Insulin resistance (IR) is a major metabolic disorder observed in heart failure (HF) and is tightly associated with patients’ poor prognosis. The triglyceride-glucose index (TyG) has been proposed as a surrogate marker of IR in HF. Yet, whether TyG is a reliable clinical marker is still under debate. Hence, we aimed to respond to this relevant question via a systematic review and meta-analysis of existing studies.A systematic search was conducted in PubMed, Embase, Scopus, and Web of Science to find studies investigating the TyG index in patients with HF or its association with the incidence of HF. Adjusted hazard ratios (HR) and 95% confidence intervals (CI) were pooled through random-effect meta-analysis. HRs were calculated using TyG as a continuous variable (1 unit increase) and by comparing the group with the highest TyG to the lowest TyG group.P < 0.01). The same result was found when pooling the HRs for a one-unit increase in the TyG index . Similarly, a more elevated TyG index was associated with a higher incidence of HF in patients with type 2 diabetes or coronary artery disease. Additionally, the incidence of adverse events  in patients with HF was associated with TyG.Thirty studies, involving 772,809 participants, were included in this systematic review. Meta-analysis of seven studies comparing the highest-TyG to the lowest-TyG group showed a significantly increased risk of HF in the former group (HR 1.21, 95% CI 1.14 to 1.29, Our findings support the TyG index as a valuable marker to assess the risk of HF incidence in different populations and as a prognostic marker in patients with HF. Further studies should be conducted to confirm these associations and investigate the clinical utility of the TyG index.The online version contains supplementary material available at 10.1186/s12933-023-01973-7. Despite improvements in managing heart failure (HF), this disorder still significantly burdens the global healthcare system , 2. The The TyG index is positively associated with diabetes and increased risk of metabolic and atherosclerotic cardiovascular diseases , 12. FurThis systematic review and meta-analysis was registered in PROSPERO (Registration Number: CRD42023437470) and was conducted in accordance with the Preferred Reporting Item for Systematic Reviews and Meta-Analysis (PRISMA) 2020 recommendations .PubMed, Embase, Scopus, and Web of Science databases were systematically searched for studies published in English up to June 16, 2023. The search terms that were used included: (“triglyceride-glucose index” OR “TyG” OR “Triglyceride/glucose index” OR “triglyceride glucose”) AND . More details about the applied search methods in each database are described in Additional file In this study, we included studies that reported the TyG Index in patients older than 18 years of age who had confirmed diagnoses or were followed for incidence of HF. TyG index is calculated from TG and FPG as follows:Also, we included studies that reported the association between the TyG Index and the prognosis or outcomes of HF patients. In addition, studies comparing the TyG Index with controls or different stages of HF disease were included. Finally, articles not reporting the TyG Index, animal studies, and conference abstracts were excluded from our research.Two authors (AK and AHB) independently conducted the study assessment based on predefined eligibility criteria. They entered the initial search results in the EndNote 21 software . After eliminating the duplicates, they started title and abstract screening and the full-text screening of potential articles according to the predefined criteria.Data extraction and quality assessment of the selected studies were accomplished by two independent authors (AK and AHB) who resolved disagreements through consensus. The following data were extracted: the first author’s name, year of publication and country of origin, sample size, mean age, sex, LV ejection fraction (LVEF), the exposure, outcomes, and adjustments. The exposure represented the TyG index level. Additionally, the outcomes included the incidence of HF, all-cause mortality, cardiovascular death, hospitalization rate, and cardiovascular complications in HF patients.The Newcastle-Ottawa Scale (NOS) was the tool employed to evaluate the included studies’ qualities . This toStatistical analyses were carried out using R [version 4.3.0]. We used the adjusted hazard ratios (HRs) with their corresponding 95% confidence intervals (CIs) as a general indicator to assess the association between the TyG and the incidence of HF. If the TyG index was considered a categorical variable, the HRs were calculated by comparing groups with the highest TyG index to those with the lowest TyG index. Moreover, if the TyG index was considered as a continuous variable, the HRs reflecting the risk per one-unit increment of the TyG index were calculated.2 statistic were used to evaluate inter-study heterogeneity. I2 > 50% or P < 0.1 reflected the presence of significant heterogeneity [P < 0.05 was considered statistically significant throughout the analyses.Random-effect meta-analysis (restricted maximum likelihood [REML]) was used to pool the HRs for HF incidence obtained by