This study aimed to establish a friendly environment of active living and healthy eating for citizens while promoting and increasing knowledge of healthy exercise. Acquisition of physical activity skills and citizens’ lifestyle changes result in reduction in rates of obesity and deaths related to underlying metabolism syndrome. This study used a non-experimental cross-sectional design to survey residents living in Taiwan’s rural Miaoli County. The inclusion criterion was positive screening for metabolic syndrome. In total, 2068 participants were recruited, and 1886 questionnaires (91.2%) were completed. An organization-spreading strategy and home convenient Lifestyles of Health and Sustainability tactic were applied to the assessment, promotion, evaluation, and planning of the project via an obesity-causing environmental scan, oriental synergy aerobics, acupuncture points massage, guide books, broadcasting, town-based “shape-it-station”, and a vending cart created to facilitate the acquisition of healthy foods. After the intervention, results revealed that health condition, regular exercise habits, diet behavior, metabolic syndrome cognition, and body weight became better than before. Appropriate promotion of healthy cities through public health measures may effectively reduce the threat of death due to metabolic syndrome, which in turn reduces overall, and represents successful control of a typical non-communicable disease. Metabolic syndrome (MetS) describes the aggregation of a spectrum of related medical conditions, including obesity, dyslipidemia, hypertension, and hyperglycemia , all of In fact, the general concept is that a patient with MetS will experience some combination of conditions, such as obesity, dyslipidemia, hypertension, and insulin resistance or hyperglycemia. To successfully manage MetS, clinicians should identify related conditions. MetS is associated with an increased risk of CVD in the general population ,9. FurthThe main purpose of this study was to use the MetS-CKD relationship as a point along each stage of the CKD spectrum to improve the diagnosis of MetS. This approach may help physicians to determine whether MetS is part of the etiology of CKD, the result of a common risk factor for MetS and CKD, or a completely unrelated entity.According to various studies, knowledge and awareness of the warning signs of MetS may help people meeting MetS criteria to take early treatments . RegardiHealth education is the main basis for all preventive interventions concerning MetS among people. A policy-planning study has highlighted the role of age-friendly promotion in the modification of environmental factors or behavioral change . With thThis quasi-experimental study was conducted in 2010 among MetS-positive residents of rural Miaoli County who were recruited through a community health assessment. From 2009–2010, public health nurses from various township health centers in the county’s 18 marginal cities and towns collaborated with volunteer residents to conduct screenings. Patients who received preventive health services or health checks  at these clinics were screened for MetS and its high-risk groups. A list of participants with MetS and its high-risk groups were collected for the study population. Public health nurses contacted these participants, briefly explained the 12-week Lifestyles of Health and Sustainability (LOHAS) plan and asked their willingness to participate. A participant signature was required to indicate agreement with the plan.Public health nurses worked with participants to implement the study questionnaire, which was developed by experts and famous scholars invited by the Miaoli County Sports and Healthy Eating Executive Committee. The questionnaire assessed demographics, exercise, diet, and weight loss. A total of 2068 participants completed this survey of MetS and its high-risk groups. The response rate was 91.2% . The incWe examined the inclusion criteria in 2 phases. Exclusion criteria include participant’s will of withdrawal or refusing to sign the informed consent. Phase I: collect MetS list from citizens. Our study collected a health checkup list of citizens through public health nurses from various township health centers. We conducted home visits to citizens who have received preventive health services or health checkups in 2008–2009. Next, we screened out citizens with MetS and completed the collection of a list with more than 2000 participants. Phase II: case contact included the following: (1) according to the list, we contacted the participants initially by phone, explained concisely the plan, and coordinated the time required for home visits; (2) public health nurses cooperated with volunteers according to previous appointments to explain the purpose and method of implementation. Then, the citizens with MetS are requested to participate in the 12-week LOHAS educational program . The stu(1)Health condition standard score = /15 × 100(2)Exercise index score = Exercise intensity score × Exercise time score × Exercise frequency score(3)Diet behavior standard score is divided into 2 parts:Outside food behavior score = /24 × 100Cooking at home behavior score = /32 × 100(4)The standard score based on the recognition of MetS =  × 100The educational intervention was developed and implemented in 3 sessions within 12 weeks . ParticiPhysical status was confirmed by the presence or absence of MetS. Subjects were classified according to the definition used in the questionnaire. Comorbidity history and age were collected via questionnaires and interviews.t-test and one-way analysis of variance (ANOVA) for continuous variables. A paired sample t-test is used for pre and post analysis, and McNemar’s test is applied for categorical variables on dependent data. We also performed post hoc analysis after one-way ANOVA analysis. Descriptive analyses used mean ± standard deviation (SD) for data presentation. The level of significance was set at p < 0.05. Statistical analysis was performed using SPSS version 24 .We explored the differences among different groups for characteristics using independent samples p > 0.05). However, there were significant differences in age, birthplace, educational level, and occupational class. We also performed the post hoc analysis presented in The participants’ ages ranged from 20 to 85 years, with a mean age of 53.6 (±SD: 13.6) years in the participant group. A comparison of scores of healthy eating behaviors among subjects of different social demographic characteristics is shown in p > 0.05). However, MetS cognition, sports index score, and healthy eating behavior standard score significantly increased after intervention in the participant group (p < 0.05). To assess the efficiency of the educational program in preventing MetS, cross-tabulation analysis was performed (p > 0.05). According to the cross-tabulation, results of McNemar’s test verified that the null hypothesis is rejected (p < 0.05). Therefore, there is a statistically significant difference between past regular exercise and current regular exercise. The cross-tabulation showed that the situation is unchanged at 52.1% of the total . The results showed that the educational intervention significantly increased the proportion of the population reporting regular exercising behaviors.erformed . The resThis study describes knowledge, behaviors, and beliefs of residents with MetS in rural Miaoli County, which is located in northwestern Taiwan. While our results showed a relatively high level of knowledge and awareness regarding healthy eating and regular exercise, prevention of MetS was consistent with findings from other studies ,19. An iPMT assumes that severity and susceptibility of risk is assessed first, followed by evaluation of the efficacy of the recommended response by using a highly perceived threat measure . In thisEnhancement of females’ self-efficacy through presentation of successful examples, followed by the encouragement of those having regular screening behaviors were among other aims of the current study, leading to the improvements of efficacy in the participant group. Thus, the study staff were recommended to consider these points when executing the educational intervention. In the present study, there were no significant differences regarding the mean score of health condition standard after intervention in the participant groups, which is consistent with results in the literature . HoweverIn this study, our results suggested that health condition, regular exercise habit, diet behavior, MetS cognition, and body weight ameliorate after implementation of the intervention. Moreover, we found that the total deaths due to MetS in Miaoli County dropped by 0.39% after the intervention to 32.28% in 2011 from 32.67% in 2010. In addition to the all-causes mortality, CKD mortality showed a similar trend, decreasing from 2.87% in 2011 to 2.81% in 2012. These benefits are owed to the promotion of “Oriental Bio-Synergy” exercise, healthy eating, and healthy weight loss in this population.The limitations of the present study include the use of a self-reported method conducted according to the essence of quasi-experimental study design for data collection and statistical population that precluded the generalizability of the results. Therefore, similar studies are needed on other groups with MetS. Regardless of these limitations, this study has some strengths. This study was conducted in a marginalized population with high rates of MetS, which increased the likelihood of their eligibility to enroll and receive intervention. The advantages of using this strategy included acceptability, ability to deliver information, access to a marginalized population, modeling, and ongoing contact. However, this study only evaluates the intervention effect before and after analysis for the case group without blood sampling or blood pressure analyzing due to limited funding.The weight-loss policy of healthy cities may indeed have a positive impact on the healthy living habits of MetS. The results showed that application of an educational intervention based on PMT would be an effective strategy for preventing MetS in residents of marginal rural areas. Therefore, application of this theory to health center education programs may lead to positive changes in the management of MetS prevention, which may have beneficial effects in the future. Our research project integrated public and civil departments, non-government organizations, and community resources to develop a model of “must move” and “healthy diet” in the strategy of sustainable development in Miaoli County, Taiwan. In conclusion, an appropriate health promotion project may effectively reduce the threat of death by MetS. This is an example of a successful project promoting the control of non-communicable diseases.


