an entire system of molecules. Interactions for individual molecules within the cluster have previously been shown in Asperger syndrome in In summary, we have established that important sex differences exist in human serum using a multiplex immunoassay system. Specifically, we found sex differences in molecules related to metabolism and immune cell function, which may be explored more deeply in the context of disorders associated with sex effects. We have also shown that a cluster of molecules associated with fatty acid metabolism and hormone levels exhibits sex dimorphic differences in a cohort of adults with Asperger syndrome. Such differences indicate that Asperger syndrome, and potentially other autism spectrum conditions, may develop differently in males and females according to sex-specific molecular pathways Table S1Clusters of molecules. Assignment of all molecules in cohort 7 using k-means clustering.(XLSX)Click here for additional data file.


Consensus is lacking on specific and policy-relevant measures of neighborhood attributes that may affect health outcomes. To address this limitation, we created small standardized geographic units measuring the transit, commercial, and park area access, intersection, and population density for the Portland, Oregon metropolitan area. Cluster analysis was used to identify six unique urban forms: central city, city periphery, suburb, urban fringe with poor commercial access, urban fringe with pool park access, and satellite city. The urban form information was linkable to the detailed physical activity, health, and socio-demographic data of 2,005 older women without the use of administrative boundaries. Evaluation of the relationship between urban forms and walking behavior indicates that older women residing in city center were more likely to walk than those living in city periphery, suburb communities, and urban fringe with poor commercial access; however, these women were not significantly more likely to walk compared to those residing in urban fringe with poor park access or satellite city. Utility of small standardized geographic units and clusters to measure and define built environment support research investigating the impact of built environment and health. The findings may inform environmental/policy interventions that shape communities and promote active living. Urban forms, or areas with different combinations of built environment characteristics, are believed to influence people's daily physical activities. Urban sprawl correlates with increasing automobile dependency and sedentary lifestyle over the past half century . In respChallenges with quantifying built environment measurements, including inconsistent attribute definitions, different scales of data, and varying data quality by jurisdictions, make it difficult to compare between studies designed to quantify the benefits of certain urban form in relation to physical activity. Studies with built environments measured at the individual level typically gathered information by surveying individuals' perceptions of the environment , 15, 16,These research gaps provided an opportunity for the current study to expand on the existing literature investigating the association between built environments and walking among older women by developing refined built environment measures in order to identify distinct urban forms. A better understanding of the relationship between built environments and walking behaviors could lead to urban design and planning policies that promote walking, thereby generating public health benefits. We hypothesized that a compact urban form promotes walking among older women. Compact neighborhoods with high population density, high street connectivity, and close proximity to transit services, commercial areas, and parks were posited to be favorable to pedestrian activity. High connectivity and convenient access to amenities were hypothesized to shape transportation choices and encourage utilitarian and leisure walking, and high population density was anticipated to support investment of infrastructure and amenities. Older women residing in these compact areas are expected to walk more than those residing in remote areas with low population density, poor street connectivity, and poor accessibility to transit services, commercial areas, and park areas. Our analysis used data from participants in the Portland, Oregon, site of the Study of Osteoporotic Fractures (SOF), a national multicenter observational study of healthy, community-dwelling women age 65 years and older recruited in 1986 from four metropolitan areas in the United States. Women were recruited irrespective of bone mineral density and fracture history; those unable to walk without assistance and those with bilateral hip replacements were excluded. All women provided written consent, and the SOF study was approved by each site's institutional review board. Although only baseline data were examined for the current study, prospective data collection included clinical exams and questionnaires to assess longitudinal change in anthropometric and demographic factors, medical history, and information on functioning, quality of life, and lifestyle . MeasureThe subset of SOF participants from Portland, Oregon, totaled 2,419 subjects. In the current analysis, we excluded 347 women (14.3%) who resided outside of the urban growth boundary (UGB) and 67 women (2.8%) whose residence could not be geocoded . Thus, the analytic sample was restricted to 2,005 subjects who resided within the Portland UGB, representing 82.9% of the total Portland, Oregon, SOF cohort.Six neighborhood measures were created using the existing Portland Metro's Regional Land Information System (RLIS) administrative data and ArcGIS 9.3 . Among this set of six measures, two measures of accessibility to transit services were included: distance to bus stop and distance to light rail station. Two measures of residential/commercial/recreational land use mix were included: distance to commercial area and distance to park area. One measure of street connectivity was created: street intersection density. One measure of residential distribution was created: population density. Spatial information was unavailable for 1986; therefore data from the earliest available year were used. The 1988 archival transit data from TriMet, the local transit agency, was digitized to develop the distance to bus stop and light rail station variables. Metro-maintained zoning and park data from 1990 were used to create the distance to commercial area and park area variables. A 1988 streets file was established for measuring the intersection density variable, and 1990 Census block population data was adopted for developing the population density variable. 2 (or 80 meters2), the length for each side of the grid would take roughly one minute of brisk walking to complete. Usage of high-resolution grid cells to quantify built environment attributes minimized the geographic unit of measure. The refined geographic units for establishing built environment measures lessened the potential bias associated with the use of coarsely grouped measures, in which neighborhood characteristics might be wrongly assumed as the experience for the individuals . The high-resolution cell size also facilitated linkage of localized resident neighborhood measures to the subjects based on their mapped residential address location. The six built environment variables were developed in a raster environment for the entire Portland metro area. Each grid cell was set at 264 feetThe neighborhood measures were standardized to ensure comparability among measures with different scales. The four distance variables  were measured in Euclidean distance; shorter distance indicated better accessibility. The two density variables, intersection density and population density, were created using the kernel density function, accounting for the number of street intersections within a quarter mile buffer from each grid cell and the number of persons in a one mile buffer; higher number indicated greater density.The reliability and validity of the built environment measures were evaluated using a combination of GIS analysis processes and statistical tests. Vector/direct