Background. Children with autism spectrum disorders (ASD) commonly exhibit uncooperative behaviors which impede oral care. Previous studies have utilized dentist-report measures of uncooperative behaviors in children with ASD but none have utilized an objective measure of children's behavior or a physiological measure of distress. This study investigated behavioral and physiological distress in children with ASD during routine oral care and examined factors associated with this distress. Methods. Participants were 44 children  aged 6–12 receiving routine dental cleanings. Behavioral and physiological measures of stress and anxiety were collected during dental cleanings. Results. Children with ASD exhibited greater distress, compared to the typical group, on dentist-report and researcher-coded measures of overt distress behaviors and on physiological measures. Correlations between physiological and behavioral measures of distress were found in the ASD but not in the typical group. Behavioral distress was correlated with age in the typical group and with expressive communication ability and sensory processing difficulties in the ASD group; physiological distress was correlated with parent-report of anxiety in the typical group and sensory processing difficulties in the ASD group. Conclusions. Novel strategies may be required to decrease behavioral and physiological distress in children with ASD in the dental clinic. Children with autism spectrum disorders (ASD) exhibit more dental behavior management problems (uncooperative behaviors) compared to typically developing children, with research indicating that approximately 50–72% of children with ASD exhibit uncooperative behavior during dental treatment –3. TheseAutism spectrum disorder is diagnosed based on the presence of specific behavioral criteria including impaired social interaction, social communication, and restricted and repetitive patterns of behavior, interests, or activities . ChildreFactors contributing to a child with ASD's lack of cooperation may include communication difficulties , changesUncooperative and aggressive behaviors during dental treatment have the potential to impede, change, or reduce access to care for children with ASD , 7, 10. Although overt behavioral displays of distress have been frequently examined, no studies have investigated the physiological stress and anxiety experienced by children with ASD during oral care. Since many children with ASD have limited expressive language skills, it may be especially difficult to assess stress and anxiety due to children's difficulty describing their experience; therefore, utilizing objective tools to measure their physiological experience is an alternative way to obtain this information. Electrodermal activity (EDA) is a non-invasive measure of the ability of the skin to conduct an electrical current, which increases when the sympathetic nervous system is activated . The symThe purpose of this study was to investigate the behavioral and physiological stress and anxiety in children with ASD during routine oral care and determine if there are factors other than ASD diagnosis that are associated with behavioral and physiological distress. Using parent- and dentist-reports of anxiety and uncooperative behavior, video-coding of overt distress behaviors, and physiological recordings of stress and anxiety, we examined three hypotheses: (1) children with a diagnosis of ASD will exhibit significantly greater behavioral and physiological stress and anxiety during routine oral care compared to their typically developing counterparts; (2) physiological stress and anxiety will be correlated with measures of overt distress behaviors; (3) child characteristics  will be significantly correlated with behavioral and physiological stress and anxiety in both ASD and typical children.This study was approved for human participants by the Committee on Clinical Investigations (CCI), the Institutional Review Board for Children's Hospital Los Angeles (CCI-11-00250), and the Institutional Review Board of the University of Southern California Health Sciences (HS-12-00521).Forty-four children were recruited for participation in this study, 22 with a diagnosis of ASD and 22 typically developing (TD) as part of the Sensory Adapted Dental Environments to Enhance Oral Health in Children with Autism Spectrum Disorders Study . In the SADE Study, ASD and TD groups underwent two dental cleanings in different environments in a counterbalanced manner; only data collected during the cleanings occurring in the regular dental environment are reported here. Eligibility requirements for both the ASD and the typically developing groups were as follows: (1) aged 6 through 12 years, (2) has an accompanying parent/guardian who speaks English or Spanish, (3) is in need of oral cleaning , (4) does not have a disability such as cleft palate, significant motor impairments , or any known genetic, endocrine, or metabolic dysfunctions that would interfere with oral care or effect EDA, and (5) is willing to participate, able to participate, and has consent of parent/guardian to participate.Additional inclusion criteria for the ASD group included a confirmed diagnosis of ASD using the Autism Diagnostic Observation Schedule (ADOS), as outlined in the Procedures Section. Additional exclusion for the TD group included (1) diagnosis of ASD or any other developmental disorder, (2) diagnosis of any psychological disorder , and (3) sibling diagnosed with ASD. Based on parent report, no children were taking anticholinergic medications which may impact EDA measures .Participants were recruited from (1) current and past Children's Hospital Los Angeles (CHLA) dental clinic patients, (2) lists of participants in previous research studies at CHLA who consented to be approached regarding additional research opportunities, and (3) recruitment flyers posted at the CHLA Dental Clinic and local therapy sites for children with ASD.n = 26), at CHLA prior to the first dental visit (n = 11), or in the home following the first dental visit (n = 8) based on parent preference (see details below in Measures section). For children in the ASD group, parents were asked to provide documentation of the professional diagnosis of autism, including a copy of results from an Autism Diagnostic Observation Schedule (ADOS). If the parent did not provide such documentation, children were assessed for this study by a psychologist research-certified in the ADOS to confirm the diagnosis of an autism spectrum disorder.Parent-report measures to obtain information regarding demographics and children's communication ability, anxiety, and sensory processing were completed in the home prior to the first dental visit  in the dental environment was sent to the participating family; parents were asked to read the story to their children prior to the dental visit in order to increase acceptability of electrode placement on children's fingers. The dental visit consisted of four components: (1) baseline resting period, (2) oral examination, (3) dental prophylaxis (cleaning), and (4) fluoride application.Demographic information was obtained via the parent-report questionnaire and included child's gender, age, ethnicity, race, and parental education level.The Autism Diagnostic Observation Schedule (ADOS) is considered to be the gold-standard for ASD diagnosis . It is a Vineland Adaptive Behavior Scales II (VABS-II), a norm-referenced, standardized parent-report measure of adaptive functioning . In regard to physiological distress in the ASD group, no parent-report measures of general anxiety, dental anxiety, or expressive communication level were significantly correlated with physiological distress during the dental cleaning. Although sensory processing difficulty total score was not correlated with physiological distress, the visual/auditory subtest was significantly correlated with both SCL  and NS-SCR frequency . A correlation approaching significance was found between age and NS-SCR frequency , indicating that the younger the child with ASD, the greater the physiological distress experienced during his/her dental cleaning.In the ASD group  and clinical (n = 1) dental anxiety based on the cut-off scores of Berge et al. [Uncooperative behavior in the TD group was correlated only with age, suggesting that the younger the child's age, the greater the uncooperative behavior. This supports previous research suggesting that younger children are less cooperative during dental treatment . Based oe et al. , we did In the ASD group, expressive communication was correlated with uncooperative behavior on both dentist- and researcher-report measures; this finding is consistent with research by Marshall et al.  which suThese findings highlight that new strategies may be required to decrease uncooperative behavior in children with ASD in the dental clinic, compared to those recommended for typically developing children. For instance, since impairments in communication are highly prevalent in ASD  and loweFor instance, Shapiro et al.  adapted There are several limitations to this study. Due to our small sample size group differences and/or variable correlations may have been masked. Children with ASD are a heterogeneous group; therefore, in this pilot study of 22 participants with ASD some differences in the population may not be evident. The majority of the children with ASD in this study were low functioning in terms of their level of expressive language, so findings may not generalize to children with ASD with more verbal skill. The physiological data of the children in both groups also varied largely, making it difficult for statistical tests to capture a difference. Additionally, due to the non-experimental, correlational nature of this study, causality of the relationship between physiological and overt behavioral distress and child factors cannot be determined. Lastly, our study was conducted at a dental clinic in a teaching hospital whose mission includes serving children with disabilities; therefore, the dental providers may have had more skill than providers in the general community and thus minimized our results. Despite these limitations, this study adds to the understanding of the oral care experiences of children with ASD, specifically as they relate to behavioral and physiological distress and their potential correlates. As the prevalence of ASD is significantly higher today than in the past, estimated in 2014 to be approximately 1 in 68 children in the U.S. , more deChildren with ASD exhibit significantly more uncooperative behaviors during routine dental cleanings compared to typically developing children.Children with ASD exhibit significantly higher electrodermal arousal (non-specific skin conductance response frequency) compared to TD children, indicating greater physiological stress during dental cleaning.Physiological stress (as measured by non-specific skin conductance response frequency) is significantly correlated with overt behavioral distress in children with ASD, indicating that as physiological stress increases so does behavioral distress.Younger age is correlated with uncooperative behavior in typically developing children; in children with ASD, lower expressive communication ability and physiological distress are correlated with uncooperative behavior.Based on this study's results, the following conclusions can be made.