individual studies for comparison of the highest TyG group and the lowest one in addition to HRs for HF incidence for one unit increase in TyG index. Cochrane’s Q test and the Iogeneity . We usedogeneity . P < 0.0Two hundred eighty-nine records resulted from the initial search in four databases. Of these, 111 were excluded as they were duplicates. Afterward, 82 records were removed in the title/abstract screening step, and 66 were removed in the full-text assessment for reasons mentioned in Fig. As illustrated in Additional file Twenty-one studies evaluated the association between the TyG index and the incidence of outcomes in their population –42, 45. P < 0.001). Moreover, a 1 SD (0.60) increase in the TyG index was associated with a higher incidence of HF in this population (P < 0.001).Using data from the Atherosclerosis Risk in Communities (ARIC) study, Huang et al.  evaluateP < 0.05). Analogously, Zeng et al. . On the same line, in a retrospective study, Han et al. [P < 0.001). Similar results were also observed by Huang and colleagues [P = 0.047) in patients with HF. Further, Guo et al. [P = 0.024).To examine whether and how TyG can be a useful prognostic indicator for HF patients, Cheng and coworkers  examinedn et al.  evaluatelleagues . Indeed,lleagues  found a o et al.  found tho et al. , in 901 P < 0.001). Next, Cheng et al. [P < 0.001) and reported an AUC of 0.745  for HF diagnosis. Next, Wang et al. [Seven studies assessed the diagnostic and prognostic performance of the TyG index in diagnosing HF or predicting outcomes in patients with HF , 44, 45.g et al.  found ang et al.  used theg et al.  evaluateg et al.  found anP = 0.169). In another report, Guo et al. [P = 0.014). Next, Huang et al. [P = 0.187).Five studies included patients with HF and compared LVEF between groups of patients classified based on the TyG index as a cut-off , 39, 41.o et al.  found log et al. , in theiIn this report, we performed a comprehensive systematic review and meta-analysis on a total of 772,809 individuals assessed in 30 studies Table  to invesHF represents the end stage of most cardiovascular diseases. Despite the enormous progress in therapy and tools development in the last decades to predict the incidence and adverse outcomes, HF prevalence continues to rise dramatically over time . TherefoSeveral methods to assess IR have been developed, and among these, the HOMA-IR and the TyG index are considered valuable and reliable markers of IR . HOMA-IRIn addition, as demonstrated in this study, including the TyG index in the prediction models of HF could sensibly improve their accuracy in determining individuals at risk for HF among the general population. Importantly, the strict association discussed throughout this study between the TyG index and HF outcomes underscores the potential role of IR in the pathogenesis of HF . Indeed,Of course, several discrepancies have been observed among the studies included here. Some of these may be attributed to differences in study populations, designs, adjustments for confounding factors, sample sizes, and applied cut-off values which could negatively influence the association of TyG or increase the risk of readmission of HF. The use of different cutoffs among the studies was inevitable since most of the studies categorized the patients based on tertiles and quartiles of the TyG index which are different among the countries, settings, and populations. Hence, there was no universal cutoff available for this index and we compared the groups within each study with each other. This necessitates the need to identify the populations and the characteristics of patients in each region and provide a local model for each setting. Since this index is easily calculated, it seems feasible for researchers to provide these cutoffs. Moreover, the need to adjust and provide a valid and reliable method to use in different settings seems unavoidable.Additionally, our meta-analysis revealed that an increase of one unit in the TyG index raised the risk of HF development in normal populations . Furthermore, the meta-analysis comparing the group with the highest TyG index to the lowest TyG index group showed a higher incidence of HF .The clinical implications of TyG in the management of HF patients could be one of our main practical findings in this study. Since the TyG index could predict HF incidence in different populations from diabetics to those with CAD, it can be added to the routine clinical assessments of individuals at risk of HF. Moreover, its clinical use in predicting adverse events in patients with HF will add value to this index. HF clinics in countries and settings with limited resources can benefit from this easily measured index and stratify the risk of patients, which eventually leads to better care and recommendations given to the patients.Our study was the first to determine the relationship between the TyG index and HF. Moreover, the high number of studies included can provide good evidence and clues for further research. In this study, we studied this association in a variety of populations from CAD to diabetics. Finally, providing the comparison of the diagnostic ability of TyG can provide useful data for