distance and density measurements for the six attributes were established for the study sample and compared to the raster approach. Various tests and graphs used for assessing the level of agreement between built environment measures developed through the raster method, and the vector method indicated reasonable agreement , meaningn = 1,572) walked five or more blocks a day.SOF participants reported the total number of blocks walked daily (12 blocks = 1 mile) for utilitarian and for leisure purposes; we added these measures to create the overall number of blocks walked daily. Since a fair share of the participants (11%) reported no walking at all, this variable was dichotomized into walking less than five blocks a day, and walking five or more blocks a day. Five blocks is equivalent to about 400 meters or a quarter of a mile. This amount of walking has been found to provide health benefit to sedentary older adults . As a reWe used k-median statistical clustering to group grid cells with similar values of accessibility to transit, land use mix, street connectivity, and residential density into clusters representing types of urban-form. The Calinski-Harabasz stopping rule was used to determine the optimal number of clusters that would maximize the between group differences while minimizing the within group differences of the built environment measures considered . Grid ce2), smoking (pack years), self-reported health, history of stroke, and history of arthritis/rheumatism. Additional potential confounding variables included block group level neighborhood characteristics from the Census: demographic composition, education, occupation, poverty, income, and household type. All potential confounders with a univariate P value less than 0.25 were considered in the preliminary model. Variables were removed from the model one by one beginning with the variable with the highest P value until all variables in the model were significant at α = 0.05. The pairwise comparisons of the impact on walking by different urban forms were also explored to identify urban forms that might have impacted walking differently. All statistical analyses were conducted using Stata 11 .Subject characteristics were summarized using descriptive statistics. Multivariable logistic regression models were used to assess the association between urban-form and walking while controlling for confounding variables. Potential confounding variables included individual characteristics of the women: age, years of education, marital status, overall exercise , BMI  or who burned more than 2500 kcal per week through exercise compared to those who exercise less (OR: 2.49). On the other hand, the likelihood of walking as compared to the reference group decreased for women who rate their health fair, poor, or very poor (OR: 0.52); smoked 1–40 pack-years (OR: 0.88) or over 40 pack-years (OR: 0.66); were overweight (OR: 0.83), or obese (OR: 0.59); had a history of stroke (OR: 0.57).Few studies have either quantified built environment characteristics using high-resolution geographic unit or have used clusters to classify attributes of the built environment as urban forms. Our analysis pulls together various objective, high-resolution, and standardized measures to identify neighborhood clusters that portray the walking potential for individuals. Cluster analysis identified six homogeneous zones optimizing the joint distribution of built environment characteristics: accessibility to transit, land use mix, street connectivity, and residential density. The analytic process classified the Portland metro area into six unique urban-forms clusters: central city, city periphery, suburb, urban fringe with poor commercial area access, urban fringe with poor park area access, and satellite city. These urban-form clusters accounted for multiple built environment measures jointly without tying to an arbitrary administrative or neighborhood boundary which arguably fails to accurately represent the complex mix of urban forms.Our analytic approach builds upon theory related to the urban built environment and physical activity; empirical use of built environment measures in combination to create a summary characterization of neighborhood type provided greater contextual meaning about the composition of different built environments without committing to a predefined neighborhood boundary. Our successful application of these methods to evaluate likelihood of walking in older women suggests potential utility for future studies. Although a variety of methods have been used to define and quantify characteristics of the built environment, challenges remain with the dissemination of spatial information at refined geographic units. We created objective and localized built environment measures using standardized geographic units that were not bigger than a city block. This measurement scale allowed for geographically relevant built environment measures that were linkable to individual-level data.In previously published research, Riva and colleagues  used cluIn our analysis, older women living in neighborhoods characterized by high population density, high street connectivity, convenient access to amenities, especially transit and commercial areas were most likely to walk for exercise and transport. Our findings are consistent with previous studies that indicate that good infrastructure and design, such as availability of transit services and high street connectivity, encourage people to navigate around the area , 28, 34.Several limitations in the current study must be recognized. Given the cross-sectional nature of our study, it is not possible to determine whether association reflects a preference among active older women to live in the central city areas for reasons such as greater transportation options or better access to amenities. However, neighborhood selection is only one of the many factors affecting mobility of the older population. Generally, factors determining the mobility of the elderly population include life cycle events, environmental factors, and economic status . MoreoveThe age of our data may limit its generalizability to the present day. The geographic and health data used for this study were collected or recorded 26 years ago. The urban process and development experienced in Portland might have since altered the clusters and the composition of neighborhood factors. Some of the findings from the current study may not be directly applicable in contemporary sense due to changes in urban forms occurred since 1986; however, the findings and relative associations may be useful to areas that remained unchanged or have transformed to different urban forms identified. Additionally, the process is still relevant and useful for analysis of the association between built environment and walking using current data or data from other places and regions. This information provides general guidance and direction to changes in built environment that can encourage walking among older women.In conclusion, we found that urban areas with the best access to transit services, close proximity to amenities such as businesses and parks, high street connectivity, and high population density were most likely to promote walking in older women. The use of cluster analysis synthesized the information to account for the complex interactions between multiple built environment attributes. The built environment characteristics of the central city were associated with increased utilitarian and leisure walking among older women relative to the city periphery, the suburb, or the urban fringe with poor commercial area access. The long-term benefits of shifting urban form to be more pedestrian-friendly are critically important with the aging population; changes in built environment would promote higher levels of physical activity among older adults and likely among people of other age groups. This change, in turn, may lower the risk of diseases related to the lack of physical activity in the population. Our analysis approach contributes to the theory related to urban-form typology and promotion of physical activity via the use of methods that quantify built environment characteristics without committing to a predefined neighborhood boundary.