A recently published NIH-funded study named “Bracing in Adolescent Idiopathic Scoliosis Trial” (BrAIST) affirmed the efficacy of bracing for moderate adolescent idiopathic scoliosis (AIS) and reduced surgical recommendations in braced patients. The implications of this study are numerous. BrAIST affirms the value of bracing, but also confirms the importance of wear time, and points to the need to assess compliance with compulsory utilization of brace monitors. Additionally, one of the key implications of the study relates to early detection, possibly heralding a new era for scoliosis screening policy adoption.To engage and enlist the feedback and potential advocacy, on behalf AIS patients, of all persons involved in relevant state agencies, scientific organizations and health care professions.After a short presentation of BrAIST results, its implications will be highlighted on a) brace treatment, b) the importance of compliance, c) the value of screening programs. Subsequently the current concepts and recommendations on screening will be analyzed.Other (Advocacy/Awareness raising report).This established bracing effectiveness, reducing the number of patients who progress to surgery, resulting in cost savings and great benefit for scoliotics, also calls for raising awareness and advocacy of all the involved related professionals. Awareness will be increased by familiarizing people with the a) history and geography of screening policies, b) current evidence about screening, c) impact of screening on frequency of surgical treatment and its negative discontinuation effects on patients, d) the analysis of evolving aim of screening, e) the encouragement for policy statement publications from professional organizations and governmental agencies regarding scoliosis screening, f) by legislating national program and g) by presentations in pertinent scientific meetings. The advocacy will be benefited by a) providing guidelines on setting up these programs, b) recommendations for improvement of a screening program and c) popularizing its additional benefits on its contribution to clinical research on IS aetiology.Due to the fact that the implementation of screening programs is inextricably bonded to non-operative IS treatment, it is believed that this reported “BrAiST” trial will have further impact on IS management swinging the pendulum.


There is a broad consensus and evidence that shows qualified, accessible, and responsive human resources for health (HRH) can make a major impact on the health of the populations. At the same time, there is widespread recognition that HRH crises particularly in low- and middle-income countries (LMICs) impede the achievement of better health outcomes/targets. In order to achieve the Sustainable Development Goals (SDGs), equitable access to a skilled and motivated health worker within a performing health system is need to be ensured. This review contributes to the vast pool of literature towards the assessment of HRH for maternal health and is focused on interventions delivered by skilled birth attendants (SBAs). Studies were included if (a) any HRH interventions in management system, policy, finance, education, partnership, and leadership were implemented; (b) these were related to SBA; (c) reported outcomes related to maternal health; (d) the studies were conducted in LMICs; and (e) studies were in English. Studies were excluded if traditional birth attendants and/or community health workers were trained. The review identified 25 studies which revealed reasons for poor maternal health outcomes in LMICs despite the efforts and policies implemented throughout these years. This review suggested an urgent and immediate need for formative evidence-based research on effective HRH interventions for improved maternal health outcomes. Other initiatives such as education and empowerment of women, alleviating poverty, establishing gender equality, and provision of infrastructure, equipment, drugs, and supplies are all integral components that are required to achieve SDGs by reducing maternal mortality and improving maternal health. Maternal health is one of the main global health challenges in which least progress was witnessed in the year 2015 . The shoUnfortunately, the workforce is distributed unevenly , 10. AsiThe shortage of emergency obstetric care (EmOC) and surgical services in LMICs over the last decade has attracted substantial attention –22. In rThe review derived evidence from randomized controlled trials (RCTs), quasi-RCTs, and prospective before/after and cohort studies on SBAs working at the national, provincial, district, and community levels . Studies were included if (a) they implemented any HRH interventions in management system, policy, finance, education, partnership, and leadership; (b) those were related to SBAs; (c) have reported outcomes related to maternal health such as changes in morbidity, mortality, coverage, or other interrelated outcomes; (d) were conducted in LMICs ; and (e)The search strategy included PubMed articles published from January 2000 to December 2015. The reason to select this time period was to evaluate what progress has been made since the 2000 deadline of the Alma Ata health for all and what improvements followed on the agreement on MDGs. The HRH Global Resource Centre was also searched to access the available studies. Detailed examination of cross-references and bibliographies of identified studies was also performed to identify additional sources of information. The following search strategy was primarily used. [ AND (training OR education OR curriculum OR teaching OR learning OR “patient centered care” OR “patient focused care” OR “staff development” OR medicine OR “postgraduate training” OR “diploma training” OR recruitment OR attraction OR deployment OR employment OR personnel selection OR incentive OR reward OR “cash award”)]. The quality of RCTs and quasi-RCTs was assessed using the Cochrane methods ; howeverThe defined search strategy identified 4565 studies. Of these, 217 were retrieved for full-text review; however, only 25 papers passed the eligibility criteria for inclusion  insertion by auxiliary nurse midwives (ANMs) with physicians at teaching hospitals and found no difference in those who were referred to a specialist after insertion of IUD  . SimilarIn Malawi , clinicaA study from Ethiopia  discusseThe cost of training and deploying trained assistant medical officers (AMOs) was also compared among physicians in Mozambique . They foA different approach was taken in studies conducted in Mozambique . AMOs wiNepal, on the other hand, trained doctors, midwives, and nurses on different aspects of basic and comprehensive EmOC services  and founWe identified four moderate-quality , 45–47 pIn the beginning of 1994, Bangladesh upgraded its EmOC facilities and trained service providers in those facilities . HoweverSimilarly, the Nepal National Safe Motherhood Project , implemeIn Cambodia, to compensate low wages, health care workers demanded unofficial payments from patients in facilities where health care services were provided free of charge. Introduction of a user fee at the national maternal and child health center of Cambodia  assisted.The Indonesian government in order to overcome the shortage of health workers  implemenWe found six low- to moderate-quality prospective before/after studies , 48–52 wIn one study from Rwanda , CARE’s Similarly, in Peru , a decliA major part of this review was aimed at exploring how HRH interventions lead to improved maternal health outcomes, and we also came across studies with successful HRH strategies pertaining to general health outcomes , 18, 53.The WHO framework Fig.  shows thThe review of 25 studies revealed certain reasons why maternal mortality and morbidity is still high in LMICs despite the efforts and policies implemented throughout these years. It is observed that in many LMICs some components of the HRH intervention were applied with positive effects on the maternal health and health care delivery to the rural areas. When a professional (doctor or midwife) is linked up with a strong referral system, maternal health outcomes improve and mortality decreases significantly irrespective of whether the birth took place at home or in a health facility . ProgramIn the review, we found that only few components of the HRH management system were investigated. Most of the studies explored the impact of training and continuing education of the health care providers on maternal health individually or as combined intervention. However, less or no work was found on the HRH systems studying the impact of recruitment, employment, hiring, deployment, migration, health safety, and retirement on maternal health outcomes. Similarly, no study was found on the financial component addressing the budget allocation for salaries and allowances, education and training, and HRH expenditure data. Gaps were identified in other HRH interventions related to staff motivations such as job satisfaction, appraisals, workplace safety, career development, and improvement in the work environment as well as the HRH information system. Moreover, studies that reported the impact of training SBAs on improved health outcomes rarely reported if those results were merely because of training alone or there was a role of other related co-interventions as well.Improvements in HRH are required to be made by LMICs to raise the awareness among women for health care seeking from SBAs and at the same time improving the delivery of health care. The need for a multi-sectoral approach to women health is emphasized. This includes the training of staff, their employment and retention, and improved management systems in the formal health care . It is iWe recommend that more studies need to be conducted on the other HRH management system components such as supervision, partnership, and proper HRH information system development especially in the context of SBAs and their impact on the maternal health. Financial constraint remains the most important barrier to achieve the targets. Therefore, interventions targeting the budget allocations for the salaries and education of the health care providers need to be implemented and their impact on maternal mortality to be studied. It is well documented that more lives of mothers can be saved if adequate importance is given to the EmOC services and if they are made an integral part of the health system , 60. TheIt is important to assess and urgently address the barriers to recruitment, deployment, and retention of skilled personnel in LMICs  and to dFurthermore, it is important to provide health care professionals with ongoing training , 73. A sThe limited management capacity is one of the main reasons of slow progress in maternal health . It is oIt is seen that HRH interventions alone cannot improve the functioning and availability of the skilled health workers. There are many other areas to gain the best outcome regarding maternal health. Female education, empowerment, and gender equality should be emphasized . EffectiThis review suggested an urgent and immediate need for formative evidence-based research on effective HR interventions for improved maternal health in LMICs. The principal challenges in these countries are to strengthen research systems, identify key research questions, and generate the capacity to turn research into practical applications . The stu