Semantic audiovisual stimuli have a facilitatory effect on behavioral performance and influence the integration of multisensory inputs across sensory modalities. Many neuroimaging and electrophysiological studies investigated the neural mechanisms of multisensory semantic processing and reported that attention modulates the response to multisensory semantic inputs. In the present study, we designed an functional magnetic resonance imaging (fMRI) experiment of semantic discrimination using the unimodal auditory, unimodal visual and bimodal audiovisual stimuli with semantic information. By manipulating the stimuli present on attended and unattended position, we recorded the task-related fMRI data corresponding to the unimodal auditory, unimodal visual and bimodal audiovisual stimuli in attended and unattended conditions. We also recorded the fMRI data in resting state. Then the fMRI method was used together with a graph theoretical analysis to construct the functional brain networks in task-related and resting states and quantitatively characterize the topological network properties. The aim of our present study is to explore the characteristics of functional brain networks that process semantic audiovisual stimuli in attended and unattended conditions, revealing the neural mechanism of multisensory processing and the modulation of attention. The behavioral results showed that the audiovisual stimulus presented simultaneously promoted the performance of semantic discrimination task. And the analyses of network properties showed that compared with the resting-state condition, the functional networks of processing semantic audiovisual stimuli (both in attended and unattended conditions) had greater small-worldness, global efficiency, and lower clustering coefficient, characteristic path length, global efficiency and hierarchy. In addition, the hubs were concentrated in the bilateral temporal lobes, especially in the anterior temporal lobes (ATLs), which were positively correlated to reaction time (RT). Moreover, attention significantly altered the degree of small-worldness and the distribution of hubs in the functional network for processing semantic audiovisual stimuli. Our findings suggest that the topological structure of the functional brain network for processing semantic audiovisual stimulus is modulated by attention, and has the characteristics of high efficiency and low wiring cost, which maintains an optimized balance between functional segregation and integration for multisensory processing efficiently. Successful human communication critically depends on efficient semantic comprehension, which refers to a collection of interactive cognitive mechanisms that support semantically derived behaviors . Many stOwing to the recent development of connectomics, many studies propose that brain functions are subserved by interactions of large-scale distributed and parallel subnetworks , in whicThe characteristics of functional brain networks can be analyzed using an approach based on graph theory. This approach has been previously applied to study network properties in various cognitive tasks . Based oIn the present study, we designed an fMRI experiment of semantic discrimination using the unimodal auditory, unimodal visual and bimodal audiovisual stimuli with semantic information. By manipulating the stimuli present on attended and unattended position, we recorded the task-related fMRI data corresponding to the unimodal auditory, unimodal visual and bimodal audiovisual stimuli in attended and unattended conditions. We also recorded the fMRI data in resting state. Then the fMRI method was used together with a graph theoretical analysis to construct the functional brain networks in task-related and resting states and quantitatively characterize the topological network properties. The global properties, local properties and the correlation between nodal efficiency and RT were calculated and analyzed. The aim of our present study is to explore the characteristics of functional brain networks that process semantic audiovisual stimuli in attended and unattended conditions, and provide new insights into the neural mechanisms of multisensory semantic processing and the modulation of attention in the human brain from a systemic perspective .Eighteen healthy volunteers  participated in this fMRI study. All subjects were right-handed, and had normal or corrected-to-normal vision , and reported normal hearing. The Experimental protocol was approved by the Ethics Committee of Changchun University of Science and Technology. After receiving a full explanation of the experimental purpose and the general attention of fMRI scanning, participants gave written informed consent for all experiments as per the protocol approved by the institutional research review board.The task utilized unimodal visual (V), unimodal auditory (A), and bimodal audiovisual (AV) stimuli. Visual stimuli were gray-scale pictures of the inanimate  or animate objects  from the international common Snodgrass-Vanderwart white–black line graphic library and were processed using AI illustrator software . And auditory stimuli were the sounds corresponding to the inanimate or animate objects obtained from the Internet and were processed using Cool Edit Pro 2.1 software . Stimulus presentation was controlled by a personal computer running Presentation 0.71 software .To ensure that the participants focused on the stimuli during the experiment, the stimuli should be presented for as short a time as possible. At the same time, in order to enable the participants to obtain semantic information to discriminate the category (inanimate or animate objects), the stimuli should be presented long enough. Prior to the formal experiment, the appropriate presentation time for pictures and sounds was examined in a behavioral pre-experiment, in which the pictures and sounds were designed to presented for 200, 300, and 400 ms. The participants were required to discriminate the stimuli to be inanimate or animate objects. A minimum presentation time with an across-subject accuracy of above 80% was selected. As a result, the pictures and sounds were determined to be presented 300 and 400 ms, respectively. The visual stimuli  were projected onto a screen placed behind the head of the participants at the end of the scanner bore, visible to participants by a mirror placed within the MR head coil. A constant distance of 80 cm was maintained between the eye and the projection screen. As shown in An event-related fMRI design was adopted to measure the responses of the brain during a semantic discrimination task. Before the formal experiment, each participant was required to continue training for adapting to the experimental environment and being familiar with the experimental equipment. When accuracy rate reached 80%, the experimenter was convinced that they understood the task. Eight sessions need to be completed for each participant, and each session consisted of 40 A stimuli, 40 V stimuli and 40 AV stimuli. The frequencies of the inanimate and animate stimuli were both 50% for each group of A, V, and AV stimuli. There were six types of stimuli (2 (inanimate and animate objects) × 3 ) presented with equal probability on the left and right sides of the participant according to a pseudorandom sequence.During the experiment, participants were instructed to minimize blinking and bodily movements to avoid movement artifacts. As shown in d′ = Z(HRs) − Z(FARs) was also calculated separately for each stimulus type  and location (left and right) using signal detection theory (SDT)  with Type  and Location (left and right) as within-subject factors. All statistical analyses for behavioral data were conducted using IBM SPSS software  for Windows. Greenhouse–Geisser corrections were applied with adjusted degrees of freedom. A value of p < 0.05 was considered to indicate a statistically significant difference. A power analysis was also implemented using GPower3.1 to supported the number of participants, and the value of power >75% was considered to indicate a statistically significant difference.Mean RTs, hit rates (HRs), and false alarm rates (FARs) for the target stimuli were computed separately for each stimulus type  and location (left and right). In addition, signal sensitivity measures ry (SDT) . The Z iBefore audiovisual semantic discrimination experiment, a 5-min resting-state scan was obtained, during which each participant was instructed to rest and focus on the fixation point presented on the central of the screen. All task-state (semantic discrimination task) and resting-state functional imaging data were acquired at the Sino Japanese Friendship Hospital of Jilin University. A 3T fMRI scanner (Siemens) was used to acquire both T1-weighted anatomical images (repetition time (TR) = 8600 ms; echo time (TE) = 4 ms; field-of-view (FOV) = 192 mm; flip angle (FA) = 90°; 128 slices; voxel size = 1 × 1 × 1 mm) and T2-weighted gradient echo planar imaging sequence . There were eight sessions with a total of 160 volume images per session. The high-resolution anatomical image volume was acquired at the end of the experiment.The preprocessing of the task-state data during semantic discrimination was conducted using the SPM8 software package  under Matlab2012 . For each run, the first six time points were discarded to account for signal equilibrium and the participant’s adaptation to the circumstances. All images were realigned to the first image volume in the series, normalized to standard anatomical space defined by the Montreal Neurological Institute atlas, and smoothed using a 6.0-mm full-width half-maximum Gaussian kernel.1. After discarding the first six time points, the remaining functional images were realigned to the first volume to correct for head motion and then spatially normalized to standard anatomical space defined by the Montreal Neurological Institute atlas. Temporal bandpass filtering (0.01 ≤ f ≤ 0.1 Hz) was performed afterward to reduce the effects of low-frequency drift and high-frequency noise. To reduce the effects of motion and non-neuronal blood oxygen level-dependent fluctuations, the head motion, cerebrospinal fluid signal, and white matter signals were further removed as nuisance covariates (The resting-state data were preprocessed using the SPM8 software package and the Data Processing Assistant for Resting-State fMRI (DPARSF)variates . Finallyp-values corrected for the false discovery rate in the CONN toolbox  to construct individual functional brain networks corresponding to the attended A, attended V, attended AV, unattended A, unattended V, and unattended AV conditions. And the resting-state fMRI data was also entered into the CONN toolbox to construct functional brain network of resting-state condition. The regions of interests (ROIs) were defined based on the anatomical automatic labeling (AAL) , which c toolbox . Overall toolbox . Hence, 2. The network architecture was investigated at both global and local levels of each functional brain network corresponding to attended A, attended V, attended AV, unattended A, unattended V, unattended AV, and resting-state conditions. First, we compared the global topological properties of bimodal AV network with those of unimodal A, V networks both in attended and unattended conditions using paired t-test. And then an ANOVA with the factor of Condition was conducted to compare the global properties in attended AV, unattended AV, and resting-state conditions. We further compared the attended and unattended AV conditions using paired t-test for exploring the modulatory effects of attention to the brain network architecture. The global network metrics, including the characteristic path length Lp, clustering coefficient Cp, normalized characteristic path length λ, normalized clustering coefficient γ, small-worldness σ, local efficiency Eloc, global efficiency Eg, assortativity, and hierarchy, were calculated. Small-worldness was originally proposed by Graph theoretical analyses were performed using the GRETNA toolboxp < 0.05 was considered to indicate a statistically significant difference.All statistical analyses were performed using IBM SPSS software  for Windows. The network metrics were calculated under ten network sparsity thresholds from 0.05 to 0.5, and the average values of the area under the curve were used for