The autism diagnosis requires deficits in social interaction and communication, yet neither occurs in isolation. This brief literature-based analysis provides evidence that other factors are involved in autistic people's atypical social communication. The brain is a complicated system where regions serve multiple, general, and overlapping roles. Sensorimotor and broad cognitive processes underlie both neurotypicals' and autistics' social cognition and behavior. Sensory strengths sometimes underlie autistic people's difficulties, especially in dynamic contexts that require multimodal integration. Social abilities and behaviors occur between people in social contexts, and autistic and neurotypical people share mutual difficulties in understanding one another. This paper challenges attempts to reduce autism to social deficits, and suggests the need for better interpersonal and societal understanding of and support for autistic people.Increasing evidence supports how brain networks integrate complex information, including the contribution of sensorimotor areas to abilities and behaviors considered social in autistic and neurotypical people. A recent study that sought to identify the components of autistic people's “social brain” identified a sensorimotor circuit as one of the subsystems (Gotts et al., A brain region called the insula exemplifies the complexity of challenges facing autistic people. Once considered to play a limited and isolated role (its name means “island”; Craig, The insula also plays a role in unpleasant situations (Wicker et al., Rather than relying on discrete social domains, interpreting other people's thoughts and emotions from their behavior or communication requires more general processes (Gernsbacher and Frymiare, Like sensory processing (Aglioti and Pazzaglia, Moreover, as in the general population (Niedenthal, Although proponents of social deficit theories of autism often emphasize poor autobiographical memory, this originates in part from the sense of smell and broader memory problems. Certain odors automatically induce memories and social contact in neurotypicals (Larsson and Willander, Any comprehensive theory of autism requires recognizing the complex nature of differences, including strengths and impairments that sometimes arise from them, as illustrated in the visual and auditory modalities. Visual strengths relate positively to language and other communication challenges (Atkinson, Similarly, autistic people's auditory strengths relate positively to their language challenges (Bonnel et al., Indeed, the greatest differences often stem from simultaneous multisensory processing and integration of information more broadly. For example, related to visual-motor integration challenges, many autistics learn new movements (Haswell et al., Despite their inclusion in the autism diagnosis as an internal problem, communication, reciprocity, and relationships happen between people and must happen both ways to function (Donnellan et al., Supporting autistic people requires flexibility between autistics and communication partners (Muskett et al., Now that the autism field has begun to intensively study sensory-movement differences, they have become better understood, with potential to spur change. Autistics' challenges with sensory processing, motor skills, emotion regulation, and executive functioning often mask the extent or expression of their social understanding or interest in neurotypical contexts. Neurotypicals do not naturally recognize the full reasons for sensory-movement differences, and their centrality to communication differences, because they involve areas they process intuitively. Critically, as scientific evidence on the presence and importance of autistic people's sensory-movement differences mounts, it increasingly reflects autistic people's lived experiences (Chamak et al.,


A core cognitive trait in EWC appears to be executive dysfunction, with a focus on decision making, response inhibition and cognitive flexibility. Differences between individuals in these areas are likely to contribute to the differences in vulnerability to EWC. The aim of the study was to investigate whether there is a common pattern of executive dysfunction in EWC while comparing anorexia nervosa patients (AN), obese subjects (OB) and healthy eating/weight controls (HC).Extreme weight conditions (EWC) groups along a Thirty five AN patients, fifty two OB and one hundred thirty seven HC were compared using the Wisconsin Card Sorting Test (WCST); Stroop Color and Word Test (SCWT); and Iowa Gambling Task (IGT). All participants were female, aged between 18 and 60 years.There was a significant difference in IGT score (F(1.79); p<.001), with AN and OB groups showing the poorest performance compared to HC. On the WCST, AN and OB made significantly more errors than controls (F(25.73); p<.001), and had significantly fewer correct responses (F(2.71); p<.001). Post hoc analysis revealed that the two clinical groups were not significantly different from each other. Finally, OB showed a significant reduced performance in the inhibition response measured with the Stroop test (F(5.11); p<.001) compared with both AN and HC.These findings suggest that EWC subjects (namely AN and OB) have similar dysfunctional executive profile that may play a role in the development and maintenance of such disorders. Eating disorders (ED) and obesity appear to show parallel patterns in animal continuum hypothesis, ED and obese patients may share certain neurobiological correlates and neural/CNS circuitry pathways related to food reward system and just vary on how frequent or severe these traits are According to reward–saliency; motivation–drive; learning–conditioning; and inhibitory control–emotional regulation–executive functionNeuroimaging studies in humans support the concept that alterations in dopamine circuits (mainly the mesocorticolimbic circuit) are implicated in both, eating behaviors and drug abuse inhibitory control–emotional regulation–executive function circuit. In general terms, and although EWC have been associated with difficulties in different cognitive variables Neuropsychological studies in EWC support the hypothesis of an alteration on the Such impairments on decision making, response inhibition and cognitive flexibility among EWC emphasizes the significance of an appropriate executive functioning for satisfactory control of eating behavior. Latest categorizations of executive functions have proposed that executive tasks vary in their motivational implication, with motivationally relevant tasks considered as “hot" and more abstract tasks considered as “cool" inhibitory control–emotional regulation–executive function circuit in EWC (from AN to obesity) while investigating if AN and obesity display a continuum dysfunctional executive profile , in comparison with HC. It is postulated that both clinical groups should have similar executive profile, although the severity of the dysfunction should differ between them. As far as we know, this is the first study comparing EWC in their executive functions profile employing well-validated measures of decision-making, response inhibition and impulsivity.To our knowledge, no comprehensive research covering the executive functioning profile of EWC has been done to date. Thus, the idea behind the study was to explore the integrity of the All participants were informed about the research procedures and gave their informed consent in writing. Procedures were approved by the Ethical Committee of each of the aforementioned institutions. Seven centers from six Spanish sites  participated: the Eating Disorders Unit , the Department of Endocrinology at the University Hospital of Santiago (Santiago de Compostela); the Department of Diabetes, Endocrinology and Nutrition ; the Department of Endocrinology ; the Diabetes, Endocrinology and Nutrition Department, Biomedical Research Institute of Girona ; the Hospital del Mar Research Institute  and the department of Basic Psychology, Clinic and Psychobiology . Enrolment into the study was between January 2010 and September 2011 and all consecutive patients referred to these institutions were included.The total sample comprised 224 participants . All participants were female, aged between 18 and 60 years and spoke Spanish as their first language. AN patients were diagnosed by experienced clinicians (according to DSM-IV-TR diagnostic criteria) The exclusion criteria in the clinical cases groups (AN and OB) include: (1) History of chronic medical illness or neurological condition that might affect cognitive function; (2) Head trauma with loss of consciousness for more than 2 min, learning disability or mental retardation; (3) Use of psycho-active medications or drugs (4) Being male; (5) Age under 18 or over 60 ; (6) obese patients who have comorbid binge eating disorder (DSM-IV criteria).Healthy controls were recruited through several sources including word-of-mouth and advertisements in the local university. Prior to assessment, HC were asked about lifetime or current presence of an ED or obesity. The lifetime history of health or mental illnesses profile was based on the general