This program has directly affected public health policies and practices. Active Bacterial Core surveillance (ABCs) was established in 1995 as part of the Centers for Disease Control and Prevention Emerging Infections Program (EIP) network to assess the extent of invasive bacterial infections of public health importance. ABCs is distinctive among surveillance systems because of its large, population-based, geographically diverse catchment area; active laboratory-based identification of cases to ensure complete case capture; detailed collection of epidemiologic information paired with laboratory isolates; infrastructure that allows for more in-depth investigations; and sustained commitment of public health, academic, and clinical partners to maintain the system. ABCs has directly affected public health policies and practices through the development and evaluation of vaccines and other prevention strategies, the monitoring of antimicrobial drug resistance, and the response to public health emergencies and other emerging infections. Active Bacterial Core surveillance (ABCs), a program in the Centers for Disease Control and Prevention (CDC) Emerging Infections Program (EIP) network, was launched in 1995 as part of the CDC strategy to address the worldwide threat of emerging infectious diseases , by 2003 ABCs added Georgia, Maryland, New York, Tennessee, Colorado, and New Mexico, for a total of 10 sites. The sites represent geographic diversity and approximate the racial composition of the US population (Streptococcus (GAS), Haemophilus influenzae, Neisseria meningitidis, group B Streptococcus (GBS), and Streptococcus pneumoniae. Surveillance for invasive methicillin-resistant Staphylococcus aureus (MRSA), which had long been recognized as a significant nosocomial pathogen, was added to surveillance in 2004 because it had emerged as a substantial cause of invasive infections in the community (http://www.cdc.gov/pertussis/surv-reporting.html) and legionellosis  in the United States and worldwide, IPD is not reportable in all states. In the late 1990s, when a new vaccine was being developed, a system was needed to determine baseline rates of IPD, evaluate vaccine effectiveness, and monitor circulating serotypes. After establishment of ABCs to fill the void of tracking the disease burden of IPD and other major causes of invasive bacterial disease in the United States, ABCs detected a large reduction in IPD detected among children <5 years of age  and among adults, who benefited from herd protection. ABCs also recognized an increase in IPD rates caused by S. pneumoniae serotypes absent from PCV7; this information resulted in accelerated approval of a 13-valent pneumococcal vaccine (PCV13) that has resulted in further reductions in IPD.Invasive pneumococcal disease (IPD) provides an example of the power of this large, sustained, population-based surveillance system for evaluating public health interventions and providing feedback for additional prevention measures. Although . These attributes enable ABCs to fulfill 2 critical objectives: 1) to determine the incidence and epidemiologic characteristics of invasive diseases under surveillance and 2) to determine molecular epidemiologic patterns and microbiological characteristics of these invasive infections.Not all infections captured under ABCs are reportable to CDC. Even for those infections included in the CDC National Notifiable Disease Surveillance System, case counts may be underestimated because they rely on reporting by laboratories and clinicians, whereas ABCs tries to actively identify 100% of the cases within the surveillance area. Additionally, epidemiologic data collected by health departments are often incomplete because of limited resources and the inflexibility of the system to capture variables of interest. Unlike the National Notifiable Disease Surveillance System, ABCs also collects isolates and serotypes and tests them for antimicrobial drug susceptibilityH. influenzae, N. meningitidis, GAS, GBS, S. pneumoniae, or MRSA from a normally sterile body site  in a resident of the surveillance area. Additionally, cases include ill persons from whom GAS is isolated from a wound or other tissue in the presence of necrotizing fasciitis or streptococcal toxic shock syndrome. Cases of GBS in a mother are also included if GBS has been isolated from the placenta or amniotic fluid in the event of fetal death.For routine surveillance, a case of invasive bacterial disease is defined as isolation of The ABCs approach to surveillance is distinctive; it is active, laboratory based, and population based. The goal is to detect 100% of laboratory-confirmed cases by actively contacting all clinical laboratories that routinely process specimens from residents of the surveillance area. Audits are performed regularly to ensure case capture. Efforts at most sites to make ABCs pathogens reportable to state public health agencies have facilitated participation of almost all laboratories (≈600) that serve the surveillance population. Because the population under surveillance is well-defined, US Census data are used to calculate disease incidence rates within the ABCs population. Because of the large population base, CDC uses ABCs data to estimate the national disease burden after adjusting for race and age distribution in the United States.S. pneumoniae, GAS, GBS, N. meningitides, and H. influenzae isolates is accessible to ABCs partners and external researchers by request (http://www.cdc.gov/abcs/pathogens/isolatebank/index.html). ABCs MRSA isolates are deposited at the Network on Antimicrobial Resistance in Staphylococcus aureus, a repository sponsored by the National Institute of Allergy and Infectious Diseases at the National Institutes of Health (http://www.niaid.nih.gov/labsandresources/resources/dmid/narsa/Pages/default.aspx).Medical records review is used to collect demographics, clinical course, outcome, infection type, underlying conditions, and vaccination history for each case-patient. For most patients, an isolate from the first positive culture is collected. Since 1995, with the exception of MRSA (for which a convenience sample of 100 isolates has been collected since 2005), ≈85% of isolates have been collected from eligible patients. Isolates undergo serologic or molecular typing and standardized antimicrobial drug susceptibility testing at CDC or other reference laboratories. A collection of ≈80,000 The ABCs infrastructure is also used to conduct surveillance for other bacterial diseases and provides a foundation for epidemiologic investigations. Examples include special surveillance for pertussis and legionellosis, case–control studies to assess vaccine effectiveness, and cohort studies to assess the uptake and effectiveness of other public health interventions.Because of the large, representative catchment area and the laboratory-linked, population-based epidemiologic data, results from ABCs have been used in the development and prelicensure evaluation of multiple vaccines. After licensure, ABCs data have been used to formulate policy recommendations and to determine the real-world impact of vaccines .>65 years of age  disease was critical for monitoring how vaccine shortages affected disease rates. Because of the availability of epidemiologic data linked to serotype determination, a shift toward non-Hib disease in adults in the post–Hib vaccine era has been recognized.Through long-standing surveillance, ABCs was able to document the persistent decline of invasive id-1980s . ABCs suAlthough trend data may show indirect evidence of a vaccine’s effectiveness, proof of effectiveness requires a more formal epidemiologic investigation to account for other factors that may influence the decline in disease incidence. The ABCs infrastructure was used to conduct case–control studies that confirmed the effectiveness of conjugate meningococcal and pneumococcal vaccines against invasive disease. These very large studies could only have been done through an integrated network, and they highlight the efficiencies gained by maintaining such an infrastructure.S. aureus, and serogroup B meningococcal disease. ABCs data have been used to predict the effectiveness in the United States of a 26-valent GAS vaccine and now a 30-valent GAS vaccine that is under development. GBS disease burden and serotype data gathered through ABCs have been used to inform development of a trivalent GBS vaccine now in phase I and II trials. ABCs data have been used to determine which population groups would be the best candidates for receipt of S. aureus vaccines to prevent invasive MRSA disease and to evaluate the potential effect of serogroup B meningococcal vaccines on disease burden in the United States.Serotype and serogroup data from ABCs pathogens are also being used to help with formulation of vaccines and evaluation of the potential effectiveness of vaccines currently under development, including those products targeting GAS, GBS, >80% decline in the incidence of early-onset GBS infection and prevention of an estimated 70,000 cases of early-onset GBS infection . An>65 years from 1998–1999 through 2008. This finding demonstrated the effectiveness of routine use of pneumococcal conjugate vaccine in children for reducing the spread of resistant strains on a national scale in all age groups .ABCs data showed that, from 1995 through 1998, a large and increasing proportion (up to 25%) of isolates from patients with IPD were resistant to penicillin (http://www.cdc.gov/drugresistance/threat-report-2013/).In contrast to IPD, GAS infections remain sensitive to penicillin. GAS isolates are collected to monitor the resistance of invasive GAS infections to not only β-lactams but also macrolides and other antimicrobial drugs. ABCs data have documented increasing resistance to erythromycin (currently 8%–11%), a macrolide commonly used for treating pharyngitis in children who are allergic to penicillin  and 1 from a bordering area of North Dakota (not an ABCs site) . From 2000 through 2009, the age-adjusted incidence of legionellosis has almost tripled, from 0.40 to 1.08 cases per 100,000 persons , outreach to partners has been provided at multiple national and international conferences. ABCs closely collaborated with the South Africa National Institute for Communicable Diseases in the establishment of a similar surveillance system in that country and in sharing lessons learned and epidemiologic findings (http://www.nicd.ac.za/?page=homepage&id=125). ABCs has also been used as the standard for evaluating and validating less expensive methods for tracking antimicrobial drug susceptibility and measuring vaccine effectiveness—methods that can be used in settings with fewer resources , pneumococcal (http://www.cdc.gov/abcs/reports-findings/survreports/mrsa12.pdf) infections are more common among black than white persons. However, racial differences are just one measure of disparity, and categorizing a person’s race is becoming increasingly difficult as the United States becomes more multiracial. ABCs analyses have incorporated census tract data to determine the association between area-level poverty and disease incidence (A major goal of ABCs is assessment of public health disparities and promotion of health equity across population groups. ABCs has documented differences in rates of disease across persons of different races; invasive GBS (ABCs is distinctive among public health surveillance systems in that it is designed to capture nearly all cases of culture-confirmed invasive bacterial diseases over a large, well-defined, and geographically diverse area of the United States. These comprehensive data enable accurate estimations of the national disease burden for severe bacterial infections under surveillance. The collection of isolates in conjunction with epidemiologic data has contributed to the microbiological and molecular characterization of pathogens, which has played a part in the development of vaccines and monitoring of antimicrobial drug resistance. Although the surveillance system alone provides powerful data for informing public health actions, the large ABCs infrastructure provides an efficient and effective platform for engaging in special investigations that would otherwise require additional resources. The infrastructure also provides the flexibility needed to respond to emergencies and to serve as a surveillance platform for other emerging pathogens. Perhaps the greatest strength of ABCs and the reason for its success have been the committed, genial, and long-lasting collaboration among local, state, and federal agencies, academic institutions, and clinical laboratories.Although ABCs has addressed many questions of public health significance that have directly affected public health policy and practice, many questions still remain . To mainExpanded version of