the statistical analysis in order to provide a scalar that did not depend on the specific threshold selection. A value of F = 1.724, p = 0.206, power = 99.99%), HRs , FARs , and d′  based on stimulus location. Therefore, the RTs, HRs, FARs and d′ to stimuli on the left and right sides were combined to increase the signal-to-noise ratio.We analyzed the behavioral data to bimodal AV, unimodal A and V stimuli to examine whether the simultaneous auditory and visual stimuli facilitated the behavioral performance. The results showed no significant differences in mean RTs . Subsequent paired t-tests revealed that participants responded faster to target AV stimuli than to target A stimuli  and V stimuli . RTs to V target stimuli were also faster than those to A target stimuli  . Paired t-tests revealed that HRs to AV was significantly higher than to A target stimuli  and to V target stimuli , but no significant difference was found between the HRs to A and V stimuli . Paired t-tests showed that the FARs to target AV were significantly lower than that to target A  and target V stimuli . And the FARs to target A and V stimuli were no significant difference observed . Paired t-tests showed that d′ values for AV target stimuli were significantly higher than those for V target stimuli  and A target stimuli . These results indicated that the bimodal AV stimulus presented simultaneously enhanced the accuracy and sensitivity of semantic discrimination, and reduced the response time and error rate. Thus, we believed that the participants effectively integrated visual and auditory information in this semantic discrimination task.We observed a main effect of Type, verifying that RTs to V, A, and AV stimuli differed significantly from one another ( 0.0005) . A signit = 2.985, p = 0.009; Eg: t = 5.409, p < 0.0005; Eloc: t = 4.652, p < 0.0005 in attended condition; Cp: t = 4.502, p < 0.0005; Eg: t = 6.911, p < 0.0005; Eloc: t = 7.112, p < 0.0005 in unattended condition) and V  networks. In addition, for both attend and unattended conditions, the values of Lp in the bimodal AV networks were significantly lower than those in the unimodal A  and V  networks. The greater global efficiency, local efficiency, clustering coefficient and the lower characteristic path length revealed that the brain has a greater capacity of functional integration (greater Eg and lower Lp in AV condition) and local processing (greater Cp and Eloc in AV condition) during bimodal audiovisual processing  and V  networks, and the value of Lp in bimodal AV network was smaller than that in unimodal A network . While for the unattended condition, the value of λ in bimodal AV network was smaller than that in unimodal V network . There was no other significant difference between bimodal AV network and unimodal A/V network in attended and unattended conditions.As shown in ocessing . In addiF = 41.540, p < 0.0005, power = 99.98%), Lp , γ , σ , Eg , Eloc , and hierarchy . However, no significant main effects of Condition were found in λ  and assortativity . These results revealed that the architectures of the functional network in the brain were altered depending on the current task (processing of attended or unattended semantic AV stimuli or being at rest). As shown in t-tests showed that there were significant differences in Cp , γ , σ , Eloc , Eg , and hierarchy  between the functional networks of attended AV and resting-state conditions, revealing that the brain network had lower clustering coefficient, local efficiency and greater global efficiency. Similar significant differences were obtained between the functional networks of unattended AV and resting-state conditions in Cp , Lp , γ , σ , Eloc , Eg , and hierarchy . In addition, a significant difference was also observed in σ  between the functional networks of attended and unattended AV conditions.The three correlation matrices and the functional connectivity patterns corresponding to the attended AV, unattended AV and resting-state conditions averaged across all participants were descripted in We calculated the node degree and efficiency of the functional brain networks in attended and unattended AV conditions to identify the nodes whose value of degree (or efficiency) were larger than the sum of average value and standard deviation across all nodes of the network as hub nodes.The distributions of the degree hubs as described in r = −0.584, p < 0.0005), right precentral gyrus , right postcentral gyrus , right pars opercularis inferior frontal gyrus , left superior parietal lobule , and right parietal operculum cortex  were significantly negatively correlated with the RT values. Moreover, the nodal efficiencies in the right angular gyrus , TP.R , TP.L , right posterior inferior temporal gyrus , and aITG.L  were significantly positively correlated with the RT values.Furthermore, we computed a Pearson correlation between nodal efficiency and RT in the attended AV condition. The results are shown in The functional brain networks in cognitive tasks and in the resting state have been previously investigated . HoweverWe compared the global network topologies between bimodal AV and unimodal A/V networks both in the attended and unattended conditions. The results showed greater Cp, Eg, Eloc, and lower Lp for attended and unattended bimodal AV networks, compared with unimodal A/V networks. The greater Cp and Eloc indicated the higher local processing capacity, and the lower Lp and greater Eg indicated the higher global processing capacity. These results suggested that the brain network for processing bimodal auditory stimuli is more optimized, which may be an important reason for bimodal AV stimulus promoting the behavioral performance .A key finding of the present study is that the σ value for the functional brain network processing semantic audiovisual stimuli is higher than that for the network at resting state , indicatImportantly, increases in functional integration , as well as decreases in segregation and specialization , were observed in task-state networks processing semantic audiovisual stimuli compared to those parameters determined in the resting-state condition. The brain regulates information flow by balancing the segregation and integration of incoming stimuli to facilitate flexible cognition and behavior. The topological features of brain networks – in particular, network communities and hubs – support this segregation and integration . Our resIn addition, brain networks also typically comprise a hierarchy of communities, and a lower degree of hierarchy was observed in attended AV and unattended AV conditions than in the resting-state condition . The hieIn our study, an increased σ value was observed in the brain network of the unattended AV condition in comparison to that of the attended AV condition , indicatIn addition, attention altered the distributions of the degree and efficiency hubs . The hubWe also analyzed the correlation between nodal efficiency and behavioral performance in the attended AV condition The results showed that the efficiencies in PreCG.L, PreCG.R, PostCG.R, IFG oper.R, SPL.L, and PO.R were negatively correlated with the RT , indicatBy contrast, the efficiencies of the nodes AG.R, TP.R, TP.L, pITG.R, and aITG.L distributed in the temporal lobe are positively associated with the RT , indicatIn the present study, we tested global and local properties of functional brain networks of processing semantic audiovisual stimulus in attended and unattended conditions, using graph theoretical analysis applied to fMRI data acquired in a semantic discrimination task. Our findings indicate that when process the semantic audiovisual stimulus, the functional network in the brain is optimized to balance the functional segregation and integration for processing the cognitive task with high efficiency and low cost. In addition, attention altered the degree of small-worldness and the distribution of hubs in the functional brain network when processing semantic audiovisual stimuli, revealing the modulatory effect of attention on the multisensory processing from a system perspective. However, one possible limitation is that the functional networks established in this study are undirected, thus lacking information on the directionality of the connections. Therefore, it is likely that some characteristics related to direction are not reflected by our results, such as the modulation of attention to the information interaction in the network. However, these issues can be explored in future studies.All datasets generated for this study are included in the article/supplementary material.The Experimental protocol was approved by the Ethics Committee of Changchun University of Science and Technology. The patients/participants provided their written informed consent to participate in this study.QL, YX, and JW designed the study. QL, YX, MZ, and GL implemented the experiment. YX, WL, and MZ analyzed the data. QL, YX, and LL wrote the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Melioidosis is known to occur in Bangladesh, but there are few reports about the condition in the published international literature. We set out to review all known cases of melioidosis in the country to date, using both retrospective and prospective data. A web-based literature search was conducted to identify all published case reports, original articles and conference abstracts. Cases were also included from a prospective study conducted in 2017. Fifty-one cases were identified between 1961 and 2017. Cases have been reported from sixteen out of the 64 districts of Bangladesh. The median age of the patients at presentation was 45 years (IQR 37–52), with a significant male (77%) predominance. Many patients  were farmers and 83% had diabetes mellitus. A skin/soft tissue abscess was the most common primary clinical presentation , followed by septic arthritis , pneumonia, and a deep-seated abscess/organ abscess . The major challenges to the diagnosis and treatment of melioidosis in Bangladesh are the lack of resources and the lack of awareness of melioidosis. Capacity development programs are urgently required to define the burden of disease and to tackle the mortality rates. Burkholderia pseudomallei [Melioidosis is an important cause of infectious disease across Southeast Asia, and it is believed to be a problem in Bangladesh, based on anecdotes and a few case reports ,2,3. Thedomallei . Bangladdomallei . In Octodomallei . The credomallei . Severaldomallei ,14,15,16The clinical presentation of melioidosis is widely varied, and a definitive diagnosis requires a skilled microbiology laboratory, making it more difficult to diagnose in low-resource settings such as Bangladesh. Agriculture is the most productive sector of the country’s economy, contributing about 30% of the nation’s GDP and providing over 90% of Bangladesh’s rural employment . A recenBurkholderia’, and ‘Bangladesh’. Additional published cases were also identified from the personal EndNote database of one of the authors (D.A.B.D.). We also conducted a prospective study during 2017 in Dhaka to identify cases among patients admitted with an acute febrile illness and included patients confirmed as having culture-positive melioidosis, in this review.This was a descriptive study involving both retrospective and prospective data analysis. A web-based literature search was conducted using PubMed, Google Scholar, Medline, ResearchGate, and the Bangladesh Journals Online (BanglaJol) database to identify all published, culture-confirmed case reports of melioidosis in Bangladesh. The key search terms were ‘melioidosis’, ‘Overall, we identified 25 case reports/case series, one original article, and three conference abstracts describing cases of culture-confirmed melioidosis in Bangladesh. Of these, one case report, one original article, and two conference abstracts were excluded due to the duplication of data. Additional cases were diagnosed through our research project in 2017. The cases were reported between 1964 and 2017. Of the 24 case reports, twelve described Bangladeshi immigrants diagnosed overseas , all of whom had a history of travelling to Bangladesh before their illness ,14,15,16(a)Pulmonary: pneumonia, including complications such as a lung abscess or a pleural effusion.(b)Musculoskeletal (MSK): septic arthritis, osteomyelitis, and others.