health questionnaire (GHQ)-28. Exclusion criteria in the HC group were: (1) Individuals who have suffered lifetime disorder of Axis I mental disorder; (2) Aged under 18 and over 60 years; and (3) Lifetime obesity (IMC>30).All participants underwent a comprehensive neuropsychological and clinical assessment. Weight and BMI on the day of assessment were measured for all subjects. The neuropsychological tests were selected to cover various aspects of executive functions including decision making, response inhibition, strategic planning and cognitive flexibility and were administered by a trained psychologist in a single session and in a randomized order.All participants were assessed with the following neuropsychological tests: (a) The Wisconsin Card Sorting Test WCST;  (b) The The WCST is a classical measure of planning capacity, cognitive flexibility, capacity of shifting among stimulus, and control of impulsive responses not aimed at achieving an objective. Subjects have to match a target card with one of four category cards: a single red triangle, two green stars, three yellow crosses, and 4 blue circles. Cards might be matched by color, number, or shape. After each trial a feedback is given to the participant, indicating if they have matched the card appropriately. However, along the task the classification rule is unpredictably changing. The test ends when the participant has completed 6 categories or 128 trials.This paper and pencil test has shown adequate reliability, and construct validity for the assessment of inhibition and switching skills. The SCWT measures interference control, flexibility and attention. The task included three pages: (1) a page with color words printed in black ink; (2) a page with “Xs" printed in color; (3) a page with names of colors printed in an incongruent color (i.e. word “blue" printed in red ink). Participants have 45 seconds to reading as many words as possible in the first page and name the ink in pages 2 and 3. Three scores are obtained after completed the task: number of words (page 1), number of color-named “X" (page 2) and number of color-named words (page 3). An additional “interference score" is obtained. Higher scores in this variable indicate better capacity of inhibition response.This computer task evaluates decision-making, risk and reward and punishment value. The subject has to select 100 cards from four decks . After each card selection an output is given: gain or a gain and loss of money. Two decks (A and B) are not advantageous as the final loss is higher than the final gain. Decks C and D, however, are advantageous since the punishments are smaller. The final objective of the task is to make the most of profit and gain as much money as possible. This test is scored by subtracting the amount of cards selected from decks A and B from the amount of cards selected from decks C and D. Higher results point to better performance, while negative results point to preference for the not advantageous decks.This is a reliable self-report questionnaire for evaluating some cognitive and behavioral traits that characterized eating disorders. The questionnaire includes 64 items from the EDI which are divided into eight scales: Drive for Thinness, Bulimia, Body Dissatisfaction, Ineffectiveness, Perfectionism, Interpersonal Distrust, Interoceptive Awareness and Maturity Fears. Twenty seven items were also added divided into three new scales: Asceticism, Impulse Regulation, and Social Insecurity. Each item is answered using a 6-point Likert scale and the answers are converted to standardized subscale scores.The SCL-90-R is a self-report questionnaire that measures a wide range of psychological and psychopathological symptoms and includes 90 items. Nine primary symptom dimensions could be obtained: Somatization, Obsession-Compulsion, Interpersonal Sensitivity, Depression, Anxiety, Hostility, Phobic Anxiety, Paranoid Ideation and Psychoticism. Additionally, three global indices are obtained: a Global Severity Index (GSI), used for evaluating the general psychological distress and considered as a summary of the test; a Positive Symptom Distress Index (PSDI), used for evaluating the intensity of symptoms; and a Positive Symptom Total (PST).The BIS version 11 is a 30-item self-report questionnaire that measures impulsivity using three subscales including Attentional, Non planning, and Motor, as well as providing a total score. This scale quantifies personality factors relating to impulsivity using three subscales to measure impulsivity: “Attentional" (cognitive instability and inattention), “Non planning" (intolerance of cognitive complexity and lack of self-control), and “Motor" (lack of perseverance and motor impulsiveness). These subscales can be combined to form a total score. Each subject was asked to answer questions that measure some of the ways in which he or she acts or thinks. These responses are scored 1 through 4 with 4 reflecting the most “impulsive" response. Total scores can range from 30 to 120.2 coefficients.Statistical analyses were carried out with SPSS 19 for Windows . First, analysis of variance (ANOVA) adjusted by the covariates age and education (measured as the number of years of completed studies) valued the association between the diagnosis subtype and the neurocognitive measures. Polynomial contrasts explored the presence of trends (linear and quadratic). Second, multiple regression models also adjusted by age and education valued the predictive accuracy of the BMI  on the neurocognitive measures. Global predictive accuracy was valued with RThe HC group differed from the AN and OB groups with respect to years of education (p<.001) and age (p<.001) See , which wData on neuropsychological test performance of the three groups are presented in Finally, no significant differences on neuropsychological performance as a function of BMI were observed .This study set out to examine whether EWC (from Anorexia nervosa to Obesity) display a similar profile of executive dysfunction. Results showed a similar pattern of abnormal scores in EWC populations across the executive domains assessed by the neuropsychological tasks. Group differences were more marked on the cognitive flexibility and decision making domains, although the inhibition response task also showed marginally statistical differences. Therefore, cognitive results are in agreement with several previous neuropsychological studies showing that EWC deficits extend to several executive processes Our results support the hypothesis that decision making ability is impaired in EWC. Different profiles in IGT performance were found between groups: HCs performed better and learned to keep away from not advantageous decks, while the performance of AN and OB subjects did not improve along the task. Both, AN and OB subjects go for choices that result in elevated immediate gains despite important future losses, showing a similar level of impairment between them. Therefore, according to previous general conducted studies However, the cognitive mechanism underlying the decision making performance in AN and OB subjects might be different. Obesity performance might be associated with an elevated level of impulsivity, which has also been observed in their self-administered questionnaire (BIS) and Stroop test results. It has been established that impulsive subjects have marked limitations for learning suitable associations between reward and punishment Concerning the WCST’s performance our results are consistent with previous research done in both AN and obese subjects Finally, only the obese group showed deficiencies in attention and performance during the Stroop test, suggesting that adult obese subjects respond more impulsively and make more errors on an interference control task. The Stroop task implicated the capacity to choose a weaker but task-relevant answer, regardless a stronger, but task-irrelevant one continuum hypothesis: subjects with either excessive food intake or food restriction show an analogous dysfunctional executive profile The executive deficits observed are not likely to be related to starvation, as shown by the lack of correlation between neurocognitive functioning and BMI score. On the contrary, our results are consistent with the Before taking behavioral actions, the prefrontal cortex control the processing in different parts of the brain, including subcortical and limbic reward areas, activating circuits that manage with current task demands, but according to our goals Our findings are also supported by limited neuroimaging data in EWC adults, which point to dysfunction on the fronto-subcortical circuits in such patients Our study has several important strengths including the relatively large sample size. Furthermore, most of the previous studies on the topic had been conducted on AN patients or obese subjects separately and generally using only one cognitive task. Conversely, our study was specifically designed to test the common executive dysfunction on these populations, by using three well validated executive tests. However, the results of this study should be interpreted in the context of some limitations. First, measures of intelligence