researchers. On the other hand, this study has five main limitations that need to be mentioned. First, the cut-off values for the TyG index were different across the included studies, which can lead to differences in classifying individuals into high or low TyG index groups, potentially affecting the observed associations with HF outcomes. Second, different study populations and sample sizes may also affect the results. Third, differences in adjustment for confounding factors and failure to adequately adjust for these factors can lead to biased estimates of the association. Fourth, most existing studies are observational, which limits their ability to establish causality. Lastly, comparing and combining the results from different studies was challenging due to using different outcome measures. These limitations contribute to the mixed findings and highlight the need for further research to clarify the relationship between the TyG index and HF outcomes.Overall, this study supports the TyG index as an easy-to-use diagnostic and prognostic surrogate marker of IR and HF events to be implemented in clinical practice. As our analysis shows, this index is associated with HF incidence and outcomes in all groups of patients, and monitoring the TyG index might be beneficial in patients with established HF as it predicts adverse events. Further studies and correlation with some of the parameters primarily influencing IR lifestyle modifications (diet and exercise), pharmacological interventions, and other confounding factors  are warranted to validate these findings.Additional file 1: Table S1. The search queries used for each database and the search results. Table S2. Qualities of included studies based on NOS. Table S3. Definition of outcomes. Table S4. Adjusted covariates in multivariable models.


Epidemiological evidence for the association of socioeconomic status with prenatal depression has been inconsistent. The current cross-sectional study examined the association between employment, job type, household income, and educational level and the prevalence of depressive symptoms during pregnancy.Subjects were 1741 Japanese women. Depressive symptoms were defined as present when subjects had a Center for Epidemiologic Studies Depression Scale score of 16 or higher. Adjustment was made for age, gestation, region of residence, family structure, personal and family history of depression, smoking, secondhand smoke exposure at home and at work, employment, household income, and education.The prevalence of depressive symptoms during pregnancy was 19.3%. Compared with unemployment, employment, part-time employment, and full-time employment were significantly associated with a lower prevalence of depressive symptoms during pregnancy: the adjusted odds ratios (ORs) were 0.65 , 0.66 (95% CI: 0.46 − 0.95), and 0.66 (95% CI: 0.48 − 0.90), respectively. Regarding the job type held, women with a professional or technical job and those with a clerical or related occupation had a significantly lower prevalence of depressive symptoms during pregnancy: the adjusted ORs were 0.67 (95% CI: 0.47 − 0.96) and 0.62 (95% CI: 0.43 − 0.90), respectively. Sales, service, production, and other occupations were not significantly related to the prevalence of depressive symptoms during pregnancy. There were no relationships between household income or education and the prevalence of depressive symptoms during pregnancy.Employment, whether full-time or part-time, and holding a professional or technical job or a clerical or related occupation may be inversely associated with the prevalence of depressive symptoms during pregnancy. Depression during pregnancy is a common public health problem. A systematic review estimated that as many as 18.4% of pregnant women are depressed during their pregnancy, with as many as 12.7% having an episode of major depression [Lancaster et al. performed a systematic review to identify risk factors for antenatal depressive symptoms and concluded that life stress, lack of social support, and domestic violence showed a significant association in multivariate analyses; with regard to socioeconomic status, lower income and lower educational levels revealed a small association, while unemployment was not related to depressive symptoms in bivariate analysis . Recent Using baseline data from the Kyushu Okinawa Maternal and Child Health Study (KOMCHS), we conducted a cross-sectional study of the association between employment, job type, household income, and educational level and the prevalence of depressive symptoms during pregnancy.The KOMCHS is an ongoing prospective prebirth cohort study that investigates risk and preventive factors for maternal and child health problems. The KOMCHS requested that 131 obstetric hospitals in Fukuoka Prefecture, the largest prefecture on Kyushu Island in southern Japan, with a total population of approximately 5.04 million, invite as many pregnant women as possible using a set of leaflets explaining the KOMCHS, an application form to participate in the study, and a self-addressed and stamped return envelope, during the period from April 2007 to March 2008. From May 2007 to March 2008, the KOMCHS also requested that 40 