(c)Genitourinary (GU): infection of the urinary and genital tract, including the kidneys.(d)Neurological: involvement of the brain and spinal cord, including the meninges.(e)Organ abscess/deep-seated abscess: Abscess involving any solid organ or in any deep-seated site such as the muscles.(f)Cutaneous: infection and abscess of the skin and subcutaneous tissue.(g)Bacteraemia without focus: acute sepsis without any specific focus.In this review, major organ involvement and clinical features were classified as follows.The monthly average mean temperature in degrees Celsius and the monthly average rainfall in millimetres for the years 1961 to 2015 were collected from the climate change knowledge portal of the World Bank .t-test was applied to determine the level of significance. Statistical analysis was performed using IBM SPSS Statistics 22 for Windows, and GraphPad Prism 7 was used to display the results. Informed patient consent was obtained from the prospectively studied cases, with ethical permission being granted by the institutional committees of Dhaka Medical College (DMC) and the Bangladesh Institute of Research and Rehabilitation for Diabetes, Endocrine, and Metabolic Disorders (BIRDEM).The results were expressed as median ± interquartile range (IQR) for continuous variables. A choropleth map was drawn using geographic information system (GIS) data to illustrate the distribution of the cases . A choroBetween 1964 and 2017, 51 cases of culture-positive melioidosis were diagnosed from Bangladesh, with all the published cases listed in p = 0.03) [B. pseudomallei through an indirect haemagglutination assay among 1244 adult febrile patients [p < 0.01) [2 = 3.835, p = 0.280) [The majority of the patients for whom data was available  were farmers by profession, which is compatible with another hospital-based serosurveillance carried out in Bangladesh in 2010, where farmers had an increased risk of seropositivity  . The surpatients . However < 0.01) . The sam= 0.280) . Over 88Cases have been reported from sixteen out of 64 districts of Bangladesh, all of which were in the eastern and northern parts of the country . In fiveB. pseudomallei was confirmed in various culture samples. Twenty-three patients (45%) were positive on pus culture. The second most common positive sample was blood . Other sources of the bacterium were joint fluid , other swabs  such as skin, nasotracheal, and tracheal; urine  and sputum . In total, fourteen patients (27%) died and thirty-seven (73%) survived.In thirty-eight cases, the period between the onset of symptoms and the diagnosis of melioidosis was calculated . The medThe majority of cases were diagnosed during the rainy season from June to September . The priIn terms of treatment, 46.3% (19/41) patients were treated with ceftazidime and 41.4% (17/41) received meropenem. Among the cases diagnosed overseas and before 1999, four (9.7%) received cotrimoxazole plus chloramphenicol, and one patient (2.4%) received doxycycline plus amoxicillin/clavulanic acid as intensive phase therapy in this series.Melioidosis is not a statutorily notifiable disease in Bangladesh, and there is no formal surveillance system in place for human melioidosis. Reported cases therefore tend to arise from individual researchers who have a specific interest. At present, the health directorate  has no specific program or operational plan on melioidosis in Bangladesh.The infrastructure and facilities for veterinary services and research in Bangladesh are very weak. There is no surveillance system for animal melioidosis currently in place. No veterinary reports have ever been issued from Bangladesh.Currently, Bangladesh does not have any national management or treatment guideline for melioidosis. The majority of indigenous cases were diagnosed and treated at BIRDEM General Hospital. The Microbiology Department of BIRDEM hospital follows the Clinical and Laboratory Standard Institute (CLSI) guidelines wherever possible. BIRDEM doctors follow current published treatment guidelines .The antimicrobial susceptibility pattern of clinical isolates showed 100% sensitivity to ceftazidime, imipenem, piperacillin–tazobactam, amoxicillin–clavulanic acid, and tetracycline by both disk diffusion and MIC methods in Bangladesh . IntraveAwareness of melioidosis among clinicians, microbiologists, and health policymakers is inadequate. Although several case reports have been published in local and international journals, the probability of clinicians considering melioidosis as a diagnosis and requesting the laboratory to look specifically for the bacterium remains low. Public awareness of this organism, particularly among farmers and other high-risk populations, is very low. Recently, the Bangladesh Association for Advancement of Tropical Medicine (BAATM) and the Bangladesh Society of Medicine (BSM) took some special initiatives to raise awareness among clinicians by organising seminars and lectures. David A. B. Dance and Susanna J. Dunachie recently visited Bangladesh on their invitations and conducted seminars in Dhaka. The third South Asian Melioidosis Congress is planned to take place in Bangladesh in 2019, which will further contribute to raising awareness.So far, the scientists of Ibrahim Medical College and BIRDEM have conducted research on melioidosis in Bangladesh despite the relatively low numbers of cases reported. Doctors at BIRDEM have diagnosed the majority of cases so far in Bangladesh. However, apart from IMC and BIRDEM, microbiologists elsewhere in Bangladesh are unfortunately not currently diagnosing melioidosis. Therefore, we plan to organise capacity development workshops with the support of Mahidol Oxford Research Unit (MORU) and LaoOxford-Mahosot Hospital–Wellcome Trust Research Unit (LOMWRU) for the microbiologists and the clinicians working at tertiary level hospitals in Bangladesh, though funding is currently pending. We also recently completed a prospective study to see if melioidosis is a significant cause of febrile illness in Bangladesh at DMC and BIRDEM in collaboration with the University of Oxford, which will form the basis for a long-term study of melioidosis in Bangladesh.B. pseudomallei are likely to discard the bacterium as a clinically insignificant environmental Pseudomonas species. Microbiologists other than those at the BIRDEM laboratory probably do not have the skills, training, and capacity to identify the organism. Therefore, diagnostic capacity development is the key area where immediate attention and funding is required. Awareness-building programs among clinicians are also necessary. Diabetes was found to be the most common risk factor for melioidosis in this series, and this was a similar observation elsewhere. The incidence of diabetes is rapidly increasing in Bangladesh, with 8.4 million people currently living with diabetes [The major challenges to the diagnosis and the treatment of melioidosis in Bangladesh are a lack of resources and a lack of awareness. Clinicians do not think about this disease in the first instance, and subsequently, microbiologists are not alerted to look specifically for the bacterium. In addition, microbiologists unfamiliar with diabetes . Therefo


Purpose: The purpose of this study was to compare state rankings of body mass index (BMI) among three different indices of income disparities  and BMI. One measure of disparities was based on national standards and the other measure was based on state-specific data.Methods: Data were from the 2016 Behavioral Risk Factor Surveillance System and analyzed in 2018. To assess differences between the two indices, Spearman Rank Order Correlation coefficient with a Bonferroni adjustment and kappa statistic were used.Results: Spearman rank-order correlation coefficient with a Bonferroni adjustment found that the two indices had a very weak monotonic relationship . The kappa value  revealed the indices were not concordant. The rankings of states based on national and state-specific disparity indices were distinctly different.Conclusion: Our study highlights the importance of choosing disparity indices. To analyze state similarities and differences, findings and interpretations are different when using a national standard applied to all states versus state-specific data as the frame of reference for the disparity index. Future research is needed to confirm the generalizability of our findings. In addition to income, our approach can be used with other sociodemographic variables such as age, race/ethnicity, sex, and education. The overall goal is to present a comprehensive and nuanced perspective of disparities contributing to the overweight/obesity epidemic. For most studies, overweight is defined as 25.0–29.9 and obesity in adults is defined as BMI of ≥30.4 There are demographic and socioeconomic disparities  that characterize the overweight/obesity epidemic.5 An Institute of Medicine's objective is to eliminate disparities related to weight status, which include documenting existing disparities and monitoring progress to reduce disparities.6 Disparity indices are essential for accurate data monitoring and reporting.Health disparities are health differences associated with social, economic, and/or environmental disadvantage and adversely affect people who typically experience greater obstacles to achieving and sustaining optimal health.7–14 Given that disparity is a multidimensional construct,7 to compare different frames of reference is useful and can provide insights into which measures are appropriate for a research study. Frames of reference can be a national standard or state-specific standard, which means data derived from the place of interest. The frames of reference can lead to different interpretations. The concordance and discordance between different frames is important information.There are no known studies that directly compared different frames of reference for disparity indices.12 The 50 states and Washington District of Columbia (D.C.) were ranked from lowest to highest disparities based on these variables.12 The specific algorithm used to calculate this index was as follows: HWDI (for income)=(24.9 − high income BMI) + (middle income BMI −24.9) + (low income BMI −24.9).12 BMI of 24.9 was chosen because according to the Centers for Disease Control and Prevention (CDCP), BMI from >18.5 to ≤24.9 is a healthy weight, >25.0 to ≤29.9 is overweight, and ≥30 is obese. Based on the literature, the high-income group would most likely have the healthiest BMI .15In a study that applied the Healthy Weight Disparity Index (HWDI), body mass indices and income disparities measures  were used.16 Overweight/obesity disparities relate to gender, race and/or ethnicity, education, income, and geographic location.5 The HWDI can be adapted to other overweight-/obesity-related disparities . As noted earlier, income was chosen for the original HWDI because empirical studies document that income is a primary disparity related to overweight/obesity.17The standard BMI >18.5 to ≤24.9 was applied to all states and Washington D.C. Similarly, the same income thresholds were applied to all states and Washington D.C. Total household income was low , middle , and high .The original HWDI algorithm applied the same standards for income and weight status to all states and Washington D.C. State-specific data as the frame of reference demonstrate flexibility and utility of the HWDI algorithm. It can be argued that individualizing the income levels and BMI values based on state-specific data can provide more meaningful comparisons among states. The rationale for this argument is that states differ in BMI and income. For example, the standard thresholds of income: low , middle , and high  may not accurately reflect the low-, middle-, and high-income thresholds of each state. Therefore, individualizing income thresholds and BMI for each state enables comparisons that are perhaps more relevant and tailored to each location.1.To develop an RHWDI based on state-specific data, income, and BMI;2.To rank states from lowest to highest based on RHWDI;3.To compare state rankings between RHWDI and the original HWDI.The original HWDI can be revised by using the mean BMI of each state as the reference for that state and similarly, income can be individualized per state. Therefore, the rankings of states by the revised HWDI (RHWDI) is based on state-specific data