quotient (IQ) were not considered, which might have influenced group differences, considering that greater scores of this variable might be related with better executive profile. However, years of education, as a cognitive level measure have been considered on the statistical analysis. Second, the obese subjects were significantly older than the AN patients and healthy controls, although differences in age were statistically controlled. In addition, only females were included in the study, thus the results are not applicable to males and replication with a group including males should be considered. Future studies should consider including additional decision-making, inhibition response and cognitive flexibility tasks in order to better understand such cognitive variables and to shed light on how they work. Measures of working memory and planning can also be included, as some studies including a prospective longitudinal approach have demonstrated alteration in those executive domains in AN patients In addition, the role of some biomarkers, such as hormones levels, on cognitive functions should also be taken into consideration. Some studies suggest that adipokines, and principally leptin, may influence the pathogenesis of dementia To our knowledge, this is the first study that investigates executive functioning in EWC populations. The finding that both, AN patients and obese subjects, exhibit similar difficulties in decision making and cognitive flexibility has several implications. Even as different in their phenotype, EWC does share some cognitive alterations associated with abnormalities of different PFC functional systems. Particularly, they are believed to have commonalities of dysfunction in prefrontal circuitry that mediates executive functions, reward and behavioral regulation. In view of our results, a therapeutic individualized approach, focalized on psychological and cognitive interventions, in line with the cognitive and motivational profiles of the patient might offer significant help in improving healthy eating behaviors, as suggested by other authors


Policymakers and stakeholders need immediate access to many types of research evidence to make informed decisions about the full range of questions that may arise regarding health systems.http://www.healthsystemsevidence.org). The research evidence types include evidence briefs for policy, overviews of systematic reviews, systematic reviews of effects, systematic reviews addressing other questions, systematic reviews in progress, systematic reviews being planned, economic evaluations, and health reform and health system descriptions. Specifically, we describe their distribution across health system topics and domains, trends in their production over time, availability of supplemental content in various languages, and the extent to which they focus on low- and middle-income countries (LMICs), as well as (for systematic reviews) their methodological quality and the availability of user-friendly summaries.We examined all types of research evidence about governance, financial and delivery arrangements, and implementation strategies within health systems contained in Health Systems Evidence (HSE) , 614 systematic reviews addressing other questions, 283 systematic reviews in progress, 186 systematic reviews being planned, 140 review-derived products (evidence briefs and overviews of systematic reviews), 1,669 economic evaluations, 1,092 health reform descriptions, and 209 health system descriptions. Most systematic reviews address topics related to delivery arrangements  or implementation strategies  with far fewer addressing financial (n = 241) or governance arrangements (n = 231). In addition, 2,928 systematic reviews have been quality appraised with moderate AMSTAR ratings found for reviews addressing governance (5.6/11), financial (5.9/11), and delivery (6.3/11) arrangements and implementation strategies (6.5/11); 1,075 systematic reviews have no independently produced user-friendly summary and only 737 systematic reviews have an LMIC focus. Literature searches for half of the systematic reviews  were conducted within the last five years.Greater effort needs to focus on assessing whether the current distribution of systematic reviews corresponds to policymakers’ and stakeholders’ priorities, updating systematic reviews, increasing the quality of systematic reviews, and focusing on LMICs. But we also need to fund research that compares the effectiveness of different systems of care – to reduce our uncertainty about which systems work best for communities. These are empirical, not ideological questions”. Atul Gawande, The New Yorker, 1 June 2009, p. 44just ideological questions”.Policymakers and stakeholders need immediate access to many types of research evidence to make informed decisions about the full range of questions they may have regarding health system arrangements and implementation strategies . While policymakers need to consider many factors for any given decision about health systems , research evidence can also help support and inform their efforts to strengthen or reform health systems or get cost-effective programs, services, and drugs to those who need them. Atul Gawande got it mostly right: “these are empirical, not The timeliness of research evidence was one of two factors that emerged with some consistency in a systematic review of the factors that increased the prospects for research use in policymaking . When thQuestions about the comparative effectiveness of one health system arrangement over another (such as using nurses rather than doctors to deliver certain forms of care) are one of the types of questions for which policymakers and stakeholders may turn to systematic reviews . The likhttp://www.healthevidence.org) if their questions about comparative effectiveness pertain to public health programs and services .Based on the profile of research evidence provided here, particularly the profile of systematic reviews, we believe that greater effort should be placed on several priorities to enhance the usefulness of research evidence about health systems and support its use by policymakers and stakeholders. First, there is a need to support efforts to regularly update systematic reviews, as doing so will ensure that policymakers and stakeholders have access to the most recent synthesized research evidence. As outlined in our findings, half of the systematic reviews in HSE were conducted five or more years ago and a large proportion of those produced by the Cochrane Collaboration have also not been updated within their recommended timeline of two years. Such efforts could be supported  by funders of systematic reviews providing resources both for new systematic reviews and for updating existing reviews .Second, there is a need to increase the average quality of systematic reviews. This is particularly evident for systematic reviews addressing questions other than effectiveness and/or for those addressing topics related to governance and financial arrangements (many of which are reviews addressing other types of questions), which generally scored lower for quality as compared to reviews addressing questions of effectiveness. Registering titles and protocols for systematic reviews and implementing specific quality standards as part of the registration process is a promising mechanism that may help increase the overall quality of reviews. This requirement from the Cochrane Collaboration contributes (at least in part) to the average level of quality for Cochrane reviews being significantly higher than the rest of the reviews in HSE. In addition, PROSPERO  now offeIt should be noted that the AMSTAR tool was designed originally for reviews of effects. However, the fundamental methodological requirements for reviews that include quantitative evidence remain the same and where they differ there is an option to mark a question as “not applicable” to the score. As noted in our results, we did not conduct quality appraisals of reviews that draw exclusively on qualitative research evidence given that there is currently no quality appraisal tool available (at least to our knowledge) that takes into account the unique methods and approaches to data analysis used in these types of reviews .Third, there is a need to use the global stock of systematic reviews to start developing global guidance to support evidence-informed policies about health systems -19. HoweDARE: Database of abstracts of reviews of effects; HSE: Health systems evidence; LMICs: Low- and middle-income countries.http://www.healthsystemsevidence.org). Michael Wilson also helped lead the creation of Health Systems Evidence and contributes to its continuous updating. Kaelan Moat coordinates the continuous updating of Health Systems Evidence.John Lavis led the creation and oversees the continuous updating of Health Systems Evidence (All authors contributed to the conception and design of the study; MGW and JNL drafted the original manuscript; MGW conducted the data analysis; and KM reviewed, revised and conducted a quality check of all data analyses. All authors reviewed and approved the final version of the manuscript.