The recent prospect of pharmaceutical interventions for cognitive impairment of Down syndrome (DS) has boosted a number of clinical trials in this population. However, running the trials has raised some methodological challenges and questioned the prevailing methodology used to evaluate cognitive functioning of DS individuals. This is usually achieved by comparing DS individuals to matched healthy controls of the same mental age. We propose a new tool, the TESDAD Battery that uses comparison with age-matched typically developed adults. This is an advantageous method for probing the clinical efficacy of DS therapies, allowing the interpretation and prediction of functional outcomes in clinical trials. In our DS population the TESDAD battery permitted a quantitative assessment of cognitive defects, which indicated language dysfunction and deficits in executive function, as the most important contributors to other cognitive and adaptive behavior outcomes as predictors of functional change in DS. Concretely, auditory comprehension and functional academics showed the highest potential as end-point measures of therapeutic intervention for clinical trials: the former as a cognitive key target for therapeutic intervention, and the latter as a primary functional outcome measure of clinical efficacy. Our results also emphasize the need to explore the modulating effects of IQ, gender and age on cognitive enhancing treatments. Noticeably, women performed significantly better than men of the same age and IQ in most cognitive tests, with the most consistent differences occurring in memory and executive functioning and negative trends rarely emerged on quality of life linked to the effect of age after adjusting for IQ and gender. In sum, the TESDAD battery is a useful neurocognitive tool for probing the clinical efficacy of experimental therapies in interventional studies in the DS population suggesting that age-matched controls are advantageous for determining normalization of DS. Down Syndrome (DS) is the most common genetic cause of mental retardation  or unknown etiology, to healthy controls of the same “mental age.” The comparison is assumed to provide an index of global level of mental maturation , gender, and age to neurocognitive variability among DS participants, and to identify specific relationships between cognitive performance and different aspects of functional outcome that could potentially serve for expecting functional change in interventional studies.Eighty-six young adults of both genders with DS, aged 16–34 years, with any of the three DS genetic variations  were enrolled in the study, mainly through the Fundació Catalana de Síndrome de Down (Barcelona) a local foundation specialized in providing health care services and educational programs to participants with DS and their families.https://clinicaltrials.gov/ct2/show/NCT01699711. All participants were drug free during the baseline assessment. Upon arrival at the research center , participants, parents and legal guardians  were informed of the ensuing protocol and they gave their written informed consent before participating. Subjects with neurological disease other than DS, relevant medical disease, unstable co-morbid mental disorder or currently taking any treatment that could interfere with cognitive function were excluded from the study. Other exclusion criteria applied to all the participants were: (i) having suffered from any major illness or undergoing major surgery in the last 3 months before the study; (ii) new or irregular medication in the month preceding the study; (iii) current ingestion of vitamin or catechins supplements or Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) in the 2 weeks preceding the study; (iv) history of gastrointestinal, hepatic, renal, or any other problems that may alter absorption, distribution, metabolism, or excretion of the drug. Genetic variations were documented by chromosomal analysis.The data reported in the present work correspond to the baseline cognitive performance of a cohort of DS participants that participated in a clinical trial NCT01699711, that has been registered in The study was conducted in accordance with the ethical standards laid down in the Declaration of Helsinki and approved by the local ethics committee . At study onset the participants underwent medical examinations and a brief cognitive assessment to estimate their intellectual disability level based on criteria from the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition-Text Revision  . (2) For the analyses of paper and pencil tests, we used normative data from 84 to 87 participants (18–34 years old) from the Spanish Multicenter Normative Studies NEURONORMA young adults Project;  were employed. (1) For the analyses of CANTAB tests, we used norms derived from 51 to 199 control subjects reported in the CANTAB standard norm database  were categorized as having ceiling or floor effects.d”), which is the difference of the means of two independent samples divided by the pooled standard deviation, together with its 95% confidence interval was calculated for all cognitive variables  in cognitive performance between DS participants and age-matched normally developed adults were considered key cognitive processes substantially impaired in DS. In order to assess the severity of impairment the following categories were established: severe impairment (effect size differences larger than three pooled standard deviations: |d| > 3); substantial impairment (|d| > 1.5); moderate impairment (|d| > 1); and mild impairment (|d| > 0.5).We compared the DS group test scores of each cognitive variable to previously published normative data from age-matched healthy controls. Test scores of our DS participants could not be compared to normative data for those tests specifically developed for the assessment of participants with intellectual disability . In order to quantify and determine the gap between DS and normative groups, Cohen's effect size  and functional outcomes of adaptive behavior and quality of life. We only report moderate and strong correlations (r ≥ 0.4). All statistical analyses were performed with the statistical software package R , v3.0.2.To study possible differences in cognitive and functional performance according to IQ, gender, and age, ANCOVA models were fitted for all neurocognitive measures including these three variables of interest. For the analyses, the IQ was categorized into two groups: mild/moderate (IQ ≥ 40) and severe (IQ <40) within the range of mental disability level. Concerning the two categorical variables, these models provide an adjusted estimation of the mean differences between persons with DS with IQ < 40 and persons with DS with IQ ≥ 40, on one hand, and female and male persons with DS, on the other hand. In case of variable age, the models provide an adjusted estimation of the mean difference associated to 1 year of age difference in persons with DS. The differences were considered to be statistically significant if the resulting SD) = 4.3 years; range 16–34 years]. The median IQ for the full sample was 41 , concentrating a slightly higher proportion of participants with moderate intellectual disability  in comparison to those within the severe mental disability range . In terms of gender, the median IQ for males was 40 [K-BIT standardized score: 102 ] and 42 for females [K-BIT standardized score: 108 ]. The average years of schooling  was 13 . In terms of DS genetic variations, the sample showed the usual proportion for this population: most participants had full trisomy 21 , two participants translocation (2.3%), one partial trisomy (1.1%), and one mosaic (1.1%).Socio-demographic data and clinical parameters of the 86 DS participants are provided in Table From the eighty-six participants that participated in the study, 75 were able to reliably complete all cognitive procedures at baseline. Eleven participants could not perform the entire cognitive assessment protocol due to cognitive or behavioral alterations that interfered with testing. From those, 7 participants presented marked language deficit (significant speech and/or comprehension limitations), and 3 participants presented behavioral disturbances or mental block. One case showed poor collaboration during the assessment. Only data from these 11 participants for those tests successfully completed were included in the analyses.Ceiling effects were found for a few variables in the following tests: the Cued Recall test (CRT), the Paired Associates Learning (PAL), the Cats and Dogs and the Simple Reaction Time (SRT). These were observed in the CRT for the total immediate recall  and the total delayed recall, in the PAL for the number of stages completed, in the Cats and Dogs for the correct score, and in the SRT for the percent of correct answers. Regarding floor effects, only