We conclude that policy makers in Northwest China appreciate that children are uniquely vulnerable, though additional regulations are needed to account for that vulnerability. Further research should examine effectiveness of the intervention on a larger scale and scope, and evaluate the usefulness of such interventions in translating research into improved care/reduced exposure to environmental hazards.The main purpose of this study was to identify policy maker opinions and attitudes towards children’s environmental health (CEH), potential barriers to child-specific protective legislation and implementation in northwest China, and evaluate knowledge and attitudes about CEH before and after an educational conference. We conducted seventy-two interviews with regional officials, researchers and non-governmental organization representatives from five provinces, and surveyed participants (forty-seven) before and after an educational conference in northwest China about CEH. Interviews identified general consensus among participants of the adverse effects of air pollution on children, yet few participants knew of policies to protect them. Barriers identified included limited funding and enforcement, weak regional governments and absence of child-specific policy-making. After the conference, substantially greater self-efficacy was identified for lead, mercury, air pollution and polychlorinated biphenyls (+0.57–0.72 on a 1–5 Likert scale,  Accelerated economic growth in the People’s Republic of China (PRC) has rapidly increased early life exposures to environmental hazards. Coal consumption and production have quadrupled, increasing mercury emissions, with fish and rice contamination with methylmercury raising concerns about adverse effects on early neurodevelopment ,2,3. LeaChildren have increased vulnerability to many common environmental toxins. This is because of specific exposure pathways such as dust and soil ingestions  based onIn a previous study, we conducted a survey of child health providers  from five provinces in northwest PRC  to assess knowledge about environmental hazards, and self-efficacy in identifying, assessing and managing these exposures and their consequences . Though Given the substantial impacts of environmental exposure on child health that providers have documented in Northwest PRC, a significant opportunity exists for policy change to prevent disease and disability. Policy maker attitudes have rarely been assessed in a rigorous way in the developing world . EducatiThis report describes findings of interviews performed with seventy-two regional officials, researchers and non-governmental organization representatives from the five provinces in Northwest PRC, to identify their opinions and attitudes towards children’s environmental health, as well as potential barriers to child-specific protective legislation and implementation. We also describe results of surveys administered to child health providers, community stakeholders and decision makers. This was used to evaluate knowledge, attitudes and beliefs about children’s environmental health before and after an educational conference in Northwest PRC.Two of the investigators  identified a sample of regional and national officials, researchers and non-governmental organization representatives, to represent a range of experiences and attitudes towards children’s environmental health in the region and to reflect a broader range of potential barriers to child-specific protective legislation and implementation. The approach followed that used to assess children’s environmental health policy in Mexico in which one of the authors (Leonardo Trasande) was involved . PotentiInterview guidelines, surveys and questionnaires were translated into Mandarin by native speakers and back-translated to confirm accuracy. Prior to commencing the interviews, an annotated outline was developed along with interview guidelines focusing on eleven questions and three major themes .Questionnaires administered at the end of the conference reprised the first part of the questionnaire to assess interval change in beliefs and attitudes. They also reprised demographic questions to facilitate matching of pre- and post-conference questionnaires. Finally, two questions asked whether the conference provided important information regarding children and environmental hazards, and whether it provided information that will/will not change practice/policy making.Statistical analyses of the survey data were performed using Stata 13.0 . In addition to descriptive analyses, Student t-tests were used to compare means of Likert scales among participants before the conference to those after the conference.This research involving human subjects was performed in accordance with the Declaration of Helsinki, and interview guidelines, surveys and questionnaires were approved by the New York University School of Medicine and Lanzhou University School of Public Health Institutional Review Boards, with a waiver of signed consent.We completed interviews of seventy-two regional officials, researchers and non-governmental organization representatives . ParticiThese interviews identified general consensus of the impact of air pollution on children’s health and their vulnerability. While consensus existed about the role of government in protecting children from air pollution exposures, few knew of policies to protect children from these exposures. A diverse array of barriers were identified that could potentially protect children from air pollution exposure—these included lack of funding, lack of enforcement of existing policies, weak regional governments and lack of proven and targeted policies aimed at protecting children. Industry was not identified as having a role in resolving issues about children’s exposure to air pollution, yet industrial processes are important sources of environmental pollution and exposure. This exclusion may have resulted from the general manner in which we posed the question, without suggesting potential responses, such as specific governmental agencies, non-governmental organizations, or industries. It should also be noted that all interviewees were from either environmental or health related fields and did not have industry experience, and they may have therefore overlooked the role of industry in their response. While additional research was also cited as necessary, the primary suggestions were for additional government regulation and education to prevent associated health effects.Forty-seven participants, including health care providers and local Health and Environmental Protection Agency officials from each of the five provinces participated in the conference, and completed pre-conference surveys, of whom forty-two (89%) responded to the post-conference questionnaire. Participants were predominantly female (78.6%), with the average age among participants of 38.6 years .Surveys of participants before the conference  revealedScientific evidence for the impact of environment on children (mean 3.10) was also rated more modestly. Health care provider control over hazards was rated much more modestly (mean 2.81) than government and industry control (means 4.13–4.21). Participants predominantly identified national (63%) and provincial (46%) environment and national health (44%) officials as key decision makers in protecting children from air pollution .Few participants identified policies to protect children from air pollution, with just over a third (38%) identifying national environmental regulations protecting children and just over a fourth (29%) identifying national health regulations with this purpose.Barriers to protecting children included lack of governmental regulation (81%), a focus on economic growth by government (58%), followed by lack of public awareness and industry profits (both 69%) and lack of medical knowledge (38%). Weak enforcement (67%) was deemed to be the chief barrier to policies to protect children, though lack of policies and research both were rated as gaps by a majority. National and provincial environmental and health agencies were identified as key strategic players in protecting children (48%–65%) with many fewer respondents identifying industry, local agencies, medical providers or researchers (<30%) as key strategic players.p = 0.002–0.013), and both scientific knowledge for the role of environment in children’s health , and health care provider control  were rated more strongly; knowledge about mold (not covered in the conference) was not significantly different after the conference (p = 0.27). Knowledge provided regarding children and environmental hazards was judged to be of great importance (mean 4.85), and was also judged to be sufficient to change practice/policy decision making (mean 4.33).After the conference, substantially greater self-efficacy was identified for lead, mercury, air pollution and polychlorinated biphenyls  policy makers in Northwest China appreciate that children are uniquely vulnerable, though additional regulations are needed to account for that vulnerability; and (2) educational interventions can improve policy maker and health care provider knowledge about environmental hazards, including but not limited to air pollution.There are some limitations that potentially affect the interpretation from study results. The usual caveats about selection bias and external validity to the population of child health providers and policy makers in Northwest PRC apply. Despite a waiver of signed consent, concerns about identifiability with respect to their attitudes may have limited respondent candidness, and there may have been a tendency to give socially appropriate answers, influencing the results. Participation may have also been limited to a subsample of policy makers and providers interested in or more willing to support initiatives to protect children from environmental hazards. In addition, we were only able to evaluate attitudes and beliefs both immediately before and after the conference, and so we cannot evaluate the permanence of changes in attitudes and knowledge that we identified. Assessing validity of self-assessed efficacy is also very difficult, as even basic assessments of children’s environmental health proficiency have not yet been developed.Due to limited sample size, we only analyzed pre- and post-conference evaluations to compare group-wide attitudes before and after the conference. Future work could assess differential impact of such educational interventions between policy makers and health care providers, or by province. The latter could be of particular interest, especially as the region we studied spans a large geographic area, and diversity within this region also exists in environmental exposures. For example, occupational nickel exposure is a substantial exposure due to the presence of the world’s third largest nickel refinery in Gansu , while QWhile lack of existing research was not identified as a barrier to prevention, authors have previously emphasized the urgent need for studies of chronic air pollution exposures in PRC. The authors also highlighted the modest capacity for translation of knowledge gained from studies from US and other industrialized countries to the PRC population . In thisThe policy maker interviews revealed substantially similar results to those previously performed in Mexico . While wIt is true that enhanced knowledge alone does not change policy and enforcement. However, this successful educational intervention could be expanded in scale and scope, potentially by local champions who have received more intensive training, to elicit more concrete policy and regulatory changes. This would follow the model successfully used for children’s environmental health policy champions in the US . FurtherPolicy makers interviewed in Northwest PRC appreciate that children are uniquely vulnerable to the adverse effects of hazardous environmental exposures, though additional regulations are needed to account for that vulnerability. An educational intervention can ameliorate gaps in effective translation of research, improving policy maker and health care provider knowledge about environmental hazards, including but not limited to air pollution. Overall, building knowledge and capacity in CEH should be considered an emerging priority in rapidly developing countries like China, to protect the health and well-being of future generations.