instead of standard thresholds for all states and Washington D.C. To assess the viability and usefulness of the RHWDI, the objectives of this study were as follows:6Testing feasibility, versatility, and robustness of disparity indices related to weight status advances the field and ultimately can assist in developing and monitoring effective interventions to address the overweight/obesity crisis. Tracking the trajectory of income disparities in overweight/obesity is important to policy makers as well as to evaluate population-level and policy interventions designed to eliminate disparities.18 BRFSS respondents were excluded if they met at least one of the following criteria: pregnant; older than 65 years; or BMI <18.5 (underweight). These criteria were applied because it has been found that body composition stabilizes between 20 and 60–70 years of age,19 and those with a BMI of <18.5 kg/m2 may be suffering from an underlying medical condition.20 For this research, Institutional Review Board approval was not required because there was no contact with human subjects.Data were from the 2016 Behavioral Risk Factor Surveillance System (BRFSS). The BRFSS is an ongoing, annual phone-based survey of adults (18 and over) in the United States conducted by the CDCP, designed to capture information on a broad range of health-related topics. The BRFSS samples households with landlines as well as cell phone-only households, and uses a complex sampling design to produce estimates that are representative of the noninstitutionalized population of U.S. adults. Further details can be found elsewhere.The following variables were included in the analysis: age ; household income ; sex ; race/ethnicity ; education : less than high school graduate, high school graduate, some college or technical school, or college graduate; number of adults in the household and number of children in the household (both continuous); and BMI .21 In addition, our income categories provide similar sample sizes for analyses, which align with Ogden's approach.There are no universally accepted definitions of low-, middle-, and high-income thresholds. Therefore, we chose the most conservative approach based on the ordinal categories presented in the BRFSS data and the best available evidence. Consistent with previous literature, we believe that the middle income (185% of poverty guidelines) based on the eligibility of state and federal assistance programs, and 75th percentile as the high-income category in our study is justified.For this analysis, we first calculated the ratio of the participant's reported household income to the poverty guidelines as established by the United States Department of Health and Human Services for a household of that size as of January 2016. We defined low income as those households whose household income and size put them at or below 185% of the poverty guidelines. We chose this approach as the demarcation between low- and middle-income thresholds because individuals from households at or below this level are eligible for a number of state and federal assistance programs, including Women, Infants, and Children, Medicaid, Children's Health Insurance Program, and Head Start. Middle-income threshold was defined as individuals from households making >185% of the poverty guidelines, but less than or equal to the state-specific 75th percentile of the distribution of the household income to poverty-level ratio. High-income threshold was defined as individuals from households whose poverty guideline ratio was greater than the state-specific 75th percentile. The BRFSS reports income as a categorical variable with ordinal values that each correspond to a specific income range. To calculate the income poverty guideline ratio, we assigned each person an income that reflected the highest value possible in that range ; those in the highest income category  were assigned an income of $75,000. This method was chosen because it presents the most optimistic scenario for household income; it places more individuals in the middle- and high-income categories than if a different method were used . As such, this method represents the most conservative approach; the RHWDI for each state would likely be larger  if a different method were used.The dataset contained nonignorable amounts of missing data. To address this challenge, multiple imputations by chained equations with 20 imputed datasets were used. Continuous variables  were imputed using linear regression, ordinal variables (education and income) were imputed using predictive mean matching, and dichotomous variables (sex) were imputed using logistic regression. Due to difficulties in achieving imputation convergence, nominal variables (race/ethnicity) were not imputed; observations missing on any of these variables were subject to case-wise deletion. Age was not missing for any observation because it was previously imputed by CDCP if a respondent did not report their age. Imputations were conducted separately for each state. Finally, the sampling weight was included as a predictor of missingness in the imputation models. Imputed datasets were used in all subsequent analyses.post-hoc adjusted means. The same model was used to compute adjusted mean BMI within each of the three income categories for each state. All models appropriately accounted for the complex sampling nature of the BRFSS. Analyses were conducted in 2018 using Stata 15.1 .To calculate state-specific adjusted BMI means, we regressed BMI on age, race/ethnicity, sex, and education, using that model to compute Using the adjusted means as inputs, the formula to calculate the state-specific RHWDI was as follows: (State-average BMI − high-income BMI) + (middle-income BMI − state-average BMI) + (low-income BMI − state-average BMI). This revised formula is different from the original formula (HWDI) because it assesses the effects of state averages of income and weight status in contrast to national income and standard BMI thresholds reflected in the original formula.To assess differences between the two indices, Spearman rank-order correlation coefficient with a Bonferroni adjustment and kappa statistic were used.Participants were primarily non-Hispanic whites (59%) and females (51%); 59% had at least some college education and 34.2% had an annual household income of at least $75,000 . The meaRHWDI values ranged from 0.004 to 2.11 . States p=0.45). To further evaluate the comparability of the two indices, RHWDI and the original HWDI were placed into terciles and compared using a kappa statistic. The kappa value  revealed the indices were not concordant. Five states  were ranked the same for both indices, Washington differed by one, and three states  differed by two ranking positions  will provide dramatically different results than indices derived from a uniform or standard reference point. To further underscore the differences between the two indices, the RHWDI had 19 negative values, which means that high-income individuals had greater BMI values than low-income individuals. In contrast, the original HWDI had no negative values.In future research, careful deliberations and a strong rationale should be the basis for deciding whether a standard or state-specific reference frame is more appropriate. If a national standard is used, then the disparity is relative to the nation. Reference points derived from within the city or geographic unit of analyses enable cross-site comparisons. Furthermore, to retain consistency, the same type of index should be used to document trends over time, ascertaining increasing or diminishing disparities.22 ICE measures (at the census track level) assess extreme concentrations of both income and racial/ethnic composition. Income thresholds were defined as low  and high income (>US$100 000) based on 2010 United States Census data and the 20th and 80th centiles of the national household income distribution.22 In contrast, in our study, income categories accounted for state-specific variations instead of one uniform standard.For a given geographic area, the Index of Concentration at the Extremes (ICE) simultaneously measures concentrations of privilege and privation. ICE was used to investigate risk of hypertension in a predominantly working-class study population.13 This approach accounts for inflation and household composition, but does not account for regional variation in prices. In our study, we accounted for state-specific variation in income and BMI.In another study, based on self-report, the poverty to income ratio was used as the income measure.23 A primary concern is reporting bias in height and/or weight  across population subgroups such as gender, race and/or ethnicity, body weight status, income, age, and geography.25 If substantial self-report biases related to sociodemographic variables are confirmed, then more objective assessments should be used. Even with these limitations, BRFSS is the only known data set with the relevant national data for our study.Data were used from the United States 2016 BRFSS, which is a probability sample of the U.S. noninstitutionalized population. Military personnel on active duty, patients in mental facilities, and older adults who are institutionalized were excluded. Survey participants' height and weight were self-reported; therefore, there are concerns related to measurement error and social desirability bias.Another concern is missing data. If nonresponders had greater overweight/obesity prevalence and lower income levels, the order of the rankings could be different. In addition, in our observational and cross-sectional study, the association between income and overweight should be not interpreted as causal.This study has several strengths. It is the only known study that specifically compared the rankings of states by income and overweight by two different approaches—state-specific versus national reference frames. The original HWDI and the RHWDI provide a unique opportunity to test two different approaches. Several analytic approaches were used to impute missing data. Different analytic measures were used to compare and contrast the two rankings to provide confirmatory evidence of the findings. Furthermore, age, race/ethnicity, sex, and education were controlled for. The only known national data set with relevant data was used in our study.22; this theory emphasizes the social and ecological context of individuals and how these contexts relate to health outcomes. Based on the availability of data, smaller geographic areas such as counties, cities, census tracts, census block groups, municipal planning districts, or ZIP codes can be considered to better embody the eco-social theory of disease distribution. Furthermore, to get a full picture of the complexity of overweight/obesity trends, researchers must examine socioeconomic disparities over time within racial and ethnic groups, as well as gender.22We used the eco-social theory of disease distribution as a guiding framework for understanding health inequities13 Another study, examining adult BMI, obesity, and morbid obesity trends from 1971 to 2012, concluded that individual increases in weight status were widely distributed across all age groups and birth cohorts.14 Furthermore, during the past three decades, there has been an increase in overweight/obesity rates among all education subgroups.26With some exceptions, long-term trends (1960–2008) have documented that increases in overweight/obesity, severe obesity, and BMI are similar across different racial/ethnic, educational, and income groups. In other words, increases in excess weight were not limited to certain subgroups. These authors concluded, “obesity in the United States is a true epidemic” affecting the entire society.27Our study highlights the importance of choosing disparity indices. To analyze state similarities and differences, findings and interpretations are different when using a national standard applied to all states versus state-specific data as the frame of reference for the disparity index. From an intervention perspective, the urgent public health challenge is to embrace successful and sustainable societal-level interventions to promote healthy lifestyles that will reverse the upward overweight/obesity trend in all population subgroups. The population-based approach and the vulnerable population approach can be complementary.