a few were detected in the verbal and visual span backwards  and in the total score of the Weigl Sort Test.d), and confidence intervals (95% CI) of cognitive performance in DS and age-matched typically developed adults are summarized in Table d) of the deficits in DS: a severe dysfunction of language capacity, a substantial deficit on attention span and executive functions, a moderate deficit in episodic memory and learning abilities, and mild differences in psychomotor speed  differences in measures of cognitive capacity between participants of IQ < 40 and those of IQ ≥ 40, with the exception of performance on the SRT, Digit Span Backwards and the Weigl Sort Test. These assessing reaction time, verbal working memory and mental flexibility, respectively. As expected, in all cases higher IQ levels were associated with greater cognitive attainment irrespective of chronological age or gender . In addition, significant effects of IQ level were observed in adaptive behavior in most functional skill areas assessed with the ABAS-II such as Communication, Community Use, Functional Academics, Home Living, Health and Safety, Self-Direction, Social Skills, and ABAS total score (p < 0.05). Once again, those participants with higher IQ showed better outcomes in adaptive behavior and thus better competence in daily living. However, no significant effect of IQ emerged on the Kidscreen-27 (p > 0.05) which assessed different aspects of quality of life.ANCOVA models were applied to analyze effects of IQ, gender, and age on the baseline cognitive performance of DS participants, adjusting for co-variables Tables –5. IQ wap < 0.05), but not in visual memory recognition . Concerning executive functions, women showed significantly better performance (p < 0.05) in cognitive flexibility and planning. Furthermore, they exhibited higher scores in receptive language and attention measures of span capacity, and better accuracy in the simple reaction time task (p < 0.05). Gender-related differences were also observed in the functional domain, with women having a significantly better performance than men in adaptive behavior, specifically in Functional Academic (emergent literacy and numeracy basics for current life use) (p < 0.05), but described lower health perception regarding their physical wellbeing as reported by parents on the Kidscreen-27 . Overall, these results indicate that gender exerts significant effects on cognitive and functional capacities in DS participants, favoring women against men in cognitive functioning and adaptive skills but not in QoL.Concerning gender, significant differences between men and women were mainly observed in cognitive performance and less in functional outcomes. Women performed significantly better than men of the same age and IQ in most cognitive tests Tables –5, with p < 0.03). Parents responding to the Kidscreen 27 Psychological and Total score items indicated poorer psychological wellbeing and overall health perception as the children grew older.Significant negative trends rarely emerged on quality of life outcomes linked to the effect of age in DS participants after adjusting for IQ and gender. Age did not affect adaptive behaviors, nor most measures of quality of life significantly. However, age did affect psychological well-being, which affected total quality of life  and executive components of verbal fluency . Positive associations were also found for working memory for visual and verbal information , planning , attention span for visual and verbal information , and memory recognition for immediate and delayed recall of visual information (PRM (%) immediate recall: r = 0.45, ; PRM (%) delayed recall: r = 0.48, ). Negative associations were found between Functional Academics and error rate in the visual associative learning task  and planning accuracy deficits . These results indicate that higher attainment in functional academic skills (emergent literacy and numeracy basics for current life use) could be strongly linked to a more efficient overall cognitive functioning in DS participants. In addition, a positive consistent association emerged between Functional Academics and IQ . These results confirm previous assumptions, and suggest that specific cognitive measures are potentially good end-point measures for estimating changes in functional outcome in clinical trials.The strongest associations were found between cognitive performance and functional academic skills (ABAS-II). Positive associations emerged between Functional Academics and measures of receptive and expressive language , receptive and expressive language . In addition, a negative association was observed between ability to communicate and the number of errors performed during visual associative learning . Community use was mainly related to cognitive measures of receptive language  and executive components of working memory for visual and verbal information  and planning . In all cases, a higher performance in specific cognitive tests was consistently related to a greater ability to communicate in daily life and higher independent functioning within the community.Communication and Community use subscales of the ABAS-II also correlated consistently with cognitive attainment. Positive correlations were found between communicative abilities and visual attention span . Other cognitive measures were consistently correlated with the ABAS Total Score such as visual attention span  and executive components of visual working memory  and planning . These results indicate that better language comprehension, attention, and executive functioning are the cognitive capacities more closely related to higher competence in overall adaptive skills and, therefore, in everyday life independence for DS participants.Finally, language comprehension emerged as having the most consistent association with the overall score in adaptive behavior  , using chronologically age-matched fully-developed subjects for comparison as a more useful approach for the characterization of the DS cognitive profile. This battery also provides clinically useful measures closely linked to prefrontal-temporal brain networks and to functional competence in everyday life following interventional studies. Finally, our study emphasizes the need to determine the modulation effects of intellectual quotient, gender, and age on cognitive treatments.The results of this study support the demonstration  in DS. Findings substantiated by the higher performance exhibited in the recognition and cued recall trials as compared to free recall, and by the higher ratio of perseverative errors compared to intrusions in the verbal learning task (see Supplementary Results). This mnemonic profile indicates that poor monitoring and executive control, rather than storage difficulties, are mainly responsible for poor memory performance. In this regard, structural neuroimaging studies have related impaired memory performance in DS adults with reductions in the prefrontal, hippocampus, and parahippocampal areas of these subjects , and with global adaptive competence. No effect of IQ was observed, however, on quality of life outcomes. A finding that could partly be explained by the fact that in euploids, emotional aspects are more closely related to QoL perception than IQ , while improvements in complex functional skills in DS require longer periods Costa,  We agreeSeveral limitations should be considered when interpreting the results of our study. First, the neurocognitive assessment tools we employed may have influenced the DS cognitive profile observed. The majority of the tests included in our TESDAD battery are, nevertheless, recognized as valid and feasible for tracking cognitive deficits in pathological conditions (Ersche et al., In summary, the TESDAD battery is a useful tool for a standardized neurocognitive assessment of DS in clinical trials. The most relevant features of this battery include a chronological age-matched approach, high sensitivity for detecting mild to moderate cognitive deficits, and a strong relationship to clinically relevant functional measures. These features make the battery suitable for capturing changes derived from therapy which allow its efficacy to be established.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


In this paper, we aim to systematically analyze the effectiveness of community based interventions (CBI) for the prevention and control of non-helminthic diseases including dengue, trypanosomiasis, chagas, leishmaniasis, buruli ulcer, leprosy and trachoma. We systematically reviewed literature published up to May 2013 and included 62 studies in this review.Findings from our review suggest that CBI including insecticide spraying; insecticide treated bednets and curtains; community education and cleanliness campaigns; chemoprophylaxis through mass drug administration; and treatment have the potential to reduce the incidence and burden of non-helminthic diseases. Lack of data limited the subgroup analysis for integrated and non-integrated delivery strategies however, qualitative synthesis suggest that integrated delivery is more effective when compared to vertical interventions; however, such integration was possible only because of the existing vertical vector control programs.Community delivered interventions have the potential to achieve wider coverage and sustained community acceptance. Eradicating these diseases will require a multipronged approach including drug administration, health education, vector control and clean water and sanitation facilities. This would require high level governmental commitment along with strong partnerships among major stakeholders. As discussed in paper 1 of this series . For a mThe World Health Organization (WHO) recommends widespread vector control and environmental management to prevent the spread of vector borne diseases including dengue, trypanosomiasis, chagas, leishmaniasis and trachoma. These should be coupled with mass and selective chemotherapy, community participation, active diseases surveillance, health education, capacity building and training of community health workers (CHW), provision of