The detection of autoantibodies that target intracellular antigens, commonly termed anti-nuclear antibodies (ANA), is a serological hallmark in the diagnosis of systemic autoimmune rheumatic diseases (SARD). Different methods are available for detection of ANA and all bearing their own advantages and limitations. Most laboratories use the indirect immunofluorescence (IIF) assay based on HEp-2 cell substrates. Due to the subjectivity of this diagnostic platform, automated digital reading systems have been developed during the last decade. In addition, solid phase immunoassays using well characterized antigens have gained widespread adoption in high throughput laboratories due to their ease of use and open automation. Despite all the advances in the field of ANA detection and its contribution to the diagnosis of SARD, significant challenges persist. This review provides a comprehensive overview of the current status on ANA testing including automated IIF reading systems and solid phase assays and suggests an approach to interpretation of results and discusses meeting the problems of assay standardization and other persistent challenges. In 1950, Coons and Kaplan described the improvement of an immunofluorescence method for the detection of antigens in tissue cells , 3. AlonThe IIF assay on HEp-2 cells has been replaced in many laboratories since the development of ANA screening assays based on ELISA and automated, high throughput multiplex assays using addressable laser bead and other array technologies for the detection of specific ANA , 10. DueIn recent years, the first digital imaging systems for ANA IIF have been developed which eliminate some major drawbacks of the method, namely, the subjectivity of observers reading the slides and the lack of an automated procedure –17. NeveFor diagnostic applications, it is important to differentiate between analytical sensitivity/specificity and clinical (diagnostic) sensitivity/specificity. Therefore, the terms clinical sensitivity and specificity, false negative, false positive, and predictive values are described in U, which tests for the median difference between scores obtained in the two continuous data sets. However, any attempt to summarize the ROC curve into a single number fails as information about the pattern of tradeoffs of the particular discriminator algorithm is not expressed.The receiver operating characteristic (ROC) analysis has a broad range of applications and was first used for military purposes during World War II . In mediThe manner by which immunoassay cut-offs are established varies significantly among researchers and scientists in diagnostic companies. A common approach to define the cut-off value for certain assays is to test specimens from patients with the respective disease and compare them to a broad range of controls including related and unrelated diseases as well as age and gender matched (apparently) healthy individuals. The mean value plus 3-fold standard deviation, the 95% or the 99% percentile, of the controls are then often used to define the cut-off value. Another popular approach for definition of the cut-off value makes use of ROC analysis. Despite broad application, most references do not specify how to use the ROC analysis to define the cut-off value . In the  vice versa when a higher cut-off is defined  has been estimated to be 24 for a positive test result and 0.27 for a negative test result . Using LTo illustrate the impact of pretest probability and assay performance on the posttest probability clinical examples are provided .3). Based on this clinical presentation, the probability for SLE is estimated to be 10%. A positive ANA by IIF increases the probability for SLE to 42%, whereas a positive SPA CTD screen increases the probability for SLE to 72%, which makes the diagnosis for SLE likely. However, a woman positive for anti-SSA/Ro could display the same clinical manifestations not necessarily having SLE . A negative ANA by IIF result would reduce the probability for SLE from 10% to <1%. The third example is a young woman with photosensitivity, malar rash, and symmetrical polyarthritis. This clinical picture is suggestive of SLE (50% probability). A positive IIF result increases the probability for SLE from 50% to 87%, whereas a positive SPA CTD screen increases it to 96%. A negative IIF result would reduce the probability for SLE to 7%, whereas a negative SPA test result would reduce the probability of SLE to 21%, illustrating the NPV of SPA is lower than the NPV of IIF.For example, a young woman with hair loss and polyarthralgias, which are very nonspecific signs of SLE, is estimated to have a pretest probability for SLE of 1%. If ANA by IIF turns out to be positive in this patient the probability for SLE increases from 1% to 6%, which is still low. If the SPA CTD screen reveals an autoantibody directed to a specific nuclear antigen (ENA or dsDNA), then the probability for SLE is higher (19%). A second example is a young woman who presents to her physician with photosensitivity and mild leucopenia  were called ANA. Similarly, the term extractable nuclear antigen (ENA), described in 1959 by Holman and Robbins was used for a group of nuclear antigens extractable by saline solutions . NowadayTo date, more than 160 autoantigens, many of them localized to the cell nucleus, have been described in sera of SLE patients . TherefoIn addition to SLE and SSc, ANA can be found in various other SARD including but not limited to IIM, SjS, and MCTD . The appThe early and accurate diagnosis of autoimmune diseases can be very challenging because the spectrum of signs and symptoms are very wide and often overlap. Initially, an AARD has to be differentiated from a wide spectrum disorders  presenting with similar signs and symptoms. For example, a patient suspected to have SLE can first present with skin manifestations which need to be differentiated from discoid lupus, polymorphous light eruption, rosacea, drug eruptions, and other dermatoses. If other organs are involved  the difFor well over the last decade, the IIF HEp-2 assay was being replaced by newer technologies for the detection of ANA  and seveComputer assisted pattern recognition for ANA testing on HEp-2 cells has been described more than ten years ago . AutomatThe currently available automated ANA IIF image analyzing systems include NOVA View  , AklidesGenerally, these automated systems are based on a microscope fitted with an automated stage, a CCD digital camera, a LED light source, and software that controls the moving parts and directs image acquisition. All systems perform some kind of fluorescent light intensity measurement and use the results for preliminarily categorization of the samples as positive or negative and for pattern analysis. The automated reading is followed by human visual interpretation of the digital images that are displayed on a computer monitor, allowing user confirmation or revision of the automated results. By providing good quality digital images and other objective information (such as preliminary classification and pattern interpretation), these automated systems support the operators' decision making and increase the consistency between readers and readings. In addition, the digital images can be stored for training, documentation, follow-up, and second opinion purposes. In the future, these digital images might also become part of the patient's electronic medical record (EMR). At present, the systems are highly reliable in their ability to discriminate positive from negative reactions and to estimate fluorescence intensity, but the accuracy and robustness of pattern recognition does not reach the accuracy of human interpretation , 78. An The final result interpretation is made by the operator, therefore subjectivity cannot be completely removed. Moreover, the characteristics of the HEp-2 substrates and conjugates influence the appearance of certain ANA specificities, and the automated pattern identification of the various systems is likely based on somewhat different programming principals. Nevertheless, automated systems for ANA HEp-2 analysis are a significant step forward to reduce variability and offer opportunities to increase harmonization of ANA interpretation .Some systems offer automated assessment of ANA endpoint titers on a single serum dilution, thereby eliminating the need for serial dilutions . MoreoveSeveral studies have demonstrated limited analytical/clinical sensitivity , 80, 81 Based on these observations, over three decades ago a transfected HEp-2 cell line overexpressing SS-A/Ro60 was developed and this cell-based IIF assay is marketed as HEp-2000 cells , 88–90. Disease classification criteria, such as the SLE criteria , 39, do During the last decade, different strategies have been utilized to develop, evaluate, and commercialize several ANA screening ELISAs –110. TheLine immunoassays (LIA) can basically be considered second generation dot-blot assays. A broad range of LIAs are available and they are typically used to confirm autoantibodies previously identified by HEp-2 ANA IIF or other screening immunoassays . HoweverMultiplex assays based on the Luminex technology  use addressable laser beads and are therefore often referred to as ALBIA (addressable laser bead immunoassays) . Today, Additional methods have been developed for automated ANA detection , 132–139Several publications have described protein arrays on planar solid phase surfaces for the detection of autoantibodies to a wide range of viral proteins and autoantigens , 145 bouMore recently novel “ANA” screening assays have been developed on fully automated closed systems such as the Phadia  or the BIO-FLASH System  . The EliFor the development and quality assurance of autoantibody assays a broad range of international reference samples are mandatory , 151. Cohttp://asc.dental.ufl.edu/home.html#text), the European Autoimmunity Standardisation Initiative (EASI) [http://www.easi-network.com/], and the Working Group on Harmonization of Autoantibody Tests (WG-HAT) in the framework of the International Federation of Clinical Chemistry and Laboratory Medicine [http://www.ifcc.org/ifcc-scientific-division/sd-working-groups/harmonisation-of-autoantibody-tests-wg-hat/]. Despite significant efforts to standardize autoantibody tests [Different committees and organizations were formed who worked to achieve a better standardized approach to autoantibody testing , 160 incdy tests , 161 anddy tests  significPerformance data (including LRs) of the method used to detect ANA and appropriate explanation should be made available to the clinician.ANA test results are only a portion of the information that aids in the diagnosis of systemic autoimmune diseases and are an adjunct to the clinician's diagnostic repertoire.Both IIF on HEp-2 cells and solid phase immunoassays have their individual advantages and limitations.Standardized nomenclature of diseases and associated autoantibodies is an important goal for immediate consideration by advisory groups.Despite significant evolution and improvements in ANA and related autoantibody testing, including the arrival of novel and promising technologies, several limitations still persist and need to be addressed. First, the terminology and nomenclature used to identify and refer to various autoantibodies need to be standardized. Second, the classification criteria and nomenclature of individual SARD and related autoimmune diseases must continue to evolve and keep abreast of biomarker identification. Third, the corresponding immunoassays and diagnostic platforms used for the various clinical applications need to be based on standardized reference samples of defined specificities. This possibility could include the development and validation of disease specific screening assays  on solid phase technologies. Fourth, a clearly defined strategy needs to be developed to facilitate clinicians and laboratory scientists alike becoming more familiar with and be able to intelligently use objective interpretation of autoantibody results through an understanding of ROCs and LRs. Lastly, diagnostic algorithms need to be adjusted to the clinical and laboratory setting considering the referral pattern, the sample testing volume, and health economic aspects .