The diagnostic value of the concentration of circulating cell-free DNA (cfDNA) for breast cancer has generated inconsistent results. The aim of this study was to evaluate the first diagnostic value of the concentration of cfDNA for breast cancer by meta-analysis. Studies were retrieved by searching PubMed, Cochrane Library, and Web of Science before June 2018. Sensitivity, specificity, diagnostic odds ratio (DOR), the summary receiver operating characteristic (SROC) curve, and the area under curve (AUC) were used to summarize overall diagnostic performance. The random-effects model was used to calculate the pooled statistics. Subgroup analysis and meta-regression analysis were carried out to detect the source of heterogeneity. A total of 13 studies were identified with 1,087 breast cancer patients and 720 healthy controls. Overall, the pooled sensitivity and specificity of concentration of cfDNA for breast cancer were 87%  and 87% , respectively. The pooled DOR was 32.93  and the SROC curve revealed an AUC of 0.93 . Meta-regression analysis showed that no covariate had a significant correlation with relative DOR (RDOR). Publication bias was not detected in this meta-analysis. This meta-analysis indicates that the concentration of cfDNA has potential first diagnostic value for breast cancer and plasma may be a better source of cfDNA for detection of breast cancer. Breast cancer is one of the most common malignancies in women. According to an estimation from the WHO, more than 508,000 women worldwide died from breast cancer in 2011 . CurrentCells can release DNA into the bloodstream, which is described as circulating cell-free DNA (cfDNA) . The celThe following databases were searched to identify all potentially relevant studies published before June 2018: PubMed, Cochrane Library, and Web of Science. The retrieving query formulation used for the search were (“cell free DNA” OR “circulating DNA”OR “plasma DNA” OR “serum DNA”) AND (“breast cancer” OR “breast carcinoma” OR “breast tumor”). Article language was limited to English. All the reference lists of the identified articles and relevant reviews were also manually screened.The inclusion criteria of eligible studies were as follows: (1) studies about the first diagnosis not the recurrent diagnosis of the concentration of cfDNA for breast cancer; (2) studies with sufficient data for describing or calculating the sensitivity and specificity values; and (3) studies that were case-control studies, prospective, and retrospective cohort studies. The exclusion criteria included: (1) studies that were reviews, case-only studies, conference letters, or editorials and (2) studies with duplicate data reported.Two reviewers (Dandan Yu and Yan Tong) screened titles, abstracts, and full texts independently according to the above criteria. The following data were extracted from enrolled studies in structured forms: first author's name, publication year, country, sample size, study type, source of cfDNA, time of sample collection, test method, reference gene, cut-off value, sensitivity, and specificity. Subsequently, two reviewers independently evaluated the quality of selected studies according to Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) .2 test and inconsistency index (I2) to quantify the statistical heterogeneity between studies. A P < 0.1 by χ2 test and I2 statistic >50% indicated substantial heterogeneity  of sensitivity, specificity, and diagnostic odds ratio (DOR) were calculated. The summary receiver operating characteristic (SROC) curve and the area under curve (AUC) were used to summarize overall diagnostic performance. Additionally, we used the χogeneity . A fixedogeneity . P < 0.0P < 0.05 was considered statistically significant, and all P-values were two-sided.All statistical analysis was performed with STATA . A The flowchart of literature search and selection were shown in The quality of selected studies by QUADAS-2 is shown in The pooled sensitivity and specificity of concentration of cfDNA for breast cancer were 87%  and 87% , respectively , Table 3Sample of cfDNA, the time of sample collection, and test method were taken into consideration for subgroup analysis. With consideration of the sample of cfDNA, studies with cfDNA isolated from plasma revealed that the pooled sensitivity and specificity were 94%  and 89% , respectively . The pooWith consideration of the time of sample collection, studies with samples collected before surgery revealed that the pooled sensitivity and specificity were 90%  and 88% , respectively . The pooWith consideration of the test method, studies with the test method of real-time qPCR revealed that the pooled sensitivity and specificity were 88%  and 89% , respectively . The pooP-value was 0.65, which showed there was no significant evidence of publication bias ,” “region (Asian),” “sample (plasma),” “time of sample collection (before surgery),” and “method ” were assessed. We used these covariates to assess their effects on the RDOR. None of them showed any definite influence on heterogeneity and the details of the calculation were showed in ion bias .As is known, mammography as a screening method for breast cancer has the limitation of having low sensitivity. Hence, the circulating biomarkers, which can be easily collected and measured, have attracted the attention of more researchers. A correlation between increased levels of cfDNA and cancer has been widely studied , 30. NowDuring the past decades, biomarkers of breast cancer have been widely discovered, such as CEA, CA15-3, HER2, and so on. CEA, which exists in the breast ductal secretions, showed a lower sensitivity of 58%, a lower AUC of 0.8750, and a lower DOR of 7.70 for breast cancer diagnosis . One stuIn this study, we found a high diagnostic value of concentration of cfDNA, of which the sensitivity and specificity reached 87 and 87%, respectively. Additionally, AUC is considered as an indicator of good diagnostic performance when the value is >0.90 . TherefoWe also conducted subgroup analyses. The results showed there were no obvious differences among the subgroup analyses for the sensitivity, specificity, and AUC. But the DORs varied from 15.80 to 79.11. When we only incorporated the studies using plasma samples, the highest sensitivity, specificity, and AUC of cfDNA on breast cancer detection were obtained, and they were also higher than pooled sensitivity, specificity, and AUC, respectively. These results indicated that plasma may be a better source for cfDNA in detection of breast cancer.The original studies included in our analysis showed obvious differences in sensitivity and specificity. It is widely accepted that malignancy will increase the bloodstream concentration of cfDNA. However, in some abnormal condition, such as inflammation , arthritThis study also contains several limitations. Firstly, as only 13 studies were included in this meta-analysis, compounded by the small number of included studies, it may be insufficient to yield a robust result. Secondly, heterogeneity existed between the selected studies, although it was impossible to determine all sources of heterogeneity. We did not include some covariates due to the unavailable data. These probable covariates included tumor stage, metastasis condition, tumor size, the risk of breast cancer, and so on. Thirdly, subgroup analyses on several covariates were unable to perform due to the various data, such as reference gene and cut-off value. Moreover, language bias might exist due to the references being restricted to English. Even so, to our knowledge, this study is the first to systematically evaluate the diagnostic value of the concentration of cfDNA in breast cancer in the whole population and various subgroups.This meta-analysis suggests that the concentration of cfDNA has potential first diagnostic value for breast cancer due to the high sensitivity, specificity and AUC, and it may be a potential screening tool for breast cancer. In particular, plasma may be a better source of cfDNA in detection of breast cancer. Further large-scaled, well-designed studies are required to confirm our findings, and to provide a basis for future clinical practice. Moreover, the first diagnostic value of concentration of cfDNA for breast cancer could be validated by clinical trials.All datasets generated for this study are included in the manuscript.DY and YT made substantial contributions to conception and design, acquisition of data, analysis of data, and drafting the manuscript. XG was involved in design and drafting the manuscript. LF, ZJ, and SY were involved in drafting the manuscript and statistical analysis. JJ and YF provided support in statistical analysis. MY and HX were involved in data interpretation. LS participated in the preparation of the manuscript and provided general support. JL designed, coordinated, and supervised the study and he was involved in data analysis and interpretation and drafted the manuscript. All authors read and approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Malignant blood disorders depend on heritable susceptibility genes and occur in familial aggregations. We suggest a model of transgenerational segregation of the susceptibility genes based on the study of malignant blood disorders in Norwegian and Danish families with unrelated parents, and in the inbred Faroese population with related parents. This model, consisting of parental genomic imprinting and mother-son microchimerism, can explain the male predominance in most of the diseases, the predominance of affected parent-offspring when parents are not related, and the different modes of segregation in males and females. The model displays a specific pattern in the distribution of affected relatives for each diagnosis, viz. a characteristic distribution in the pedigrees of family members with malignant blood disorder related to the proband. Three such patterns, each reflecting a