drugs, surgical treatment and rehabilitation for deformities . For traWe systematically reviewed literature published up to May 2013 to identify studies on the effectiveness of CBI for the outlined non-helminthic diseases. Our priority was to select existing randomized, quasi-randomized and before/after studies, in which the intervention was delivered within community settings and the reported outcomes were relevant to the diseases under review. A separate search strategy was developed for each disease using appropriate key words, medical subject heading (MeSH) and free text terms. Search was conducted in the PubMed, Cochrane Libraries, Embase, and WHO Regional Databases. Studies that met the inclusion criteria were selected and double data abstracted on a standardized abstraction sheet. Quality assessment of the included randomized controlled trials (RCT) was done according to the Cochrane risk of bias assessment tool . The outWe identified 3452 titles from search conducted in all databases. After screening titles and abstracts, 348 full texts were reviewed, of which 62 studies; 21 RCT and 41 before after studies, were included in the review  for dengue, chagas and leishmaniasis; mass drug administration (MDA) for the prevention and treatment of leprosy and trachoma and SAFE strategy for trachoma. Two of the studies focused on removing affected dogs and using insecticide treated dog collars for preventing leishmaniasis ,7. All tCBI for dengue preventive measures including use of ITN and curtains significantly reduced dengue positive serostatus by 70%  while community education alone did not have a significant impact Figure . TreatmeMajority of the studies support that community delivered interventions have the potential to achieve wider coverage and sustained community acceptance -19 with One of the major reported enabling factor in community directed programs included intersectoral cooperation involving close coordination between external organization, local municipality and the Ministry of Health ,17. AnotA few of the barriers reported to hinder effective program implementation and coverage included incomplete surveillance coverage, climatic conditions favorable to the vectors and lack of adequate and sustained community participation . House-tFindings from our review suggest that CBI including insecticide spraying; ITN and curtains; community education and cleanliness campaigns; chemoprophylaxis through MDA; and treatment have the potential to reduce the incidence and burden of non-helminthic NTDs. Figure Lack of data limited the subgroup analysis for integrated and non-integrated delivery strategies however, qualitative synthesis suggest that community delivered interventions with a combination approach have the potential to achieve wider coverage and sustained community acceptance. It also suggests that integrated delivery is more effective when compared to vertical interventions; however such integration requires pre-existing vertical vector control programs. We did not find any quantifiable data for buruli ulcer and African trypanosomiasis. These two diseases continue to pose great economic burden as the treatment costs for buruli ulcer often exceed per capita government spending on health . SimilarIn January 2012, WHO published a roadmap setting targets for the prevention, control, elimination and eradication of all the NTDs; setting 6 targets for the elimination of 5 NTDs by 2015, and a further 10 targets by 2020, either globally or in selected geographical areas, for 9 NTDs. Since then progress has been made to increase coverage for the MDA. Essential preventive and control measures including community-based early detection, health education and MDA can be achieved through CHW training and capacity building . These pEradicating NTDs will require a multipronged approach and our review findings suggest that a range of CBI including drug administration, health education, cleanliness campaigns, vector control and clean water and sanitation facilities have the potential to prevent and control this set of diseases. This would require efforts to overcome the barriers to sustainable implementation including improved surveillance, access and coverage. High level governmental commitment along with strong partnerships among major stakeholders with continuous support by the WHO, United Nations Children’s Fund, World Food Programme and the World Bank, relevant national and international non-governmental organizations and key donors to mobilize resources. A major component of CBI should always be the community itself as success of existing NTD programs depends on community structures, customs, beliefs and values that keep community health worker proud and motivated.CBI: Community based interventions; CHW: Community health workers; HAT: Human African trypanosomiasis; IDoP: Infectious Diseases of Poverty; ITN: Insecticide Treated Nets; MDA: Mass drug administration; MeSH: Medical subject heading; NTD: Neglected tropical diseases; PHC: Primary health care; RCT: Randomized Controlled Trials; WHO: World health organization.The authors declare that they have no competing interests.ZAB was responsible for designing and coordinating the review. AA and HM were responsible for: data collection, screening the search results, screening retrieved papers against inclusion criteria, appraising quality of papers and abstracting data. RAS and JKD were responsible for data interpretation and writing the review. ZAB critically reviewed and modified the manuscript. All authors read and approved the final manuscript.


The level of phylogenetic congruence between the individual genes has been investigated utilizing Bayes factors. We also explore how changes in the substitution models affected the observed incongruence between partitions of our data set.The typical antbirds (Thamnophilidae) form a monophyletic and diverse family of suboscine passerines that inhabit neotropical forests. However, the phylogenetic relationships within this assemblage are poorly understood. Herein, we present a hypothesis of the generic relationships of this group based on Bayesian inference analyses of two nuclear introns and the mitochondrial cytochrome Terenura antwrens, the wing-banded antbird (Myrmornis torquata), the spot-winged antshrike (Pygiptila stellaris) and the russet antshrike (Thamnistes anabatinus) are sisters to all other typical antbirds. The remaining genera fall into two major clades. The first includes antshrikes, antvireos and the Herpsilochmus antwrens, while the second clade consists of most antwren genera, the Myrmeciza antbirds, the "professional" ant-following antbirds, and allied species. Our results also support previously suggested polyphyly of Myrmotherula antwrens and Myrmeciza antbirds. The tests of phylogenetic incongruence, using Bayes factors, clearly suggests that allowing the gene partitions to have separate topology parameters clearly increased the model likelihood. However, changing a component of the nucleotide substitution model had much higher impact on the model likelihood.The phylogenetic analysis supports both novel relationships, as well as traditional groupings. Among the more interesting novel relationship suggested is that the Myrmeciza antbirds and the Myrmotherula antwrens obviously need taxonomic revisions. Although, Bayes factors seem promising for evaluating the relative contribution of components to an evolutionary model, the results suggests that even if strong evidence for a model allowing separate topology parameters is found, this might not mean strong evidence for separate gene phylogenies, as long as vital components of the substitution model are still missing.The phylogenetic results are in broad agreement with traditional classification of the typical antbirds, but some relationships are unexpected based on external morphology. In these cases their true affinities may have been obscured by convergent evolution and morphological adaptations to new habitats or food sources, and genera like  The typical antbirds (Thamnophilidae) is a speciose family within the furnariid radiation (sensu ) of the In traditional classifications, the antpittas  and antthrushes (Formicariidae) were grouped together with typical antbirds in an even larger family. However, the support for the expanded antbird family was indeed weak, and both morphological -6 and moMyrmotherula to Formicivora )However, when independent evidence is lacking and incongruence occurs between individual data partitions, it may be difficult to determine whether particular partitions are better estimates of the species tree than others. Researchers might favor the "total evidence approach" for this particular reason (even though the argument for not combining data partitions with significant levels of incongruence have strong merits). However, the degree of incongruence between individual gene trees could be used to determine whether the phylogenetic conclusions should be based on the combined data set, or only those parts that are similar among the different partitions. A commonly used approach for analysing combined data with maximum likelihood is to assume a single (the same) substitution model for all of the combined genes . A sb and the two nuclear genes (myoglobin and G3PDH), but all combinations of the three genes were examined. However, limitations in the substitution models might be the most important explanation to observed incongruence between data partitions, rather than an intrinsic phylogenetic incongruence  eTamnistes and Pygiptila), antvireos and Herpsilochmus antwrens in clade B  and the "large" antshrikes  are two examples where our results are congruent with traditional classifications. The suggested relationships between the Hypocnemis and Drymophila antbirds, and the Herpsilochmus antwrens and the antvireos (Dysithamnus), respectively, have also been proposed previously based on molecular data )The posterior probabilities of trees and parameters in the substitution models were approximated with MCMC and Metropolis coupling using the program MrBayes . The gen1 compared to another M2, given the data X, and is calculated as the ratio of the model likelihoods, B12 = f(X|M1)/ f(X|M2). The model likelihoods f(X|Mi) are difficult to calculate analytically but can be estimated by using the output from an MCMC  for typical antbirds, and Irestedt et al. [1] for families. Abbreviations: AHMN = American Museum of Natural History, New York; FMNH = Field Museum of Natural History, Chicago; LSUMZ = Louisiana State University, Museum of Natural Science; NRM = Swedish Museum of Natural History; ZMCU = Zoological Museum of the University of Copenhagen. References: (1) Irestedt et al. [1]; (2) Fjeldså et al. [45]; (3) Johansson et al. [65]; Fjeldså et al. [66].Click here for file