In addition, he will be able toassess the quality of RCTs throughout its entire structure. In order to render analysiscomprehension easier, the CONSORT checklist was divided into six categories, according tothe parts of an article: 1 - Title and abstract: the title should be concise and the word "randomized"should be used. The abstract should be structured and include: trial design, methods, mainresults and conclusions. 2 - Introduction: it should include a brief literature review, the rationalefor the trial and the objective or hypothesis, all of which reported in a clear andobjective manner.3 - Method: it should be carefully reported as follows: trial design;eligibility criteria for participants, with explanation of rationale for such criteria; howand where data were collected; thorough description of intervention, which allows resultsto be reproduced; description of sample size calculation; changes during the course oftrial, with clear reasons; thorough description of methods used for allocation into thetrial groups, participants and evaluators blinding; and proper statistical analysis. 4 - Results: primary intervention results should be assessed for each group;the number of participants, assessment losses and exclusions should also be reported foreach group, reasons should be clearly stated; post intervention assessment and follow-upperiods should be reported; statistical methods used to obtain values of primary andsecondary outcomes for each group  should be reported. 5 - Discussion: it should present: trial limitations addressing sources ofpotential bias, imprecision and methodological weaknesses; external validity; applicabilityand interpretation consistent with results, balancing benefits and harms, considering otherpublished evidence. 6 - Other information: the RCT should be registered and the registry numberpresented; full trial protocol should be available; sources of funding and other support,as well as the role of funders should be highlighted. In addition to the checklist, CONSORT also encompasses a flow diagram which provides thereader with information about how the trial was conducted, reporting enrolment, allocation,follow-up and analysis of patients involved in the RCT .5 ImportThe aforementioned CONSORT criteria have been used for RCTs analysis by more than 600international periodicals.While critically assessing an RCT, the clinical orthodontist should pay close attention tohow coherent CONSORT checklist items and the characteristics of the assessed trial are.Clinicians should understand that, in some studies, there is no need for complete adhesionto all CONSORT items. One example is a study that assessed the level of adhesion to theCONSORT checklist by the American Journal of Orthodontics and Dentofacial Orthopedics.Results revealed that articles conformed with 33 of 37 items from the checklist. Accordingto the author, the following four items were not contemplated: changes to methods (3b),changes to outcomes (6b) after the trial commenced, interim analysis (7b), and trialstopping (14b), which were not rendered necessary for the assessed variables.Another valuable tool used to guide the clinical orthodontist towards an evidence-basedpractice is the search for systematic literature reviews and meta-analysis of RCTs.The orthodontic clinical practice should not be based only on RCTs reading and acceptanceof results as being absolute truths. The orthodontist is responsible not only for usingsuch results, but also for critically assessing RCTs. Thus, CONSORT becomes an importanttool used to aid clinicians in conducting and assessing the methodological quality of RCTs,which renders these professionals more scientifically aware and confident for choosing thebest treatment or diagnosis method to be used.


Studies of racial/ethnic variations in stroke rarely consider the South Asian population, one of the fastest growing sub-groups in the United States. This study compared risk factors for stroke among South Asians with those for whites, African-Americans, and Hispanics.Data on 3290 stroke patients were analyzed to examine risk differences among the four racial/ethnic groups. Data on 3290 patients admitted to a regional stroke center were analyzed to examine risk differences for ischemic stroke  among South Asians, whites, African Americans and Hispanics.South Asians were younger and had higher rates of diabetes mellitus, blood pressure, and fasting blood glucose levels than other race/ethnicities. Prevalence of diabetic and antiplatelet medication use, as well as the incidence of small-artery occlusion ischemic stroke was also higher among South Asians. South Asians were almost a decade younger and had comparable socioeconomic levels as whites; however, their stroke risk factors were comparable to that of African Americans and Hispanics.Observed differences in stroke may be explained by dietary and life style choices of South Asian-Americans, risk factors that are potentially modifiable. Future population and epidemiologic studies should consider growing ethnic minority groups in the examination of the nature, outcome, and medical care profiles of stroke. The incidence and death rate from stroke have declined in the United States Although White and colleagues investigated the incidence of ischemic stroke subtypes among racial/ethnic groups Data on all acute stroke cases were prospectively collected at the time of admission to the New Jersey Neuroscience Institute at John F. Kennedy (JFK) Medical Center in Edison, New Jersey. All variables related to stroke diagnosis, treatment, and outcomes were abstracted from the medical records of patients by trained personnel using a standardized algorithm and entered into a computerized registry system. These included the Center for Disease Control's Paul Coverdell Stroke Registry variables, and the trial of Org 10172 in Acute Stroke Treatment (TOAST) etiologic classifications elements. Predictive factors for stroke included age, sex, race/ethnicity, obesity, diabetes mellitus, hypertension, cardiac diseases, and lipid profiles. Data on history of cigarette smoking, past stroke or Transient Ischemic Attack (TIA), prior prescription medication use, and other comorbidities were collected, along with clinical and anthropometric measures.There were 3,540 acute stroke admissions between 2006 and 2011. After excluding 250 (7.1%) patients who did not meet the racial/ethnic categorization  and those who were ≤18 years of age, 3,290 acute stroke patients were selected for this analysis. All patients who self-identified India or Pakistan as country of origin were classified as South Asian; as many South Asians self-identify as white; the surnames of the remaining patients were examined to determine race/ethnicity. International medical graduates of South Asian origins that were trained in data abstraction and surname recognition performed surname identification. They categorized patients with surnames common to Bangladesh, Bhutan, India, Nepal, Pakistan, Sri Lanka, and the Maldives as South Asians All patients were evaluated with standard blood tests for fasting glucose, hemoglobin A1C (HbA1c) as well as lipid and coagulation profiles. Computed tomography (CT) scans of the brain were performed at the time of initial evaluation and again in 24 hours. The majority of patients underwent magnetic resonance imaging (MRI) of the brain. Patients had extra-cranial vascular imaging using CT angiography (CTA), and MR angiography (MRA). All patients undergoing CTA or MRA also had intracranial vascular imaging and 2D trans-thoracic echocardiography, and either Holter monitor or a minimum of 24 hours of telemetric cardiac monitoring. Patients with a suspected embolic source underwent trans-esophageal imaging.Acuity and extent of neurological deficits from stroke were determined according to the NIHSS scoring system Diagnosis of diabetes was established if a patient was under treatment with an anti-diabetic medication or insulin or had a fasting glucose level ≥140 mg/dL, or a history of type I or II diabetes Institutional Review Board approval to evaluate the data was obtained both from the JFK Medical Center and the University of Medicine and Dentistry of New Jersey. Patient informed consent to examine the medical record was not obtained since data abstractions were anonymized/de-identified and included no Patient Health Information (PHI). All variables were summarized by race/ethnicity and reported as mean ± standard deviation (SD) or median and interquartile range as appropriate. Variables were compared among racial/ethnic groups with χ2 or Fisher's exact tests for categorical variables and the Kruskal-Wallis tests for continuous variables, while differences in means between racial/ethnic groups were compared using analysis of variance (ANOVA). Because triglycerides, hemoglobin A1c, fasting blood glucose and BMI values were positively skewed, natural logarithmic transformation was used and results were expressed as geometric means with 95% confidence intervals (CI). Finally, the distributions of ischemic stroke subtypes were examined by race/ethnicity. All analyses were done using SAS statistical software, version 9.2 .The socio-demographic characteristics of study subjects are detailed in Stroke related clinical measurements at the time of admission by race/ethnicity are detailed in A comparison of the overall race/ethnicity effect in the incidences of stroke types and ischemic stroke subtypes showed a significant variation, p = 0.0040; however, pairwise comparison of South Asians to the other racial/ethnic groups did not show any statistical effect, Stroke remains a major health issue, particularly among minority and ethnic sub-groups. For example, despite being almost a decade younger than white patients, having more college graduates, and residing in neighborhoods with the highest median income compared to other study subjects, South Asians had clinical risk factors for stroke comparable to those of African Americans and often worse than those for Hispanics. It is well established that hypertension is potent risk factor for stroke. This analysis showed it to be the most prevalent risk factor for all stroke victims, distantly trailed by diabetes mellitus and cardiac diseases. South Asian and white patients in our cohort had higher proportions of subjects with hypertension than Hispanics. Prevalence of smoking among South Asians in this study (which included Asian Indians) was consistent with a 2012 report by the Center for Disease Control and Prevention (CDC) Great care should be taken in interpreting the findings of this study, especially because the diagnosis of hypertension and diagnosis for diabetes based on FBG levels ≥140 mg/dL are often questionable if not performed during a medically quiescent period. However, the prognosis of developing diabetes on HbA1C and FBG levels is generally considered reliable.White and colleagues reported that blacks are at a higher risk for intracerebral atherosclerosis compared with whites Risk factors for ischemic stroke varied significantly by race/ethnicity among our cohort. There was>25% increased risk for developing SAO among South Asian patients than whites. This can be explained by the substantial age difference between these two groups in that South Asians tended to be a decade or so younger than whites and more likely to suffer from SAO at earlier ages. This competing morbidity perhaps reduced their risk of LAA at older ages. Indeed, SAO was more common among South Asians than any other racial/ethnic group. However, the conclusion regarding these factors among South Asians may not hold true when examining South Asians living in their home countries.The strength of our study stems from the fact that the data were collected on subjects that were assessed immediately following the onset of stroke symptoms by neurologists and a dedicated stroke team at a comprehensive stroke center. Data gathered in this manner have been reported to have a less than 2% error rate of stroke clinical diagnosis In order to improve stroke outcomes and to achieve the impact goals set by the American Heart Association to reduce stroke death by 20% by 2020, future epidemiologic studies that investigate and identify the most efficient and effective clinical approaches to both prevention and treatment are important. The higher prevalence of known stroke risk factors among South Asian immigrants in this cohort may have been attributable for the larger proportion of ischemic stroke incidence among South Asians as compared to whites, including the increased incidence of small vessel disease”. These findings support the need for genetic and metabolomics studies that may lead to an understanding of the mechanisms of at least one stoke subtype. The further examination of the interaction between race/ethnicity and stroke risk factors can provide data that will enable clinicians to predict subtypes of stroke following an acute stroke admission and to act on that knowledge accordingly.