obstetric hospitals in Okinawa Prefecture, an island in the southernmost area of Japan, with a total population of almost 1.37 million, invite pregnant women using the same documents. In addition, to increase the sample size, from August 2007 to March 2008, pregnant women living in six prefectures on Kyushu Island other than Fukuoka Prefecture, with a total population of approximately 8.22 million, were invited using these documents at 252 obstetric hospitals. Pregnant women who intended to participate in the KOMCHS returned the application form to the data management center. In the end, a total of 1757 pregnant women between the 5th and 39th week of pregnancy gave their full informed consent in writing to participate and completed the baseline survey. Excluded from our analysis were 16 pregnant women with incomplete data on the variables under study; the final analysis sample thus consisted of 1741 pregnant women. The KOMCHS was approved by the ethics committee of the Faculty of Medicine, Fukuoka University.In the baseline survey, each participant filled out a set of two questionnaires, then mailed the completed questionnaires to the data management center. Research technicians completed missing or illogical data by telephone interview.One of the questionnaires collected information on age, gestation, number of children, family structure, personal history of doctor-diagnosed depression, family history of depression, smoking habits, secondhand smoke exposure at home and at work, employment status, job type, household income, and educational level. A family history of depression was considered to be present if one or more parents or siblings of the study subjects had been diagnosed with depression by a physician. Most recent employment status in the year when the baseline survey was conducted or in the previous year was ascertained; women were classified as being unemployed if they were unemployed both in the year when the baseline survey was conducted and in the previous year, regardless of the cause of such unemployment.Depressive symptoms were assessed by means of a Japanese version  of the CThe second questionnaire was a validated self-administered diet history questionnaire. Data regarding diet were not used in the present study.a priori as potential confounding factors. These factors, other than family structure and family history of depression, were significantly related to the prevalence of depressive symptoms in univariate analysis in this population. Previous studies found that nuclear family structure and family history of depression were significantly associated with perinatal depressive symptoms [Age, gestation, region of residence, family structure, history of depression, family history of depression, smoking, and secondhand smoke exposure at home and at work were selected symptoms ,13,16. LThe prevalence of depressive symptoms during pregnancy was 19.3% among the 1741 pregnant women. The mean age of all subjects was 31.2 years , 0.66 (95% CI: 0.46 − 0.95), 0.66 (95% CI: 0.48 − 0.90), 0.67 (95% CI: 0.47 − 0.96), and 0.62 (95% CI: 0.43 − 0.90), respectively. After further adjustment for employment and education, the additional adjusted OR for a household income of six million yen or more fell just short of the significance level. The inverse relationship with education completely disappeared after further adjustment for employment and household income.The present study found that, compared with unemployment, employment was independently related to a lower prevalence of depressive symptoms during pregnancy, regardless of whether the employment was full- or part-time. With respect to job type, holding a professional or technical job and holding a clerical or related occupation were independently inversely associated with the prevalence of depressive symptoms during pregnancy. There were no relationships between household income and education and the prevalence of depressive symptoms during pregnancy after mutual adjustment for employment, household income and education.In a study of 5404 pregnant US women, employment, income, and education were significantly inversely related to the depression severity score based on the Beck Depression Inventory after mutual adjustment . The curBecause we found a non-significant inverse relationship between household income and depressive symptoms during pregnancy, the observed significant positive association between unemployment and depressive symptoms during pregnancy is likely to be attributable to some extent to financial stress. In a meta-analysis of 46 studies, employees with lower levels of job satisfaction tended to have higher levels of depression . Given tSeveral methodological limitations of our study warrant mention. First, we assessed depressive symptoms using the CES-D scale rather than structured diagnostic interviews. The CES-D includes questions on physical symptoms such as fatigue and physical discomfort, which are also typical complaints of pregnancy; the consequence of this symptom overlap could have been an overestimation of depression. The prevalence of depressive symptoms in this population was, however, lower than that in a representative sample of the Japanese general