The Endocrine Disruptor Screening Program (EDSP), mandated by the United States Congress in the Food Quality Protection Act of 1996, attempts to protect public health from adverse endocrine effects of synthetic chemical compounds by establishing a new testing regime. But the complexities and uncertainties of endocrine disruption and its broader regulatory and social context all but ensure the failure of this policy. This article addresses the issues facing EDSP comprehensively and in detail, in order to move beyond the current regulatory paradigm and foster discourse on a positive role for scientists in support of EDSP's end goal: to protect public health. The United States Environmental Protection Agency (EPA) created the Endocrine Disruptor Screening Program (EDSP) to regulate endocrine-disrupting chemicals (EDCs) as mandated in the Food Quality Protection Act of 1996 (FQPA) and the Safe Drinking Water Amendments Act of 1996 (SDWAA). Unlike the more easily appreciated effects of toxic chemicals, EDCs interact with the human body indirectly by mimicking, blocking, or otherwise disrupting the normal function of hormones. The prolific study of endocrine disruption has since uncovered many unconventional and worrisome mechanisms, exposures, and effects [[D]evelop a screening program, using appropriate validated test systems and other scientifically relevant  information, to determine whether certain substances may have an effect in humans that is similar to an effect produced by a naturally occurring estrogen, or such other endocrine effects as the [EPA] Administrator may designate  Administrator shall, as appropriate, take action under such statutory authority as is available...as is necessary to ensure the protection of public health" .Unfortunately, due to four complicating factors, EDSP cannot protect public health. The first complication is practical considerations. EPA estimates the universe of potential EDCs numbers more than 87,000 items. Testing this many chemicals would take an unreasonable investment of time and resources, but even scientifically prioritizing among them is highly problematic. The second complication is hazard complexity. Establishing relationships between EDCs and health hazards proves very difficult if not impossible. Endocrine-disrupting action breaks all the rules and assumptions that have guided toxicology through the era of modern chemical regulation. Without these simplifying assumptions, science cannot establish causation efficiently or with sufficient certainty for regulation. The third complication is exposure complexity. Determining exposure levels becomes more important and more difficult because the low-dose effects of many EDCs means that low-dose and transient exposure can be just as or more dangerous than high-dose and prolonged exposure. Assessments typically discount these ill-defined exposures, but we can no longer assume them insignificant. The final complication is regulatory deficiencies. Although FQPA and SDWAA provided new authority to test for endocrine disruption, they provided no new authority for the regulation of EDCs. As a result, multiple government agencies must manage future test-positive EDCs under their jurisdiction using fragmentary and incomplete statutory authorities and different regulatory standards. This introduces significant confusion to the institutional and decision-making aspects of the EDSP regulatory framework.and legal standards, and an ethical position that prioritizes profit over human health by placing the burden of proof on public and environmental health advocates. These assumptions remain all but unchallenged in the U.S. context, and thus comprise a paradigm. While this paradigm has faced some critique in the context of carcinogenic pesticides and toxic industrial chemicals, questions of its efficacy remain unresolved. Because EDCs present new and fundamental difficulties for the science underlying the regulatory paradigm, a critical analysis of EDSP provides a more compelling case that the current chemical regulatory paradigm is in need of radical revision.The EDSP policy design represents revision at the margins of U.S. chemical regulatory policy, not a radical revision. EDSP employs the same basic strategy used to regulate carcinogenic pesticides or toxic industrial chemicals – scientifically proving harm prior to regulating a chemical. Two important aspects of this strategy include an epistemological assumption that science has the capacity to 'prove' harm under the relevant scientific This study investigates the policy design of EDSP and its broader context. The above four complications play varying roles in each stage of the EDSP policy design as discussed below. See figure The following discussion provides a comprehensive empirical basis for considering alternatives to the status quo. This study aims to integrate the many factors conditioning the failure of EDSP for the purpose of fostering constructive discussion on U.S. regulatory policy concerning EDCs and chemicals more generally. The author does not possess a unique answer to the many and complicated issues surrounding endocrine disruption and the U.S. chemical regulatory paradigm. Given that no simple, well-developed alternatives exist that merit immediate consideration by decision-makers, it stands to reason that more creative and open discussions of EDCs, the chemical regulatory paradigm, and possible roles for the scientific community may provide long-term payoffs in public and environmental health protection well worth our attentions today.The design of EDSP consists of three main stages: priority setting, screening and testing, and a risk analysis leading to potential regulation. The complications shown in figure Politics section below). Politics and policy design play significant roles in the modern chemical regulatory regime. Hence, a comprehensive analysis of EDC regulation must take politics and policy design as well as science into account. The appropriate standard by which to judge these disparate policy elements is Congress's mandated end goal: to protect public health. We will return to this issue.In other words, there is reason and precedent to doubt our ability to accomplish this feat. More importantly, despite our best efforts to mobilize science in support of this difficult task, policy mechanisms allow chemical use and abuse to go forward regardless of scientific results or lack thereof. "Pesticides are registered for use while important health and safety data are still being generated; they may continue to be used after evidence of their hazards is given to EPA; they may be registered through alternative processes that bypass important tests; and they may never be required to be tested for certain kinds of hazards"  and quantitative structure activity relationships (QSAR) both discussed below, have attracted attention and resources due to a general recognition of this problem. But more important than our current lack of data, EDCs operate with a high degree of complexity. Because of system complexity, some uncertainty about endocrine disruption probably cannot be resolved – resulting in some abiding doubt about the significance of a chemical as a potential endocrine disruptor. The scientific community and EPA seem quite cognizant of this complexity, but its relevance for policy and for the end goal of protecting public health deserves careful attention.EPA has not realized their ideal of priority setting based on hazard and exposure information because of the catch-22 mentioned above. As a result, "EPA's proposed approach focuses on human exposure-related factors rather than on a combination of exposure- and [hazard]-related factors" . While tScreening and testing section below) implies that exposure to some EDCs at extremely dilute doses may have a greater effect than massive exposure to that same chemical. Transient or low-concentration EDCs may also pose a greater risk than other high-exposure chemicals. Low-dose effects and other exposure complexities make exposure alone a poor proxy for setting priorities. Since different vulnerabilities and sometimes different health effects manifest at different developmental stages, any exposure-only judgment will run into significant difficulties defining spatial and temporal boundaries for exposure determinations. Some short-lived chemicals may have important endocrine- disrupting effects, but may not show up in EPA's most robust exposure data sources: biological sampling and environmental monitoring  to the point where people think it's real" . Non-monOther factors complicate a scientific determination of hazard. Two chemicals can interact in ways that alter their effects. Some chemicals together inhibit their individual effects, reducing or preventing an adverse effect where one is expected. Others simply add their effects together, and yet others interact synergistically, magnifying the effect either or both would normally have. "Synergistic interactions are the most problematic, because they indicate that the effects of multiple chemicals together can be significantly more powerful than might be predicted simply by adding up their effects one at a time. Regulatory science rarely incorporates any interactions; it is incapable, at present, of coping with synergies" . RegardlAnother serious complication involves the selection of testing endpoints, or dysfunctions possibly caused by EDCs. Some of the dysfunctions already identified through animal