Objective To quantify the dose-response associations between total physical activity and risk of breast cancer, colon cancer, diabetes, ischemic heart disease, and ischemic stroke events.Design Systematic review and Bayesian dose-response meta-analysis.Data sources PubMed and Embase from 1980 to 27 February 2016, and references from relevant systematic reviews. Data from the Study on Global AGEing and Adult Health conducted in China, Ghana, India, Mexico, Russia, and South Africa from 2007 to 2010 and the US National Health and Nutrition Examination Surveys from 1999 to 2011 were used to map domain specific physical activity (reported in included studies) to total activity.Eligibility criteria for selecting studies Prospective cohort studies examining the associations between physical activity (any domain) and at least one of the five diseases studied.Results 174 articles were identified: 35 for breast cancer, 19 for colon cancer, 55 for diabetes, 43 for ischemic heart disease, and 26 for ischemic stroke (some articles included multiple outcomes). Although higher levels of total physical activity were significantly associated with lower risk for all outcomes, major gains occurred at lower levels of activity  minutes/week). For example, individuals with a total activity level of 600 MET minutes/week (the minimum recommended level) had a 2% lower risk of diabetes compared with those reporting no physical activity. An increase from 600 to 3600 MET minutes/week reduced the risk by an additional 19%. The same amount of increase yielded much smaller returns at higher levels of activity: an increase of total activity from 9000 to 12 000 MET minutes/week reduced the risk of diabetes by only 0.6%. Compared with insufficiently active individuals , the risk reduction for those in the highly active category (≥8000 MET minutes/week) was 14%  for breast cancer; 21%  for colon cancer; 28%  for diabetes; 25%  for ischemic heart disease; and 26%  for ischemic stroke.Conclusions People who achieve total physical activity levels several times higher than the current recommended minimum level have a significant reduction in the risk of the five diseases studied. More studies with detailed quantification of total physical activity will help to find more precise relative risk estimates for different levels of activity. Although the protective effect of physical activity on various chronic diseases is well studied and supported in the literature, relatively few studies have systematically quantified the dose-response relations between physical activity and chronic disease endpoints. Systematic reviews that examined the dose-response associations between physical activity and breast cancer,10Whereas it is important to assess total physical activity and its dose-response association with health outcomes, there are several challenges to accomplish this. The measurement and classification of physical activity in individual studies are heterogeneous. There is a lack of consistency across studies in terms of the domains being assessed  and the metric of measurement . The categorization of activity levels also varies widely across studies. As a result, most meta-analyses did not assess dose-response associations but compared only the least active with the most active individuals. A limitation of this approach is that being the most active in recreational activities might not be comparable with being the most active in occupational activities, indicating a need for standardization of physical activity across studies.WHO recommends at least 600 metabolic equivalent (MET) minutes of total activity (irrespective of domains) per week for health benefits; this would be, for example, about 150 minutes/week of brisk walking or 75 minutes/week of running.We conducted this systematic review following PRISMA and MOOSE guidelines.Prospective cohort studies that assessed physical activity as the exposure variable  and at least one of the five chosen diseases as an outcome and provided risk estimates  with confidence intervals or standard errors  were eligible for inclusion. Disagreements on eligibility were resolved by consensus. We included only prospective cohort studies to minimize recall and selection biases that are common in case-control studies. For studies that categorized physical activity qualitatively, they also had to report number of individuals or person years in each activity category. If multiple studies reported on the same dataset and study period, we included the one with a more detailed report of physical activity and better control of confounding variables. We considered the following variables to be the main potential confounders: age , sex (ischemic heart disease and ischemic stroke), family history of the outcome of interest , estrogen and progesterone exposure (breast cancer), and lifestyle factors .Four authors  independently extracted data using a standardized data extraction form. HHK and LTA independently checked the data. The following variables were extracted from each included study: author, year of publication, study location, duration of follow-up, sex, age at baseline, type of physical activity , measurement method of physical activity, category, duration, frequency and/or intensity of physical activity, dose of physical activity , sample size, response rate, number of cases and participants in each category, and risk estimates with corresponding confidence intervals (age/sex adjusted and multivariate adjusted) for each activity category.We used the Newcastle-Ottawa scale (NOS)2/kg body weight/min.11In preparation for the dose-response meta-analysis, we standardized domain specific physical activity measures to total MET minutes of activity a week. Domain specific physical activity measures refer to the activity undertaken in different domains of life . MET represents the ratio of the working metabolic rate to the resting metabolic rate. One MET is defined as the amount of oxygen consumed while a person is sitting quietly and is about 3.5 mL OFor studies that assessed physical activity qualitatively  with no additional information on duration and intensity of activity, we calculated the centiles of the activity distribution and mapped them to the GBD 2013 exposure distribution in MET minutes/week  to generate estimates of total physical activity. More specifically, we assigned a centile cut off to each reported activity category based on the percentage of the study population falling into that activity category. A centile value was also assigned to each of the GBD 2013 MET minute cut points  based on the GBD 2013 estimated exposure distributions. The method used to estimate physical activity exposure in GBD 2013 has been reported in detail elsewhere.We used Dismod-MR 2.0,Publication bias was assessed with funnel plots and the Egger test.33We assessed the impact of the quality of studies on the findings by sensitivity analyses including only higher quality studies. To evaluate the influence of imprecise measurement of exposure, we also conducted sensitivity analyses separately for studies that measured physical activity quantitatively and those that assessed it qualitatively, for which MET minutes were estimated with the GBD 2013 exposure data.No patients were involved in setting the research question or the outcome measures, nor were they involved in developing plans for design or implementation of the study. No patients were asked to advise on interpretation or writing up of results. There are no plans to disseminate the results of the research to study participants or the relevant patient community.Our literature search identified a total of 11 166 citations , the risk of breast cancer among those in the low active (600-3999 MET minutes), moderately active (4000-7999 MET minutes), and highly active (≥8000 MET minutes) categories was reduced by 3%, 6%, and 14%, respectively. Compared with insufficiently active individuals (both men and women), the risk of colon cancer among those in the low active, moderately active, and highly active categories was reduced by 10%, 17%, and 21%, respectively. The corresponding reductions in risk were 14%, 25%, and 28% for diabetes, 16%, 23%, and 25% for ischemic heart disease, and 16%, 19%, and 26% for ischemic stroke, respectively.Tables A-E in appendix 4 show the quality assessment scores for each study. The scores varied from a maximum of 9 to a minimum of 3. Sensitivity analyses in which we excluded studies with a score <7 showed similar results, except for diabetes .Egger’s testThis is the first meta-analysis to quantify the dose-response association between total physical activity across all domains and the risk of five chronic diseases. Using data from 174 cohort studies, we estimated relative risks of diseases for each dose of total physical activity in MET minutes/week. The results of our meta-analysis showed that higher levels of total physical activity were significantly associated with lower risk for all outcomes: major gains occurred at lower levels of activity and there were diminishing returns at levels higher than 3000-4000 MET minutes/week. There was no evidence that the findings differed between studies with a higher or lower risk of bias for activity levels where most health gains occurred.The findings of this study extend previous meta-analyses in several important ways. First, this study included a lot more studies than previous quantitative dose-response meta-analyses. For example, we included 55, 35, and 43 cohort studies on diabetes, breast cancer, and ischemic heart disease, respectively, in our study compared with 16 studies on diabetes,Of the previous meta-analyses examining the dose-response associations of leisure time physical activity with breast cancer,Our findings have several important implications. They suggest that total physical activity needs to be several times higher than the current recommended minimum level of 600 MET minutes/week to achieve larger reductions in risks of breast cancer, colon cancer, diabetes, ischemic heart disease, and ischemic stroke. Focusing on a particular domain such as leisure time physical activity, which represents only a small fraction of total activity, as was done by most studies, restricts the scope of applicability of the findings in the real world by limiting the opportunity of increasing activity in different domains in daily life . Taking into account all domains of physical activity increases opportunities for promoting physical activity. Further work with studies with more detailed quantification of total physical activity is warranted to provide more precise estimates for different levels of physical activity. Finally, the methodological innovation of this study could be applicable to other systematic reviews  meta-analyzing studies with variation in categorizations of exposure.Our study included much larger data coverage than previous dose response meta-analyses on breast cancer, diabetes, and ischemic heart disease. It is the first to examine the dose-response associations between physical activity and colon cancer and ischemic stroke. Other strengths included the quantification of total physical activity instead of restricting it to a single domain of activity, the enhancement of comparability across studies through standardization of the measure of physical activity, and the ability to include data with various categorizations of physical activity while incorporating random effects across studies.It does, however, have some limitations. First, we might have missed articles