specific transgenerational passage, were identified: (1) alterations in the number of affected relatives in paternal lines alone, e.g. in patterns for probands with multiple myeloma; (2) alterations in the number of affected relatives in both paternal and maternal lines for probands with chronic lymphocytic leukemia; and (3) no alterations in the numbers of male and female affected relatives in the parental lines, e.g. for probands with some types of malignant lymphoma. Heritable susceptibility genes, so called risk genes, are necessary for the production of tumor in the form of a mutated blood cell monoclone9. A repertoire of susceptibility genes for each diagnosis comprises one or a few specific genes combined with a number of unspecific genes that differ from patient to patient with the same diagnosis. Genome-wide association studies clearly show this so-called “genomic landscape”, e.g. in the lymphoproliferative diseases (LPD) including chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), Hodgkin’s lymphoma(HL), non-Hodgkin’s lymphomas (NHL) and multiple myeloma (MM); and in the myeloproliferative diseases (MPD), e.g. chronic myeloid leukemia (CML), acute myelogenous leukemia (AML), myelofibrosis (MF), polycythemia vera (PV), and essential thrombocytosis (ET)17. There are silent bystanders within this polygenic model of susceptibility (persons having congenic susceptibility without developing the pathognomonic mutation), and there is a range of aggressiveness (stage of disease) in patients with the same diagnosis, so that low-stage diseases with weak or no symptoms are easily overlooked and not included in the registration of hereditary, familial MBD. Genealogical studies of MBD in families19, and large-scale screenings from cancer registries24 confirm a wide variety of different diagnoses within LPD and MPD (pleiotropy), but show no clear signs of a Mendelian or other specific pattern in the transgenerational transfer. Until now, no satisfactory explanation of the predominance of males has been given, e.g. in CLL. Further open questions concern anticipation 4, and sib ship birth order effect (non-random in the ages of affected siblings)25, and a pronounced inconsistency with regard to co- and contravariation of diagnoses (degree of linking)24.Strong evidence supports the notion that leukemia, lymphoma, myeloma and other malignant blood disorders (MBD) in man constitute an entity of heritable diseasesWe now describe a novel model of the segregation of susceptibility to MBD. Based on new genealogical investigations of a large number of families with MBD, we are able to recognize distinct transgenerational pathways of the susceptibility genes and to identify the mechanisms likely involved in the inheritance of MBD.Our study is based on a genealogical investigation of familial MBD in two groups. One group comprises 315 patients from the inbred population of the Faroe Islands. The other group comprises 301 patients from 112 families with MBD and unrelated parents from Norway and Denmark. In both groups, cross-checked pedigrees were used for study. For comparison, diagnosis frequencies were extracted from the National Cancer Registries in Norway and Denmark.26 related to clinical diagnosis, laboratory findings, radiological assessments, symptoms and course of disease. The diagnosis of each patient was reassessed according to the diagnostic criteria valid at the time of diagnosis. In malignant lymphomas, for example, the Faroese Diagnostic Registry includes during the observation period cases according to the American Registry of Pathology (1934), Rappaport- , Lennert- (1967), Kiel- (1974), WHO- (1976) Working- (1982) and Real- (1994) classifications8. Therefore, in order to obtain a common denominator for the study group, all included patients were grouped according to the ICD-10 diagnostic system27. NOS-diagnoses (not otherwise specified) have been used in 45 cases: 25 cases where the cross-check could not definitely confirm the subtype of NHL , in 15 cases in which a clear distinction between myelodysplasia (MDS) and other types of MPD was not ascertained , and in five cases of lymphoid leukemia in elderly desolate patients who died without further diagnostic procedure .Based on data from the Diagnostic Registry in Torshavn , all 341 known cases of MBD from the Faroe Islands up to December 2011 were considered for study. In a five year period after 2011, it was ensured that all patients with delayed diagnoses were enrolled after proper cross-check. Three patients failed inclusion due to lost medical record or insufficient data for the verification of MBD, and 23 patients failed because their exact position in the family tree was uncertain due to extramatrimonial relationship and unauthorized adoption. They hardly represent a selective loss, the diagnoses were MM 4, AML 4, ALL 3, CLL 3, NHL NOS 3, ML 3, DLBCL 2, CML 1. .The National Civil Registry in Torshavn provided the pedigrees showing the position of patients with MBD and their kinship with unaffected family members over 5 to 6 generations in one big family. Progeny Software was used for the processing and storage of the pedigrees29. Before 1900 foreign settlers, mainly European traders, crafts, Danish priests and administrative staff, constituted a minority with minimal effect on the Faroese genome. One hundred years ago, the influx of foreign people, mainly from other Scandinavian countries, was only about 10 persons per 5 years29. The population increased from about 15,600 people in 1900 to about 49,700 in 2011, and the mean lifespan increased from about 45 years in 1900 to 82 years in 201129. In this inbred population, fishermen and sailors from abroad and later British soldiers during WW II who found a bride on the Faroe Islands most often brought the females home, so the Faroese genome remained largely unaffected30. The Coefficient of Inbreeding has never been calculated30.The genetic founders are the nearly two thousand descendants of the original Vikings who survived the Black Death around 1350 and reproduced themselves in about 20 generations to the approximately 50,000 inhabitants of today31. The age of the mother at first delivery was nearly the same as in Norway32 and in Denmark33. The late fetal death rate per 1000 live births was 11.0 on the Faroe Islands compared with 5.0 in Norway and 5.6 in Denmark when investigated in the late 1990s31. Estimated from data on first born singletons, the mean Faroese live born birth weight is significantly higher (3610 g plus/minus standard deviation 609 g) than that of Norway (3520 g plus/minus 574 g) and that of Denmark (3411 g plus/minus 585 g), the live born weight increasing with mother’s age and parity31. These data on parity and birth weight are used in the discussion of growth factors (cf. Discussion).The Faroese parity is unique. The mean number of live births per female was 7.4 in 1900 and 2.7 in 2011, some of the highest figures in EuropeThe oldest patient included was a female with CLL, born 1884. Data from the Cancer Registries in Norway and Denmark was used for comparison with the familial cases. Within the observation period, the diagnostic intensity in the main islands appears to be nearly the same as in Denmark and Norway, but lower elsewhere on the Faroe Islands, especially in the beginning of the period and on small, remote islands far out in the ocean with few or no general practitioners. Apart from the last few decades there has been no tradition for a systematic report to the National Danish Cancer Registry in Copenhagen, and no Faroese cancer statistic on incidence and prevalence is available.All methods were carried out in accordance with relevant guidelines and regulations concerning Cancer Registry Data and all protocols were approved by relevant licensing authorities (cf. Acknowledgements). Further, all patients were included with informed consent (cf. Informed consent). Participants under the age of 18 years were included with informed consent from a parent or a legal guardian.27, in the same way as described for the Faroese material. All patients belonged to the genuine Scandinavian population of Norway and Denmark. There were no twins and no consanguinity. The first known cases of CLL, a 51-year-old man born in Norway in 1872 with CLL since 1923, and a 54-year-old female from Denmark, born 1864 with CLL in 1918 were included.Our joint database on familial MBD has 301 patients  up to December 2011  and all patients were included with informed consent (cf. Information consent). Participants under the age of 18 years were included with informed consent from a parent or a legal guardian.34 and Copenhagen35, and from the LYFO-Registry36  and/or maternal (MA) lines Fig. . The AR A given AR was registered only once per Pc in either PA or MA, the one chosen being the one closest to the proband. The united pedigree with the total overview of the large, inbred Faroese family made it feasible to rule out double entry of a given AR to the same Pc. However, a given patient in the pedigree could act as AR to several Pc, especially in parts of the pedigree with many patients, viz. a high density of Pc and many shared AR. This explains why the total number of observed AR Table  can be s38 to identify the mechanism behind the distribution of AR and Pc. We considered all relevant mechanisms we could think of . There are four different groups of Pc-AR with different parental affiliation  was compared with the theoretical value and expressed as the 95% confidence interval (CI 95%). The Wilcoxon signed-ranks test was used for control, comparing the sum of positive (older) and negative (younger) rank numbers of affected sibs in the sib ship with zero representing the median age of all healthy and affected sibs in the sib ship.The birth order effect, i.e., the rank in the sib ship by age of affected sibs, was estimated for every Pc by means of the Haldane Smith testTo