studies include cancer susceptibility and birth defects, but also more subtle endpoints like immunological dysfunction, suppression of secondary sex characteristics, decreased fertility, increased aggression, decreased mental capacity and focus, disrupted brain development, etc ,35. WhilA risk analysis concludes the EDSP policy design. EPA claims it will use its standard human health risk assessment process for EDCs . Simply Priority setting section and the hazard complexities treated in the Screening and testing section. These complexities include: HAZARD – low-dose effects, mixtures and synergies, and uncertain endpoints; and EXPOSURE – transient and low-concentration exposure to EDCs, maternal metabolism of bioaccumulated EDCs, varying vulnerability and response by developmental stage, poorly understood exposure sources, vulnerable subpopulations, and cultural, social, and economic patterns and spatial and temporal bounds of chemical release and exposure. More science cannot resolve all of these complexities and uncertainties.Because EPA's risk analysis demands an explicit integration of hazard and exposure data, the risk assessment itself is vulnerable to the exposure complexities treated in the in utero might easily be a chaotic or stochastic system. Ambiguity refers to a situation in which existing scientific data support equally valid but competing interpretations of risk , feedback loops, temporal delays between cause and effect, chaotic or stochastic system behavior, large numbers of intervening variables, and inter-individual variations. Uncertainty refers to limitations of the human analysis of a complex system. While science is often employed 'to reduce uncertainty,' the complexity of a system sets bounds on the prospective certainty of informed scientific judgment. For example, further science can never remove the chaos from a chaotic system or the randomness from a stochastic one. And to illustrate the point, exposure of a fetus to environmental EDC contamination isk , the Federal Food, Drug, and Cosmetic Act (FFDCA), the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA), or the Safe Drinking Water Act (SDWA). The agencies with regulatory jurisdiction for EPA's list of 87,000 chemicals are: the Environmental Protection Agency (EPA), the Food and Drug Administration (FDA) in the U.S. Department of Health and Human Services, and the Food Safety and Inspection Service (FSIS) in the U.S. Department of Agriculture. EDSTAC recommended and EPA adopted the following list of chemicals for endocrine disruptor testing: 75,500 commercial chemicals listed under TSCA, 900 pesticide active ingredients, 2,500 pesticide inert ingredients, 5,000 cosmetic ingredients, 3,000 food additives, an unspecified number of nutritional substances, and an unspecified number of natural hormonally active plant residues .Testing and enforcement authority for this universe of chemicals is fragmentary. For example, EPA has authority under FIFRA and FFDCA to set tolerances for pesticides on food, but enforcement authority falls to FSIS for meat and poultry products, and FDA for other food items. The authority is also incomplete. For example, FDA has authority over the estimated 5,000 cosmetic chemicals, but FDA has no authority to require any information from the manufacturer or to mandate product safety testing. FDA's regulatory authority over cosmetics begins only after a product (possibly without any safety information) enters the market. Additionally, the standards by which to regulate differ. Under TSCA and SDWA the economic costs of regulation must be balanced against the public health threat, but under FIFRA and FFDCA, economics can be considered in only narrowly crafted situations – the standard is largely health-only based. FFDCA and FIFRA as amended by FQPA use the "reasonable certainty of no harm" standard. This standard translates into a 95% certainty that fewer than one in a million additional cancer deaths will occur due to the expected exposure over a lifetime. No translation specific to EDCs of this standard is yet available. TSCA, on the other hand, must prevent "unreasonable risk" of injury to health or the environment. A risk is "unreasonable" if the risks exceed the benefits associated with that activity, including economic benefits. SDWA explicitly requires a consideration of the cost of compliance to state, local, and other water systems when setting safety standards.The estimated 2,500 pesticide inert ingredients may defy regulation due to trade secret norms, poor EPA data quality, and historic government neglect ,40. AddiThe complexity of the institutional and legal landscape (multiple interacting agencies with multiple overlapping mandates and authority) creates substantial regulatory confusion. In this situation, the powers and responsibilities of different government agencies might be interpreted differently by other agencies or by affected parties. Such confusion leaves room for interpretation that may require long delays and intensive court battles to resolve. The history of TSCA indicates that such confusion  as well as the menace of legal action can lead to crippling regulatory inaction . By requFinally, the role of politics in regulatory decision-making deserves note. The conventional ideal of regulation under the current paradigm is that good science leads to an informed decision-maker who can then remove or limit a proven hazardous chemical from commerce . The complexities of endocrine disruption science, practical considerations, and the regulatory deficiencies discussed above impose limitations on this conventional ideal. Neglecting the role of politics in regulatory decision-making, however, is perhaps this ideal's most significant omission. A variety of academic and government research as well as environmental and public interest group analysis points to the failure of testing regimes to produce significant regulation or protect public health . Hazard complexities, including low-dose effects, mixtures and synergies, and uncertain endpoints, contribute further obstacles to an unambiguous scientific determination of harm (see Screening and testing section). Under current policy mechanisms, these complications of endocrine-disruption science will prevent any meaningful regulatory action. Essentially, endocrine disruption is too complex and our science too uncertain; most scientific information regarding EDCs will remain ambiguous, with the available information supporting quite different judgments of risk.The internal validity of 'science leads to regulation' presumes the capacity of science to prove harm with sufficient certainty to regulate. Exposure complexities, including transient and low-concentration exposure to EDCs, maternal metabolism of bioaccumulated EDCs, varying vulnerability and response by developmental stage, poorly understood exposure sources, vulnerable subpopulations, and cultural, social, and economic patterns and spatial and temporal bounds of chemical release and exposure, place the ability of science to make solid exposure determinations in significant doubt  came to the conclusion that the failure of testing in the past means we need to test better in the future ,41. ThouThe relevance of science for regulatory decision-making lies predominantly outside the current trend of increasingly detailed mechanistic investigation of endocrine disruption. While endocrine disruption science can contribute much to a decision-maker, it cannot provide unambiguous information that 'objectively' determines the correct decision. But science could help guide decision-making under conditions of ambiguity; uncertainty does not entail 'anything goes.' On the contrary, the uncertainty itself might guide decision-making better than any other factual information. The 2001 Intergovernmental Panel on Climate Change reports provide a precedent in the explicit treatment of uncertainty – the reports indicate the relevance of scientific information for decision makers by ranking scientific conclusions by Bayesian confidence estimates  . This emA franker treatment of uncertainty can improve the relevance of science to decision-making and promote realistic expectations of science and the scientific community. Such progress might turn the spotlight on more significant impediments to regulatory decision-making under conditions of ambiguity, such as the difficulty of testing 87,000 chemicals and the role of politics and values in making regulatory decisions. Scientists can take action within their own communities to support the policy goal of protecting public health by exploiting and improving the role scientific information plays in chemical regulation. The possibility that scientists can empower decision makers and the public by developing community standards and norms explicitly addressing uncertainty is one creative idea, but more are needed. The key to progress is taking an active and creative role in support of the protection of public health. Waiting for a solution in the form of national legislation has failed to inspire significant change over the last several decades. But explicit action within the scientific community that discourages unrealistic expectations of science will support long-term progress on chemical regulatory policy and the protection of public health.DDT – dichlorodiphenyltrichloroethaneEDC(s) – endocrine disrupting chemical(s)EDSP – (U.S.) Endocrine Disruptor Screening ProgramEDSTAC – Endocrine Disruptor Screening and Testing Advisory CommitteeEPA – (U.S.) Environmental Protection AgencyFDA – (U.S.) Food and Drug AdministrationFFDCA – (U.S.) Federal Food, Drug, and Cosmetic ActFIFRA – (U.S.) Federal Insecticide, Fungicide, and Rodenticide ActFSIS – (U.S.) Food Safety and Inspection ServiceFQPA – (U.S.) Food Quality Protection ActHPV – high production volumeHTPS – high-throughput pre-screeningPCBs – polychlorinated biphenylsQSAR – quantitative structure activity relationshipsSDWA – (U.S.) Safe Drinking Water ActSDWAA – (U.S.) Safe Drinking Water Amendments ActTSCA – (U.S.) Toxic Substances Control ActThe author(s) declare that they have no competing interests.