as a result of restricting our search to two databases and studies published in English. Previous systematic reviews without language restrictions found none or few non-English studies.In conclusion, the findings of this study showed that a higher level of total physical activity is strongly associated with a lower risk of breast cancer, colon cancer, diabetes, ischemic heart disease, and ischemic stroke, with most health gains occurring at a total activity level of 3000-4000 MET minutes/week. Results suggest that total physical activity needs to be several times higher than the recommended minimum level of 600 MET minutes/week for larger reductions in the risk of these diseases. With population ageing, and an increasing number of cardiovascular and diabetes deaths since 1990,Many cohort studies and meta-analyses have shown the health benefits of physical activity, resulting in WHO recommending a minimum total physical activity level  of 600 MET minutes a week, but the upper limit of total activity required is not knownMeta-analyses that examined the dose-response associations between physical activity and chronic diseases focused mainly on a single domain of activity such as leisure time physical activity, which constitutes a relatively small part of total daily activity, and thus the relation between total physical activity and chronic diseases has not been well characterizedThis dose-response meta-analysis focused on total physical activity across different domains of life  and included about three to five times more prospective cohort studies than previous dose-response meta-analyses that focused on a single domain of activity onlyThe continuous risk curves for the associations between total physical activity and breast cancer, colon cancer, diabetes, ischemic heart disease, and ischemic stroke show that although the risks of these diseases decrease with increasing level of total activity, most health gains occur at relatively lower levels of activity (up to 3000-4000 MET minutes/week), with diminishing returns at higher levels of activity


Increases in body mass index (BMI) and the prevalence of overweight in low- and middle income countries (LMICs) are often ascribed to changes in global trade patterns or increases in national income. These changes are likely to affect populations within LMICs differently based on their place of residence or socioeconomic status (SES).Using nationally representative survey data from 38 countries and national economic indicators from the World Bank and other international organizations, we estimated ecological and multilevel models to assess the association between national levels of gross domestic product (GDP), foreign direct investment (FDI), and mean tariffs and BMI.We used linear regression to estimate the ecological association between average annual change in economic indicators and BMI, and multilevel linear or ordered multinomial models to estimate associations between national economic indicators and individual BMI or over- and underweight. We also included cross-level interaction terms to highlight differences in the association of BMI with national economic indicators by type of residence or socioeconomic status (SES).There was a positive but non-significant association of GDP and mean BMI. This positive association of GDP and BMI was greater among rural residents and the poor. There were no significant ecological associations between measures of trade openness and mean BMI, but FDI was positively associated with BMI among the poorest respondents and in rural areas and tariff levels were negatively associated with BMI among poor and rural respondents.Measures of national income and trade openness have different associations with the BMI across populations within developing countries. These divergent findings underscore the complexity of the effects of development on health and the importance of considering how the health effects of “globalizing” economic and cultural trends are modified by individual-level wealth and residence. In the past two decades, mean BMI has increased in lower income countries, prompting some researchers to argue that obesity and chronic disease prevention should become higher public health priorities in these areas Examinations of the effects of globalization on health have measured globalization using two types of national economic indicators. Some studies have assessed the associations between per capita income, measured as per capita GDP (gross domestic product) or GNP  and BMI, with the underlying assumptions that exposure to global markets increases with national income, and that increased per capita income leads to higher BMI either through greater resources available to purchase foods or through changes in labor requirements leading to increased sedentary employment The current discourse on globalization and obesity focuses on national-level trends in dietary consumption and body weight; however, broad changes in food availability and consumption will have differential effects on individuals within populations based on their geographic location and socioeconomic status Urban-rural differentials are particularly important to consider in the context of globalization because of the role cities play as nodes for international trade and culture Because economic development associated with globalization is also likely to differentially affect wealthy and poor populations, it is also important to consider changes in socioeconomic differentials in health as a possible outcome of globalization. While studies in a few middle-income countries have identified null or inverse associations between SES and BMI or overweight, particularly within urban areas of developing countries This analysis uses ecological and multilevel analyses to assess associations between changes in national-level GDP, foreign direct investment (FDI), and tariffs on BMI and prevalence of over and underweight among adult women. Individual-level data for this study came from Demographic and Health Surveys (DHS) of women of reproductive age (15–49 yrs.) conducted in 38 countries at two time periods between 1991 and 2010 www.measuredhs.com/pubs/pdf/DHSG4/Recode4DHS.pdf) www.measuredhs.com/pubs/search/search_results.cfm?Type=5&srchTp=type&newSrch=1DHS surveys employ extensive interviewer training, standardized measurement tools and techniques, an identical core questionnaire, and instrument pretesting to ensure standardization and comparability across diverse sites and time  and women who were outside the 15–49 year age range  were also excluded from analysis. An additional 120 women were missing data on other covariates used in the analysis  and were removed from the analysis, leaving a final analytic sample of 697,573 women .2). Weight was measured by trained investigators using a solar-powered scale with accuracy of ±100g, and height was measured using an adjustable board calibrated in millimeters The primary outcome for this analysis was body mass index (BMI) among non-pregnant DHS respondents ages 15–49 years. Respondent BMI was calculated as weight in kilograms divided by height in meters squared  and percent underweight (BMI<18.5 kg/m2) were included as secondary outcomes to encourage comparison of results with other studies using these outcomes. Overweight is a commonly recognized marker of individual chronic disease risk BMI was chosen as the primary outcome because it provides a readily available measurement of adiposity, it is comparable across countries and settings, and it has been found to be strongly correlated with the densitometry measurements of adiposity commonly cited as the “gold standard” of adiposity measurement For individual-level analyses, the outcome variables used were either measured BMI or over- and underweight status of individuals. For ecological analyses, we calculated mean BMI or percent overweight for each country and survey year, and estimated the average annual change in national mean BMI or proportion over- or underweight. These annualized changes served as outcomes in the ecological analyses.The primary predictors in these analyses are national per capita GDP, FDI in 2005 dollars as a percent of national GDP, and average tariff rates, entered into models as continuous variables centered around the grand mean. Because economic variables are expected to have a lagged effect on individual body weight and data on GDP and FDI were readily available, both these variables were entered into models as the average of values from the survey year and five prior years. Because average tariff data was sparse for years prior to 2000, the estimated average tariff for the year of survey only was included in models. For country and survey years where data were not reported by the World Bank, values were imputed linearly from existing data before and after the survey year within each country. Additional details on these data and data sources are provided in Individual-level analyses included both main associations of national economic variables and interactions between national-level variables and markers of SES and urban residence. SES, as measured using a wealth index, and urban residence were included in the analysis as modifiers. Urban residents were respondents living in an urban area as defined by the national census or statistical bureau in each country at the time the survey was conducted, and is measured at the level of primary sampling unit. The primary measure of SES was an index of overall household assets. This index compares the wealth of respondents within countries by comparing the assets available within households in each country. The index was calculated using principal components analysis (PCA): z-scores for each variable measuring a household’s assets and utilities were developed, PCA was conducted on these standardized variable to identify the principal component underlying asset ownership, and the values of the indicator variables were multiplied by the factor loadings for each household and summed to produce a standardized household index value with a mean of 0 and a standard deviation of 1. This standardized score was then divided into quintiles for each country All individual-level models were also adjusted for respondent age, educational attainment, marital status, and year of survey. Respondent age was entered to the models in 5-year age categories. Educational attainment was specified as having no education or incomplete primary education, having completed primary education, or having some secondary or higher schooling. Marital status was entered as a binary variable, with ever-married also including widowed, divorced, and co-habiting women. Year of survey was entered as a categorical variable, with 1991 as reference.The analysis plan included both ecological analyses assessing the association between average annual changes in national-level economic variables and changes in BMI and proportion overweight and underweight, as well as multilevel models incorporating both individual- and national-level predictors of BMI. For country-level ecological analyses, we estimated ordinary least squares regression analyses with robust standard errors, using the following single level model:i represents country. A series of ecological models were fitted. First, we estimated the association between change in GDP on changes in BMI. Next, we estimated the association between change in FDI and BMI after adjusting for GDP, and the association between change in tariffs and BMI after adjusting for GDP.In the model