estimate anticipation, the number of patients in each diagnosis in the familial material (“observed”) was compared with the National Cancer Registry findings (“expected”) by chi-squared test.Co- and contra variation in the Faroese material was estimated by means of a systematic comparison of AR per Pc, observed versus expected .Statistical analysis was done with programming language R version 3.3 (www.r-3-3project.org).The patients were informed about the purpose of the study, that it was free to decline, of course, and that the investigation was approved by the Scientific Ethical Committee. Furthermore, that data would remain confidential and unrecognizable outside the study, and that data could be crosschecked with the National Cancer Registry and with the Civil Person Registry if necessary. Each patient confirmed participation by completing a questionnaire, approved by the National Ethical Committees.The myeloproliferative disorders are more frequent in the Faroe material  than in the families from Norway and Denmark (8%). Table  AML is pRegarding the lymphoproliferative pleiotropic diversity, CLL is increased in the Norwegian and Danish families compared with the percentage of CLL reported by the cancer registries (P < 0.01). In contrast, the percentage of MM is increased on the Faroe Islands (P < 0.01) where MM is as common as CLL. A reduction of familial DLBCL compared with the occurrence of DLBCL in the cancer registries is confirmed in both the Norwegian and Danish families (P < 0.01) and in the Faroese family (P < 0.05). A near halving of FL is seen in families with MBD (P < 0.05), even when the uncertainty related to NHL NOS is taken into account .HL is increased in familial MBD, compared with the figures from the cancer registries, reporting 6% HL out of all LPD and 12% HL out of all malignant lymphomas (HL plus NHL) in Norway and Denmark. The Norwegian and Danish families showed 16.9% HL among all malignant lymphomas, and the Faroese family showed 19.4% (P < 0.01).The percentage of ALL reported by the cancer registries is not significantly different from the percentage in the Norwegian and Danish families (P > 0.05) while in the Faroes material, the proportion of ALL is nearly twice as high (P < 0.01).The Faroese material has the most pronounced signs of malignancy and anticipation, for example the highest frequency of ALL and the lowest frequency of some indolent lymphomas, e.g. FL, and the lowest age at onset of disease, LPD (P < 0.05), MPD (P < 0.01). Male patients had in general a lower mean age at onset of disease than female patients in both the Faroes and in the Norwegian and Danish material, LPD (P < 0.05), MPD (P < 0.01). The male/female ratio is higher on the Faroe Islands (P < 0.05).A significant birth order effect is only observed in the Norwegian and Danish CLL-families related to patrilineal inheritance where affected sons appeared late in the sib ship (P < 0.05).Each patient referred to in Table In contrast, the Norwegian and Danish families with unrelated parents shows that Ps-MA is larger than Ps-PA . In both PA and MA, parent- offspring pairs are predominant (P < 0.01).All LPD and MPD in the Faroese material have an entirely stereotypic pattern where Pc-females have more AR than Pc-males (P < 0.001), and the AR/Pc ratio m/m is larger than f/m (P < 0.001) and m/f is larger than f/f (P < 0.001) (Table Table  In AR/PsAR/Ps displays three distinct patterns of distribution (PD). Each PD has a characteristic configuration of the probands and their affected relatives, males and females, related to the parental affiliations. (1) The most common PD, seen in LPD/MM, LPD/LPD, MPD/LPD, LDP/MPD, MPD/MPD, MPD/AML and MPD/CML, has in PA a higher number of AR-males related to Ps males and fewer AR-males related to Ps females than expected while in MA, the numbers of AR-males and AR-females are as expected. (2) A PD for Ps-CLL with increased male-AR to Ps-males in both PA and MA combined with decreased male-AR related to Ps-females in both PA and MA. This tendency was also seen in MM/CLL, CLL/CLL and LPD/other LPD, even though consisting of only small sample sizes. Finally, (3) a PD for NHL and ALL, where the numbers of AR-males and AR-females were generally not different from what was expected in PA and MA.In contrast to the Faroese AR, belonging to one big family, there are 112 Norwegian and Danish families with a total of 301 MBD-patients, so that the mean number of MBD-patients per family is only 2.7, and the mean number of AR per Pc, (301-112)/112), is 1.7, too small for a reliable comparison with the huge numbers of AR in the Faroese material. However, taking data from Table All diagnoses have been systematically screened for co- and contra variation, comparing observed data versus expected. In HL, for example, Pc is 19 12, 7), total , and the total of Pc-LPD is 219  : HL, DLBCL, MM, AML.38 exposes parental genomic imprinting39 together with mother-offspring microchimerism44 as the likely mechanisms involved in the transgenerational segregation of the susceptibility genes. Figures New cumulative data from families with multiple cases blood disorders (MBD) reveal three patterns of the distribution (PD) of the patients in the family Table . AssuminC) where the sons will proceed into the next generations as PA-lines with affected males in every generation. In contrast, affected females are produced only in every other generation on one line of descent with low expressive microchimeristic genomic changes, with offspring along the MA-lines that break up the continuous lines of AR-males available per female proband. Thus, affected females in PA-lines will have fewer affected males available, “spread of the AR in the pedigree”, than the affected males  related to male-Ps (proband standard) and fewer AR-males related to female-Ps in paternal (PA) lines than expected, and no significant changes in maternal (MA) lines , the fetus will have Prader-Willi syndrome. In contrast, a fetus receiving the partially deleted chromosome from the mother and the imprinted gene from the father  will have Angelman syndrome. Similarly, MBD is a syndrome closely related to the growth of monoclonal hematopoietic cells. Women with CLL46 or NHL55 have in general a better prognosis than male patients, including a better response to treatment with less toxicity and generally a higher age at onset of disease. These differences in MBD between the sexes, otherwise not definitely explained, could be seen as a different inheritance of susceptibility according to pathway 1 to 3. All known systems of meiotic drive (Non-Mendelian segregation) cause segregation ratios that are different between the sexes52.Parental genomic imprinting is seen in the segregation of mammalian growth factor genes31. A relationship between development of MBD (ALL is the most studied) and a high body weight of the patient as newborn has been shown in other studies as well as an increased frequency of miscarriages and abortions in mothers to MBD patients57.The relationship between alterations in growth factors and MBD is also seen, most likely, from the combined data on the high frequency of MBD on the Faroe Islands, the high birthweight and the high rate of miscarriages and stillborn 59. Therefore, a modifier to our model was theoretically expected. Microchimerism was an option in our pattern recognition for such a modifier. Microchimerism has previously been described in MBD as a mechanism for development of autoimmunity44, graft-versus-leukemia effect60, and the mechanism of birth order effect due to increased acquired tolerance of the mother in step with her parities and the number of her male partners62. Also, the specific type of microchimerism in MBD has been discussed in the light of tolerance related to the degree of tissue-type compatibility (HLA-match) between mother, offspring and father62. Microchimerism has furthermore been related to the pathophysiology of some types of solid cancer, e.g. breast cancer63.In such systems of interacting genes, modifier genes may invade the system during the evolutionMicrochimeristic susceptibility could be one mechanism behind anticipation, seen in the accumulation of susceptibility in the pedigree with increased genomic diversity in “the genomic landscape” down through the generations. Anticipation can be interpreted as a process that enhances the expression of the susceptibility. It is fascinating that the model also suggests a strategy for loss of susceptibility and thereby a delicate balance between genomic accumulation and depletion, so that affected families after a number of generations will not be overloaded with susceptibility. Anticipation produces an increased number of high-malignant diseases, especially in younger patients. ALL, having a high frequency in the inbred Faroes material Table , is such18 and ascribed to familial HLA-association12. Also, the modest risk of familial NHL seen in the present study  with the families with MBD in Norway and Denmark (unrelated parents), HL and DLBCL have the highest percentage in the Faroese family where both parents due to inbreeding theoretically can transfer interfering susceptibility52.The familial clustering of HL, seen in the present study  has previously been reportedIn conclusion, the model suggested is an operational interaction between parental genomic imprinting of susceptibility genes and mother-son microchimerism. Theoretically, the intensity of the mother-son microchimerism depends on the tissue-type compatibility among mother, sons and the father. This may well explain why the segregation has been observed to be tardive with related parents, and immediate (from parent to offspring) with unrelated parents. The model explains the male predominance, the unique pathway 2 in the segregation of susceptibility to chronic lymphocytic leukemia, and draws attention to the relevance of growth factor genes for monoclonal expansion.