Consumers of research  frequently use standard critical appraisal tools to evaluate the quality of published research reports. However, there is no consensus regarding the most appropriate critical appraisal tool for allied health research. We summarized the content, intent, construction and psychometric properties of published, currently available critical appraisal tools to identify common elements and their relevance to allied health research.A systematic review was undertaken of 121 published critical appraisal tools sourced from 108 papers located on electronic databases and the Internet. The tools were classified according to the study design for which they were intended. Their items were then classified into one of 12 criteria based on their intent. Commonly occurring items were identified. The empirical basis for construction of the tool, the method by which overall quality of the study was established, the psychometric properties of the critical appraisal tools and whether guidelines were provided for their use were also recorded.Eighty-seven percent of critical appraisal tools were specific to a research design, with most tools having been developed for experimental studies. There was considerable variability in items contained in the critical appraisal tools. Twelve percent of available tools were developed using specified empirical research. Forty-nine percent of the critical appraisal tools summarized the quality appraisal into a numeric summary score. Few critical appraisal tools had documented evidence of validity of their items, or reliability of use. Guidelines regarding administration of the tools were provided in 43% of cases.There was considerable variability in intent, components, construction and psychometric properties of published critical appraisal tools for research reports. There is no "gold standard' critical appraisal tool for any study design, nor is there any widely accepted generic tool that can be applied equally well across study types. No tool was specific to allied health research requirements. Thus interpretation of critical appraisal of research reports currently needs to be considered in light of the properties and intent of the critical appraisal tool chosen for the task. Consumers of research  frequently use standard critical appraisal tools to evaluate the quality and utility of published research reports . CriticaAlthough the importance of critical appraisal tools has been acknowledged ,3-5 therCritical appraisal tools can be broadly classified into those that are research design-specific and those that are generic. Design-specific tools contain items that address methodological issues that are unique to the research design ,7. This Moreover, there appears to be little consensus regarding the most appropriate items that should be contained within any critical appraisal tool. This paper is concerned primarily with critical appraisal tools that address the unique properties of allied health care and research . This apThe unique nature of allied health practice needs to be considered in allied health research. Allied health research thus differs from most medical research, with respect to:• the paradigm underpinning comprehensive and clinically-reasoned descriptions of diagnosis . An example of this is in research into low back pain, where instead of diagnosis being made on location and chronicity of pain (as is common) , it woul• the frequent use of multiple interventions within the one contact with the patient (an occasion of service), each of which requires appropriate description in terms of relationship to the diagnosis, nature, intensity, frequency, type of instruction provided to the patient, and the order in which the interventions were applied • the timeframe and frequency of contact with the patient • measures of outcome, including appropriate methods and timeframes of measuring change in impairment, function, disability and handicap that address the needs of different stakeholders  ,12,13.In supplementary data see .Two independent researchers  participated in all aspects of this review, and they compared and discussed their findings with respect to inclusion of critical appraisal tools, their intent, components, data extraction and item classification, construction and psychometric properties. Disagreements were resolved by discussion with a third member of the team (KG).Data extraction consisted of a four-staged process. First, identical replica critical appraisal tools were identified and removed prior to analysis. The remaining critical appraisal tools were then classified according to the study design for which they were intended to be used ,2. The sStudy aims and justification• Methodology used, which encompassed method of identification of relevant studies and adherence to study protocol;• Sample selection, which ranged from inclusion and exclusion criteria, to homogeneity of groups;• randomization and allocation blinding;• Method of Attrition: response and drop out rates;• Blinding of the clinician, assessor, patient and statistician as well as the method of blinding;• Outcome measure characteristics;• Intervention or exposure details;• data analyses;• Method of bias; and• Potential sources of external validity, which ranged from application of evidence to other settings to the relationship between benefits, cost and harm.• Issues of miscellaneous", was used to describe items that could not be classified into any of the groups listed above.An additional group, "Data was synthesized using MS Excel spread sheets as well as narrative format by describing the number of critical appraisal tools per study design and the type of items they contained. Descriptions were made of the method by which the overall quality of the study was determined, evidence regarding the psychometric properties of the tools  and whether guidelines were provided for use of the critical appraisal tool.One hundred and ninety-three research reports that potentially provided a description of a critical appraisal tool (or process) were identified from the search strategy. Fifty-six of these papers were unavailable for review due to outdated Internet links, or inability to source the relevant journal through Australian university and Government library databases. Of the 127 papers retrieved, 19 were excluded from this review, as they did not provide a description of the critical appraisal tool used, or were published in languages other than English. As a result, 108 papers were reviewed, which yielded 121 different critical appraisal tools -102,116.We identified 14 instruments  which were reported as having been constructed using a specified empirical approach ,103,116.Seventy-eight percent N = 94) of the critical appraisal tools were developed for use on primary research 4 of the ,34,37-41One thousand, four hundred and seventy five items were extracted from these critical appraisal tools. After grouping like items together, 173 different item types were identified, with the most frequently reported items being focused towards assessing the external validity of the study (N = 35) and method of data analyses N = 28) (Table 8 (Table • Eligibility criteria (inclusion/exclusion criteria) (N = 63)• Appropriate statistical analyses (N = 47)• Random allocation of subjects (N = 43)• Consideration of outcome measures used (N = 43)• Sample size justification/power calculations (N = 39)• Study design reported (N = 36)• Assessor blinding (N = 36)Eighty-seven different items were extracted from the 26 critical appraisal tools, which were designed to evaluate the quality of systematic reviews. These critical appraisal tools frequently contained items regarding data analyses and issues of external validity Tables .Items assessing data analyses were focused to the methods used to summarize the results, assessment of sensitivity of results and whether heterogeneity was considered, whereas the nature of reporting of the main results, interpretation of them and their generalizability were frequently used to assess the external validity of the study findings. Moreover, systematic review critical appraisal tools tended to contain items such as identification of relevant studies, search strategy used, number of studies included and protocol adherence, that would not be relevant for other study designs. Blinding and randomisation procedures were rarely included in these critical appraisal tools.One hundred and twenty thirteen different items were extracted from the 45 experimental critical appraisal tools. These items most frequently assessed aspects of data analyses and blinding Tables  and 2. DForty-seven different items were extracted from the seven diagnostic critical appraisal tools. These items frequently addressed issues involving data analyses, external validity of results and sample selection that were specific to diagnostic studies  Tables  and 2.Seventy-four different items were extracted from the 19 critical appraisal tools for observational studies. These items primarily focused on aspects of data analyses  and data analyses .Seventy-eight different items were contained in the ten critical appraisal tools that could be used for all study designs . The majority of these items focused on whether appropriate data analyses were undertaken  and external validity issues   ,58,59,65Forty-nine percent N = 58) of critical appraisal tools summarised the results of the quality appraisal into a single numeric summary score 8 of crit-93,96,97• An equal weighting system, where one point was allocated to each item fulfilled; or• A weighted system, where fulfilled items were allocated various points depending on their perceived importance.However, there was no justification provided for any of the scoring systems used. In the remaining critical appraisal tools (N = 62), a single numerical summary score was not provided ,98-102. Few critical appraisal tools had documented evidence of their validity and reliability. Face validity was established in nine critical appraisal tools, seven of which were developed for use on experimental studies ,51,63,70Forty-three percent N = 52) of critical appraisal tools had guidelines that informed the user of the interpretation of each item contained within them , with most designed for use on experimental studies . This finding is not surprising as, according to the medical model, experimental studies sit at or near the top of the hierarchy of evidence ,8. In re7%, with We also found a considerable number of critical appraisal tools for systematic reviews (N = 26), which reflects the trend to synthesize research evidence to make it relevant for clinicians ,107. SysIn contrast, we identified very few qualitative study critical appraisal tools, despite the presence of many journal-specific guidelines that outline important methodological aspects required in a manuscript submitted for publication -110. ThiOf the small number of generic critical appraisal tools, we found few that could be usefully applied , because of the generalist nature of their items, variable interpretation (and applicability) of items across research designs, and/or lack of summary scores. Whilst these types of tools potentially facilitate the synthesis of evidence across allied health research designs for clinicians, their lack of specificity in asking the 'hard' questions about research quality related to research design also potentially precludes their adoption for allied health evidence-based practice. At present, the gold standard study design when synthesizing evidence is the randomized controlled trial , which uA major finding of our study was the volume and variation in available critical appraisal tools. We found no gold standard critical appraisal tool for any type of study design. Therefore, consumers of research are faced with frustrating decisions when attempting to select the most appropriate tool for their needs. Variable quality evaluations may be produced when different critical appraisal tools are used on the same literature . Thus, iThe variability in the content of critical appraisal tools could be accounted for by the lack of any empirical basis of tool construction, established validity of item construction, and the lack of a gold standard against which to compare new critical tools. As such, consumers of research cannot be certain that the content of published critical appraisal tools reflect the most important aspects of the quality of studies that they assess . MoreoveBased on the findings of this evaluation, we recommend that consumers of research should carefully select critical appraisal tools for their needs. The selected tools should have published evidence of the empirical basis for their construction, validity of items and reliability of interpretation, as well as guidelines for use, so that the tools can be applied and interpreted in a standardized manner. Our findings highlight the need for consensus to be reached regarding the important and core items for critical appraisal tools that will produce a more standardized environment for critical appraisal of research evidence. As a consequence, allied health research will specifically benefit from having critical appraisal tools that reflect best practice research approaches which embed specific research requirements of allied health disciplines.No competing interests.PK Sourced critical appraisal toolsCategorized the content and psychometric properties of critical appraisal toolsAEB Synthesis of findingsDrafted manuscriptNMW Sourced critical appraisal toolsCategorized the content and psychometric properties of critical appraisal toolsVSK Sourced critical appraisal toolsCategorized the content and psychometric properties of critical appraisal toolsKAG Study conception and designAssisted with critiquing critical appraisal tools and categorization of the content and psychometric properties of critical appraisal toolsDrafted and reviewed manuscriptAddressed reviewer's comments and re-submitted the articleThe pre-publication history for this paper can be accessed here:Search Strategy.Click here for file