above, Multilevel linear analysis was used to estimate the associations of individual- and national-level predictors on BMI. We modeled these data using a four-level data structure, with individuals nested within primary sampling units (PSUs), sampling regions, and countries i,j, k, and l represent the individual, sampling unit, region, and country, respectively. Y is the respondent’s BMI, (q)x is the q-th individual-level predictor, (r)x is the r-th PSU-level predictor, and (s)x is the s-th country-level predictor and (w)x is the w-th year indicator; r,β, γ and sδ represent the associations of individual-, PSU-, and national-level predictors, respectively; and wθ represents the association of being surveyed in year w. Residuals at all four levels  are assumed to be normally distributed with mean zero. In the secondary analysis, probability of under- and overweight were modeled as outcomes using similar equations with a multinomial outcome and normal weight as the reference group.In this equation, The analysis strategy for the multilevel analyses was as follows: we first fit models including individual-level predictors such as age, educational status, and wealth index; year of survey; urban residence; and the main effect of per capita GDP. We then assessed whether the association between GDP and BMI differed by type of residence and household wealth by adding cross-level interaction terms. Finally, we assessed the main associations interacted with urban residence and wealth of FDI or average tariff rates after adjustment for individual-level covariates and per capita GDP. The secondary analysis with under- and overweight as outcomes followed the same pattern. Because a large proportion of the final sample came from two surveys conducted in India, we conducted a sensitivity analysis with data from India excluded to ensure that results were not driven primarily by these surveys. Multilevel models with the continuous BMI outcome were estimated using an interactive generalized least squares estimation algorithm. Models with the non-linear outcome used the MQL estimation procedure and first-order linearization. Descriptive statistics and ecological models were calculated using Stata SE 12.0 National-level GDP per capita, FDI, and average tariffs are summarized in 2 in 2008) and Jordan (28.34 kg/m2 in 2007) and was lowest in Ethiopia (20.36 kg/m2 in 2005). Percent underweight was highest in India (29.6% in 2005) and percent overweight was highest in Egypt (76.0% in 2008). Mean BMI decreased between time periods in 6 of 38 countries, but percent overweight and percent underweight increased in 17 of 38 countries.Individual BMI for each survey is summarized in S2). .Results of the country-level ecological analyses are presented in  and model results excluding data from India are included as table S5). In analyses using the full dataset, GDP had a small but positive main association with BMI . However, this result was not seen in either the ecological analysis or in the multilevel analysis excluding data from India: neither of these showed a significant association between GDP and BMI.Associations between of national-level GDP and individual BMI are presented in 2, 95% CI: 0.458, 0.528; association with highest wealth group compared to lowest: 2.001 kg/m2, 95% CI: 1.960, 2.042). The positive association of GDP with BMI was much smaller among urban residents   (table S6). However, there was a small but positive differential association of GDP per capita on underweight among urban residents, suggesting GDP increases may have less of a beneficial impact on under nutrition among urban populations .Both urban residence and wealth had significant and positive associations with BMI (urban association: 0.493 kg/m −0.187) figure 12, 95% CI: −0.053, 0.053). However, FDI did have significant differential associations in rural and urban areas, with stronger positive associations of FDI and BMI seen in rural areas  . (table S7).Associations of FDI as percent GDP with BMI are presented in  −0.227) figure 32, 95% CI: −0.001, 0.007), there were significant interactions between both urban residence and tariff rate and SES and tariff rate. Tariff rates had a stronger positive association among urban residents   (table S8 presents associations between tariffs and over- and underweight.).Associations between average tariff rates and individual BMI are presented in , 0.028) figure 5The ecological analyses presented above indicate that there were no significant associations between change in economic factors and change in BMI or prevalence of overweight at the national level. However, multilevel analyses found that individual wealth and place of residence modify the associations between these national-level indicators and BMI, underscoring the need to measure how national trends affect both mean changes in health indicators and how they increase or decrease health disparities.These analyses also suggest that, among rural and poor women in the countries included in this study, increasing GDP is associated with increased mean BMI, decreased odds of underweight, and increased odds of overweight. In the poorest countries, these women tend to have lower body weight than their urban and wealthy counterparts in lower income countries Both measures of economic openness tended to have the same result: increased openness, whether measured through increases in foreign investment or decreases in average tariff rates, tend to have strong associations with the BMI of the wealthiest respondents or respondents living in urban areas. This finding confirms that those who are expected by globalization to have the most access to global markets in developing countries – wealthy urban residents – see the strongest associations between trade openness and BMI. This also suggests that, as openness to trade increases, the variability in BMI across the population may also increase, leading to higher rates of both under- and overweight, rather than a general shift of the population distribution of BMI away from underweight.The inverse association between FDI and BMI among only the wealthiest respondents is notable, and does not fit with the general trend of positive associations between indicators of development or trade openness and BMI. This finding may suggest that increased foreign presence leads to shifts in perceptions of obesity. One possible mechanism underlying this shift is changing attitudes toward obesity among the wealthiest in places with increased exposure to foreign cultural influences. Studies have found that high body mass is generally positively perceived among women in Africa This study has several limitations and strengths. First, the global scope of this study serves as both a strength and a weakness: while, on the one hand, the breadth of the population included allows for the identification of broad international trends in mean BMI, it at the same time makes it difficult to pinpoint specific mechanisms, such as behavioral trends, policy changes, or environmental modifications, linking trade or development and BMI. Particularly missing from this study is information collected at the city or regional level; while our study includes individual and national data, regional economic development trends and the local built environment are likely to affect nutritional status as well. Studies including more detailed economic data from smaller geographic areas, data collected over a longer time span, and longitudinal data on both women and men could provide more nuanced information on the roles of trade and economic development in shaping individual health over time.This analysis uses recent data from Demographic and Health Surveys, which are primarily conducted in lower and lower-middle income countries. Consequently, the geographic scope of the analysis is somewhat limited, and several middle-income countries that frequently appear in the literature on chronic disease, including China, Mexico, and Brazil, are not included in this analysis. This limits the generalizability of these findings primarily to lower-income countries, where rates of obesity and overweight are relatively low. The surveys used in this analysis were conducted at different times across countries, and the measures of urban residence and overall wealth are country-specific. In this analysis, urban residence is defined by each country, and these definitions vary widely within regions There are also limitations to the data on GDP and FDI used. The data on FDI is not fully comparable across countries, because of national discrepancies in the definition of FDI, methods of collecting FDI data, and accounting and valuation practices Finally, while the ecological analyses failed to identify significant associations between national change in economic indicators and mean body weight, this may be due to the small number of countries and short timeframe included in the dataset. However, recent models of adult metabolism have suggested that weight change as a result of changes in caloric intake happen relatively quickly, with half of body weight increase occurring within one year and 95% within three years To summarize, this analysis does not identify large or statistically significant associations between changes in economic development indicators and mean changes in BMI. However, there appear to be marked differentials in how these indicators are associated with BMI among individuals within populations of lower-income countries. While GDP and FDI tended to be positively associated with BMI among poor, rural individuals, increasing tariffs tended to be associated with increases in overweight among the wealthiest, and also led to small increases in underweight. These divergent findings underscore the complexity of the effects of development on health, the variety of mechanisms through which cultural change may effect body weight, and the importance of considering how the health effects of “globalizing” economic and cultural trends are modified by individual-level wealth and residence.Table S1Annual change in GDP, FDI, and average tariffs by annual change prevalence of overweight for 38 countries.(DOCX)Click here for additional data file.Table S2Annual change in GDP, FDI, and average tariffs by annual change in prevalence of underweight for 38 countries.(DOCX)Click here for additional data file.Table S3Associations of age, educational attainment, wealth, marital status, urban residence, and national GDP with BMI.(DOCX)Click here for additional data file.Table S4Odds ratios comparing underweight and normal weight and overweight and normal weight respondents by age, educational attainment, wealth index, marital status, urban residence, and national GDP.(DOCX)Click here for additional data file.Table S5Associations of GDP with BMI and interactive associations of GDP and wealth and GDP and urban residence with BMI, 37 countries (India excluded).(DOCX)Click here for additional data file.Table S6Odds ratios comparing underweight and normal weight and overweight and normal weight respondents by GDP and wealth and GDP and urban residence.(DOCX)Click here for additional data file.Table S7Odds ratios comparing underweight and normal weight and overweight and normal weight respondents by FDI and wealth and FDI and urban residence.(DOCX)Click here for additional data file.Table S8Odds ratios comparing underweight and normal weight and overweight and normal weight respondents by tariff rate and wealth and tariff rate and urban residence.(DOCX)Click here for additional data file.