In the last years, new evidences of the relationship between immune system and bone have been accumulated both in animal models and in humans affected by bone disease, such as rheumatoid arthritis, bone metastasis, periodontitis, and osteoporosis. Osteoporosis is characterized by low bone mass and microarchitectural deterioration of bone tissue with a subsequent increase in bone fragility and susceptibility to fractures. The combined effects of estrogen deprivation and raising of FSH production occurring in menopause cause a marked stimulation of bone resorption and a rapid bone loss which is central for the onset of postmenopausal osteoporosis. This review focuses on the role of immune system in postmenopausal osteoporosis and on therapeutic strategies targeting osteoimmunology pathways. In the last few years, there have been important advances in understanding the processes that regulate physiological and pathological bone turnover. Moreover, a relationship between the immune system and bone has long been speculated, as bone loss is a common condition of autoimmune and inflammatory disorders –3. In thIn this review we focus on the involvement of immune system in the pathogenesis of osteoporosis with particular regard to postmenopausal osteoporosis and on the new therapeutic advances in its treatment.To maintain a structural integrity, the skeleton needs to constantly remodel and repair the microcracks that develop both in cancellous bone, the “spongy” bone present in the vertebrae, pelvis, and metaphyses of long bones, and in cortical bone, the “compact” bone present in the diaphysis of the long bones and surrounding the cancellous bone in the vertebrae and pelvis. Osteoporosis is a systemic skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue with a subsequent increase in bone fragility and susceptibility to fractures , 14.Skeletal fragility can result from failure to produce a skeleton of optimal mass and strength during growth; excessive bone resorption resulting in decreased bone mass and microarchitectural deterioration of the skeleton; or inadequate response to increased resorption during bone remodeling [modeling .The process of bone remodeling occurs in basic multicellular units (BMUs) which include OCs, OBs, and osteocytes and begins with the activation of hematopoietic precursors to become OCs, which normally requires an interaction with cells of the OB lineage. OCs are members of the monocyte-macrophage family and are derived from the fusion of marrow-derived mononuclear phagocyte, the OC precursors (OCPs), which circulate in peripheral blood (PB) . These cMature multinucleated bone resorbing OCs are recognized by the expression of key OC markers including TRAP , calcitoBecause the resorption and reversal phases of bone remodeling are short and the period required for OB replacement of the bone is long, any increase in the rate of bone remodeling will result in a loss of bone mass . MoreoveAside from postmenopausal osteoporosis which affects 30% of woman, there are many causes of secondary osteoporosis which occurs in almost 30–60% of men and more than 50% of premenopausal women . OsteopoInstead, osteoporosis circumscripta, characterized by focal osteolytic lesions , is a peThe evaluation of subjects presenting with osteoporosis should include a detailed history, physical exam, and laboratory testing for secondary causes of osteoporosis, according to the guidelines of the American Association of Clinical Endocrinologists (AACE) . The decline of ovarian function at menopause results in decreased production of estrogen and a parallel increase in FSH levels. The combined effects of estrogen deprivation and raising FSH production cause a marked stimulation of bone resorption and a period of rapid bone loss which is central for the onset of postmenopausal osteoporosis . SeveralEstrogen is the major hormonal regulators of bone metabolism in women and men. Estrogen inhibits the activation of bone remodeling, most likely via the osteocytes, and also inhibits bone resorption, largely by direct actions on OCs, but also by modulation of OB/osteocyte and T-cell regulation of OC formation and activity .α (ERα) binding to a scaffolding protein, BCAR1; the ERα/BCAR1 complex then sequesters TNF receptor-associated factor 6 (TRAF6), leading to decreased activation of NF-κB and impaired RANKL-induced osteoclastogenesis [The direct effects of estrogen on OCs include the induction of OC apoptosis and the inhibition of OC formation. In particular, this hormone inhibits OC formation decreasing the responsiveness of OCPs to the osteoclastogenic cytokine RANKL . Moreoveogenesis . In addition to these direct effects on OCs, estrogen also appears to regulate OC formation and activity indirectly. Combined in vitro and in vivo studies have demonstrated that estrogen suppresses RANKL production by OBs and T and B cells  and alsoα (TNF-α), M-CSF, and prostaglandins [In mouse models, estrogen modulates the production of a number of bone-resorbing cytokines, including interleukin (IL)-1, IL-6, tumor necrosis factor-glandins –53. Thusglandins .Regarding the role of estrogen on OBs, it has been demonstrated that they inhibit OB apoptosis and increase OB lifespan .Estrogen deficiency increases OC formation by increasing haematopoietic progenitors and providing a larger recruited OCP pool –58. The In this respect, studies on humans are few, and the majority of the data have been derived from animal models and cellular cultures, but no consensual picture has emerged from these models.In one of the most interesting studies surface RANKL expression was quantified by two-color flow cytometry on isolated bone marrow mononuclear cells derived from premenopausal women, early postmenopausal women, and age-matched, estrogen-treated postmenopausal women. The surface concentration of RANKL per cell was increased in postmenopausal women compared to premenopausal women and estrogen-treated postmenopausal women by two- to threefold for MSCs, T cells, B cells, and total RANKL expressing cells . This stAnother clinical study underlines the role of T cells in the human postmenopausal bone loss.α and RANKL compared to healthy postmenopausal controls inducing OC formation and activity [This work reported that women with postmenopausal osteoporosis exhibit an increased T-cell activity and elevated production of TNFactivity . In partactivity .α, which is increased in estrogen deficiency, may stimulate the expression of sclerostin via the MEF2 transcription factor. Thus, the increase of sclerostin mediated by TNF-α may at least partially contribute to the pathogenesis of postmenopausal osteoporosis [Recent clinical studies reported that postmenopausal women had a significantly higher concentration of circulating sclerostin than premenopausal women, and that serum sclerostin levels were inversely correlated with the free estrogen index in postmenopausal women . In vivooporosis .A recent study provides evidence that IL-17—a member of Th17 cytokine—promotes bone loss by favoring OC production and inhibiting OB differentiation, whose production is under the negative regulation of estrogen . MoreoveB-cell alterations are well documented during aging and estrogen deficiency, but less is known on B lymphocyte status during osteoporosis. Recently, increasing evidence emerged on an intimate link between B lymphocytes and bone metabolism .Although all women experience menopause and estrogen deficiency, only one third of them suffer from osteoporosis. In a recent study, Breuil et al. studied the phenotypic and functional characteristics of immune cells of 26 postmenopausal women with osteoporotic fractures compared to 24 healthy controls similar for age and estrogen level . They obThe treatment of osteoporosis aims to reduce the incidence of vertebral and nonvertebral fractures responsible for the disease-associated morbidity  and stabThe two main pharmacological approaches to osteoporosis are the anticatabolic and anabolic therapy, which, respectively, decrease bone resorption  and stimThe anticatabolic agents comprise bisphosphonates: etidronate, alendronate, risedronate, and zoledronic acid; estrogen and the selective estrogen receptor modulator (SERM) raloxifene; salmon calcitonin; and denosumab. The only anabolic agent currently available is teriparatide . The treIn the last years, many studies has been made to understand how the immune system impacts and regulates the skeleton in physiological and pathological conditions through the immunoskeletal interface. Although the majority of data derived from studies on animal models, recently new evidence of the crosstalk between immune system and bone has been accumulated in humans in many disease such as postmenopausal osteoporosis.α seem to play a central role inducing OC formation and activity, while IL-17 promotes bone loss by favoring OC production and inhibiting OB differentiation.These data demonstrate that bone loss induced by estrogen deficiency in menopause is a complex effect of a multitude of pathways and cytokines working in a cooperative fashion to regulate osteoclastogenesis and osteoblastogenesis. Among these cytokines, RANKL and TNFThese discoveries have potential for developing new therapeutic strategies for the treatment of these bone disorders. In this respect, denosumab, a fully human monoclonal antibody to soluble RANKL, represents a new therapeutic advance in the treatment of osteoporosis with a novel mechanism of action that leads to the decrease of bone resorption and fracture risk.