The diagnostic accuracy of fine needle aspiration cytology (FNAC) of head and neck lesions is relatively high, but cytologic interpretation might be confusing if the sample is lacking typical cytologic features according to labeled site by physician. These errors may have an impact on pathology search engines, healthcare costs or even adverse outcomes. The cytology archive database of multiple institutions in southern Iran and Australia covering the period 2001–2011, were searched using keywords: salivary gland, head, neck, FNAC, and cytology. All the extracted reports were reviewed. The reports which showed discordance between the clinician's impression of the organ involved and subsequent fine needle biopsy request, and the eventual cytological diagnosis were selected. The cytological diagnosis was confirmed by histology or cell block, with assistance from imaging, clinical outcome, physical examination, molecular studies, or microbiological culture. The total number of 10,200 head and neck superficial FNAC were included in the study, from which 48 cases showed discordance between the clinicians request and the actual site of pathology. Apart from the histopathology, the imaging, clinical history, physical examination, immunohistochemical study, microbiologic culture and molecular testing helped to finalize the target organ of pathology in 23, 6, 7, 8, 2, and 1 cases respectively. The commonest discrepancies were for FNAC of “salivary gland” , “lymph node” , “soft tissue”  and “skin” . The primary physician requesting FNAC of head and neck lesions are incorrect in their clinical impression of the actual site in nearly 0.5 percent of cases, due to the overlapping clinical and imaging findings or possibly due to inadequate history taking or physical examination. The head and neck region includes skin, bone, salivary glands, thyroid, soft tissue, and lymph nodes. All of which are subject to neoplastic and nonneoplastic changes The cytology archive database of multiple institutions in southern Iran and Australia covering the period (2001–2011) were searched using keywords: salivary gland, head, neck, FNAC, and cytology. The total number of 10,200 head and neck superficial FNAC were included in the study from which 48 cases showed discordance between the clinicians request and the actual site of pathology. All FNAC were done under the guidance of sonography by cytopathologists. All the extracted reports were reviewed. The reports which showed discordance between the clinician's impression of the organ involved in FNAC request form, and the eventual cytological diagnosis were selected from total controversial reports. Metastatic tumor in a lymph node was considered discordant when the primary tumor site was outside the head and neck or in intracranial regions. Further investigations performed by the cytopathologist and physician to make the final diagnosis, were reviewed in available records. The cytological diagnosis was confirmed by surgical biopsy, cell block, and immunostaining, with assistance of imaging, clinical outcome, physical examination, molecular studies, or microbiological cultures.The hospital centers were head and neck surgical referral centers from different cities from Iran and Sydney, Australia. The discordant cases were almost evenly distributed in these centers and mainly by general practitioners. Ear, Nose, and Throat (ENT) physicians do better than general surgeons or general practitioners.The data base search revealed 48 cases showing discordance between the clinicians request and the actual site of the pathologydemonstrated in FNAC.Patients had an age range of 1–72 years. Clinical data, including the organ site on which the clinician requested the FNAC, along with the cytological and surgical pathology diagnoses and the procedure that assisted with the diagnosis such as the cell block, immunohistochemistry (IHC), molecular, microbiological culture, imaging, history, and physical examination, are presented in TableThe clinicians requested fine needle aspiration biopsy (FNB) on the following target organs: salivary gland (20), lymph node (12), soft tissue (11), and skin (5). Besides histopathology, imaging, clinical history, physical examination, immunohistochemical studies, microbiologic culture, and molecular tests helped to finalize the target organ of pathology in 28, 6, 8, 10, 4, and 1 cases, respectively.There were 20 FNAC requests for “salivary gland” FNA, including seven cases where an initial FNA diagnosis favored a salivary gland tumor, however, further excision, IHC and imaging study showed osteogenic sarcoma There were 12 FNA request for “lymph node” FNA. The cytological diagnosis of five cases were carcinoma, granuloma, small round cell tumor, epidermoid cyst, and pleomorphic adenoma and these cases were shown to be metastatic meningioma One case on cytology and histology was a carotid body tumor (Case 26) and two cases were mandibular neurofibromas (Cases 27 and 28) . The diagnoses on FNA in three cases were salivary lymphoepithelial lesion (Case 29), calcified material There were 11 requests for FNA on “soft tissue”. In two cases the lesions were a skin basal cell carcinoma (Case 33) and hydatid cyst (Case 34) based on cytology, surgical biopsy, and imaging. In another five cases the diagnoses were salivary gland pleomorphic adenoma (Case 35), bone chondrosarcoma (Case 36), metastatic squamous cell carcinoma (Case 37), and histiocytosis (Cases 38 and 39) based on FNA biopsy, imaging, IHC, history, and physical examination. In two cases, the FNA was noncontributory but the surgical diagnosis was fibrous dysplasia (Cases 40 and 41) supported by imaging. In two cases, the cytology diagnosis was actinomycetesoma (Case 42) and multiple myeloma There were five requests for FNA of “skin” and the final target diagnoses of three cases were adenoid cystic carcinoma (Case 44), soft-tissue fungal infection (Case 45) and osteomyelitis (Case 46) confirmed by physical examination, microbiological culture, imaging, and histology. The final two diagnoses were leishmania lymphadenitis supported by physical examination and molecular studies (Cases 47 and 48).Head and neck lesions can be easily seen and palpated due to their superficial locations and are highly suitable targets for FNA as the initial diagnostic test because of its high sensitivity and specificity for both neoplastic and nonneoplastic lesions In our experience, physicians often request FNAC for any abnormal growth before they take thorough history, perform an adequate physical examination, diagnostic ultrasound or other imaging studies The clinical features of palpable mass lesions in the head and neck region overlap for skin, soft tissue, salivary gland, and bone or even with the frequency of different organ pathology (infectious and neoplastic processes). This very overlapping of clinical presentation makes the FNAC such an excellent minimally invasive first diagnostic test for head and neck lesions. Clinician's presenting history, physical examination, and imaging of head and neck growth need to be best correlated with the FNAC findings.Providing a previous history of malignancy by the referring clinician will assist the pathologist in assessing lymph nodes and other palpable lesionsaccording to patterns of nodal spread in head and neck. Proper history was complementary in lymphoma involvement (Case 11), metastatic meningioma Thorough physical examination of skin lesions of histiocytosis or neurofibromatosis (cafe au lait spots) by cytopathologist can be clues to correctly diagnose a bone or neural lesions which were missed/not mentioned by referring clinician (cases 27 and 38).Multifocal lesions on the face suggest a primary skin lesion rather than a pleomorphic adenoma (Case 32), although recurrent pleomorphic adenoma can be multifocal, or the previously undetected submandibular tumor in a patient with requested skin FNAC (Case 44), or in endemic areas for leishmaniasis the recognition of skin lesions that direct a FNAC of the localized leishmania lymphadenitis and its diagnosis (Cases 47–48).Recently, cytopathologists have learned to use ultrasound machines to assist them in performing FNA procedures. Imaging particularly the more readily available and clinically flexible ultrasonography should be used as an ancillary tool for both clinicians and pathologists to significantly improve FNAs in smaller, nonpalpable lesions and target complex lesions to confirm both organs of origin as well as the diagnosis with confidence and accuracy, and achieving a better outcome. For example, mandibular tumors can be cytologically and histologically mistaken for salivary tumor FNA biopsy of bone lesions is a reliable diagnostic test for metastatic and primary bone tumors. Areas of difficulty were due to inadequate sampling or misclassification with regard to the exact site of malignancy . A bony mandibular lesion with an overlying suppurative sinus is suggestive of actinomycetes or osteomyelitis .Imaging also helps confirming a calcified goiter or salivary duct stones . Color Doppler and immunostains on cell block helps in diagnosis of a hypocellular carotid body tumor (Case 26). Demonstration of bilaterality of salivary lesions and the absence of a true mass in imaging, helps to diagnosis lymphoepithelial disease rather than lymphadenitis (Case 29).Cell blocks where available can be corroborated with immunophenotyping and immunocytochemistry as a method complementary to cytology in “tumor of origin/diagnostics” of lymphoma, round cell tumors, and spindle cell carcinomas In conclusion mislabeling of the target organ for a FNA requested by a clinician may be due to the overlapping clinical and imaging findings of head neck lesions but is exacerbated by an inadequate history taking or incomplete or poor physical examination by the clinician. The clinicians should provide us with all possible clinical and radiological information, it is also good practice to look for this information if the morphological findings do not fit the clinical suspicion, especially in the current era of electronic medical records or a phone call should suffice. Cytopathologists should be ready to seek clinical clues by directly questioning the patient and examining the patient as required, prior to performing the FNAC, or returning to ask questions of the patient after rapid on site assessment of the FNAC material. Imaging prior to the FNAC or at the time of the FNAC plays a crucial role in defining the site and organ involvement of the lesion. Microbiological cultures, immunocytochemical study of FNA, and cell block biopsy material and molecular methods are essential ancillary tests to confirm the diagnosis, when available.FNAs of the Head and neck can be easily confused, not only because of the clinical similarity between lesions but also because of the overlap in cytomorphologic features of the aspirated cells. Although no one single cytomorphologic feature is diagnostic, a combination of clinical parameters noted earlier should raise the possibility of diagnosis.Proper technique and recognition of these pitfalls, as well as simultaneous cytopathologist and clinician work ups are needed to achieve a successful FNA diagnosis and avoid discrepancy of target sites between clinician and cytopathological reports.None declared.