The affiliation for the fifth and sixth authors is incorrect. Domenico Masuero and Urska Vrhovsek are not affiliated with institution number 1, but rather with the following institution: Department of Food Quality and Nutrition, Research and Innovation Centre, Fondazione Edmund Mach, San Michele all’Adige (Trento), Italy.


Healthy Kids, Healthy Communities (HKHC) is an initiative of the Robert Wood Johnson Foundation to prevent obesity among high-risk children by changing local policies, systems, and environments. In 2009, 105 community partnerships applied for funding from HKHC. Later that year, the Centers for Disease Control and Prevention (CDC) released recommended community strategies to prevent obesity by changing environments and policies. The objective of this analysis was to describe the strategies proposed by the 41 HKHC partnerships that received funding and compare them to the CDC recommendations.We analyzed the funded proposals to assess the types and prevalence of the strategies proposed and mapped them onto the CDC recommendations.The most prevalent strategies proposed by HKHC-funded partnerships were providing incentives to retailers to locate and serve healthier foods in underserved areas, improving mechanisms for purchasing food from farms, enhancing infrastructure that supports walking and cycling, and improving access to outdoor recreational facilities.The strategies proposed by HKHC partnerships were well aligned with the CDC recommendations. The popular strategies proposed by HKHC partnerships were those for which there were existing examples of successful implementation. Our analysis provides an example of how information from communities, obtained through grant-writing efforts, can be used to assess the status of the field, guide future research, and provide direction for future investments. The Centers for Disease Control and Prevention (CDC) and the Institute of Medicine (IOM) promote adding environmental and policy changes to the existing methods of health promotion to prevent obesity ,2, and tThe objectives of this research were to undertake a content analysis of 41 funded HKHC proposals and compare them with the CDC recommendations to better understand 1) how the HKHC proposed strategies aligned with CDC recommendations that came later, 2) which strategies were proposed by funded HKHC communities with different characteristics, 3) which strategies were proposed by communities despite limited information about effectiveness, and 4) the relationship between broad national recommendations and concrete local community strategies.RWJF received 540 brief proposals for the second round of HKHC funding in February 2009, after launching 9 leading sites in December 2008. From this pool, 110 community partnerships were invited to submit full proposals. Finally, 41 grantees were selected from 105 full proposal submissions based on guidelines laid out in the call for proposals and on reviewers' predetermined criteria. Reviewers included RWJF staff, HKHC staff, members of the National Advisory Committee for the HKHC initiative, and other external representatives with expertise in childhood obesity prevention or community-based initiatives. Each review committee had at least 1 representative from each group. Communities were considered high-priority if they had a high representation of children from low-income households, had a high percentage of racial/ethnic minority groups at higher risk of obesity, and were in states with a high prevalence of childhood obesity .HKHC defined a community as a municipality, county, or region. The HKHC call for proposals focused on approaches that involved policy, systems, and environmental changes for preventing childhood obesity in settings outside the school day. Although the community partnerships were to propose their best thinking on the types of changes they might pursue, the grant program included a planning period during which communities conducted assessments and received technical assistance from the HKHC National Program Office to refine their strategies to meet their community's needs. The HKHC call for proposals was developed independently from the CDC recommendations, despite RWJF involvement in both. The technical assistance provided to applicants focused on guiding them toward selecting approaches that focused on policy, systems, and environmental changes and not on selecting specific strategies.Proposals were submitted to RWJF using an online submission system. Funding decisions were based on need, apparent capacity, feasibility of implementation, and geographic and demographic diversity. The detailed content analysis described in this article was limited to full proposals submitted by the 41 HKHC grantees.We analyzed the content of proposals in a 3-step process that used standardized abstraction and analysis forms. In Step 1, information from the proposal narrative was abstracted into Excel spreadsheets and classified according to the following themes: organizational capacity ; community partnerships ; proposed initiative ; and readiness . Variables describing the communities and partnerships were quantified from the abstracted information. A more detailed analysis conducted on abstracted sections described communities' proposed plans and strategies to map them onto the CDC recommendations. In Step 2, the proposed HKHC strategies were sorted into the 6 broad categories of CDC recommendations described in the box. In Step 3, each proposed strategy was matched with the corresponding CDC recommendation in the identified category. For some, information was available only for broad initiatives from the community; such cases were classified as "strategy to be determinedd" under the appropriate category. The research staff conducted the initial proposal abstraction (Step 1) under the supervision of one of the authors (L.B.). The lead author (P.O.V.) mapped and matched proposed strategies (Steps 2 and 3) with help from a trained research assistant; they both mapped the proposed strategies onto the CDC recommendations, and in cases of disagreement a resolution was made in consultation with another author (L.C.L.).Most of the community strategies proposed were highly consistent with the CDC recommendations and with CDC's suggested indicators to measure progress over time. If a community strategy matched the general aim of a CDC recommendation but was not consistent with the proposed CDC indicator of progress, it was classified as a match with the CDC recommendation. For example, CDC recommendation 18 is to enhance infrastructure to support walking. This recommendation can include a variety of efforts to promote walking; however, the suggested indicator of progress quantifies only paved sidewalk miles in the jurisdiction. HKHC communities chose various strategies to enhance walking, in addition to paving new sidewalks: signalized intersections, signage, and traffic-calming measures. All these strategies were classified as consistent with the CDC recommendation 18.Although CDC used 6 general categories of recommendations, we analyzed only 4 in the analysis. Given HKHC's focus on children aged 3 to 18 years, communities did not propose to encourage breastfeeding (CDC category 3). Also, because the HKHC call for proposals required communities to work through multidisciplinary partnerships (CDC category 6), all communities had established partnerships, and no variability in assessment was anticipated.Not all of the community strategies fit the CDC recommendations. Nevertheless, all community strategies were abstracted to capture the HKHC partnerships' understanding of the possible approaches to policy, systems, and environmental change. These strategies were categorized as community gardens, food policy councils, health promotion, and education.Twenty-three of the funded communities were from the priority states . All butOf the 41 proposals selected for funding, 12 community partnerships proposed to work at the county level, 21 at the municipal level, and 5 at the regional level. In most cases, leadership for these proposals was provided by nonprofit organizations (19 sites) and government departments (14 sites) .CDC category 1: strategies to promote the availability of affordable healthy food and beveragesThirty-one partnerships proposed at least 1 strategy to promote the availability of affordable healthy foods and beverages . ProvidiEleven of the partnerships also proposed increasing the availability of healthier foods and beverages in public service venues, including day care and after-school settings and parks.CDC category 2: strategies to support healthy food and beverage choicesOnly 4 partnerships proposed strategies for supporting healthy food and beverage choices . LimitinCDC category 4: strategies to encourage physical activity or limit sedentary activity among children and youthFifteen of the 41 partnerships proposed strategies to encourage physical activity or limit sedentary activity among children and youth . HKHC paCDC category 5: safe communities that support physical activityThirty-five partnerships proposed strategies to create safe communities that support physical activity, making these the most frequently adopted set of strategies . ImproviHKHC partnerships proposed additional strategies for preventing childhood obesity. Twenty-three partnerships proposed community gardens, making it 1 of the 2 most common community strategies . Seven partnerships proposed creating local food policy councils. The focus of the call for proposals was on policy, systems, and environmental change approaches; health education, marketing, and other promotion strategies were acceptable as part of the overall plan, as long as other funding sources supported such efforts. Eleven partnerships proposed health promotion  and education efforts .Of the 4 partnerships that proposed strategies to support healthy food and beverage choices, all were urban communities from priority states, 3 were in the lowest median household income group, 2 were large , and 2 were communities with low proportions of Hispanics and African Americans . PartnerThe content analysis of 41 HKHC-funded proposals suggests that these community partnerships were already moving in several directions that CDC would recommend soon thereafter. Although RWJF was involved in both projects, the HKHC call for proposals was developed independently from the CDC recommendations. The way in which the HKHC proposals reflected the soon-to-be recommended strategies are therefore noteworthy and encouraging because it implies that the HKHC community partnerships perceive the CDC recommendations to be feasible. The communities could visualize and describe how they would implement such abstract concepts as "promote food access" to achieve their aims. In the absence of evidence for effectiveness, implementation decisions are often based on perceptions of impact, taking into consideration community assets and challenges .Better access to food and recreation facilities and increased personal and traffic safety were common approaches among the 41 grantees. Their community partnerships could envision how to implement these environmental changes. Indeed, many examples of successful food-access efforts in other communities are now available ,8. MoreoSome approaches, however, were not as common among proposals: influencing healthy food choices, limiting calorie-dense foods and beverages outside of school, and zoning for mixed-use development to encourage physical activity. Most examples of success in setting these standards and limits are from schools -14, and HKHC partnerships proposed some strategies that CDC did not recommend. Foremost in that category are community gardens. Despite scant evidence for their role in improving nutrition  and in pFor the most part, the CDC-recommended strategies were applicable to the communities regardless of their size, demographic makeup, location, type of leadership, or age of their partnership. Community differences did appear, however, for the strategies to encourage physical activity and limit sedentary behavior. Urban communities and communities with the lowest proportions of African American and Hispanic populations were most likely to choose strategies to encourage physical activity and limit sedentary behavior. The greater probability of joint-use agreements between communities and schools in urban areas may be due to easier access to school and community facilities compared with access in communities with less dense populations. The lack of these strategies in proposals from predominantly African American and Hispanic communities is of concern. Environmental and policy change strategies show enormous potential, yet are often underused in populations with health disparities ,18.Our analysis has several limitations. The proposals were selected on the basis of criteria of community need , and grants were awarded based on a selection committee's joint assessment of merit. Therefore, they are not necessarily representative of community plans for preventing childhood obesity in the United States. Abstracting strategies from the proposal narratives was challenging because applicants presented their plans in multiple places in their proposals. Every effort was made to abstract information, but some proposed strategies may have been overlooked. Lastly, abstracting and matching proposed strategies with CDC recommendations was a subjective process. To improve the reliability of abstraction, 2 coders matched the strategies and, in case of discrepancies, reached consensus through discussion with another author.A comparison of strategies proposed by the HKHC-funded partnerships and CDC's recommendations for preventing obesity shows that the 2 overlap considerably. Areas for which CDC recommendations were more commonly proposed included providing incentives to food retailers to offer healthier options in underserved areas, increasing the number of farmers' markets, improving access to outdoor recreation facilities, enhancing cycling and walking infrastructure, and enhancing personal and traffic safety. The communities likely consider these strategies feasible to implement, especially given examples in the field. On the other hand, few strategies were proposed by HKHC partnerships in areas where previous implementation had been limited to schools. Changing environments and policies relevant during the school day was not the focus of HKHC. With the exception of joint-use agreements being more popular in urban areas and in areas with lower African American and Hispanic populations, use of strategies did not differ by community demographic characteristics.In addition to providing a snapshot of communities' thinking on approaches for policy, systems, and environmental change strategies for preventing childhood obesity, our analysis provides an example of how information from communities, obtained through grant-writing efforts, can be used to assess the status of the field, guide future research, and provide direction for future investments.