population: the prevalence of depressive symptoms (CES-D score of ≥16) was 30.7% in 2315 women aged 30–39 years . MoreoveSecond, the participation rate could not be calculated because the exact number of eligible pregnant women who were provided with the KOMCHS documents and application form by the 423 collaborating obstetric hospitals is not available. Nevertheless, the participation rate must have been fairly low, given that the present study used data from only 970 pregnant women who lived in Fukuoka Prefecture, while, according to the government of Fukuoka Prefecture, the number of childbirths was 46,393 in 2007 and 46,695 in 2008. We were not able to assess the differences between participants and non-participants because information on personal characteristics such as age, socioeconomic status, and history of depressive symptoms was not available for non-participants. Nevertheless, we can presume that our subjects were probably not a representative sample of Japanese women in the general population. For example, educational levels were higher in the current study population than in the general population. According to the 2000 population census of Japan, the proportions of women aged 30 to 34 years in Fukuoka Prefecture with <13 years of education, 13–14 years of education, ≥15 years of education, and unknown were 52.0%, 31.5%, 11.8%, and 4.8%, respectively . The corThird, although adjustment was made for a variety of potential confounders, residual confounding could not be ruled out. In particular, we could not control for sociocultural factors and personal and family relations.Finally, the nature of cross-sectional studies prevents conclusions from being drawn about causality.The current cross-sectional study in Japan showed that both full-time and part-time employment, holding a professional or technical job, and holding a clerical or related occupation were independently associated with a lower prevalence of depressive symptoms during pregnancy. Further well-designed investigations of the effects of socioeconomic factors on depression during pregnancy are required, especially in Asian populations.CES-D: Center for Epidemiologic Studies Depression Scale; CI: Confidence interval; KOMCHS: Kyushu Okinawa Maternal and Child Health Study; OR: Odds ratio.The authors declare that they have no competing interests.All authors contributed to the study concept and design and the acquisition of data. YM was responsible for the analysis and interpretation of data and the drafting of the manuscript. All authors participated in critically revising the manuscript and approved the final version of the manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-244X/12/117/prepub


Pain is a subjective sensory and emotional experience, and it has been reported that many different brain regions are regulated by pain, and that pain can impact attention. Acupuncture is an important treatment component of Chinese traditional medicine, and has been used for thousands of years to treat a wide variety of conditions. Although several studies have shown that acupuncture improves consciousness, the precise impact of both acupuncture and painful stimulation on attention is unclear. Are all of the attention networks modulated, or do these stimuli act on a specific network? Is the effect of painful stimulation similar to that of acupuncture? We administered the attention network test to 30 participants  to investigate the relative efficiencies of three independent attention networks  under three conditions: baseline, after painful stimulation, and after acupuncture. The degree of pain experienced was assessed on a horizontally oriented visual analogue scale. The results showed that painful stimulation and acupuncture had similar effects on the orienting and executive control networks; however, there was a significantly different effect between the three conditions on the alerting network. In conclusion, (1) painful stimulation can selectively impact attention; (2) acupuncture can also selectively impact attention; i.e., both have selective influences on the alerting and executive control networks, but not on the orienting network; (3) the effects of acupuncture and painful stimulation are not identical. The mechanisms by which painful stimulation and acupuncture influence attention warrant further research. Pain is one of the most studied topics in neuroscience, and an almost ubiquitous symptom in a clinical setting. Pain has been defined as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage” by the International Association for the Study of Pain. It signResearch has demonstrated the involvement of both the peripheral and central nervous systems in pain processing. Pain involves a multifactorial, multipathway system, and each component is thought to be regulated by different brain regions. Human brain imaging studies have identified nociceptive nerve fibers passing through the nuclei of the thalamus, and projecting to higher cortical areas via two main pathways—the lateral and the medial. The lateral pain pathway travels through the ventral posterolateral nucleus and the ventral posteromedial nucleus of the thalamus, and then projects to the primary and secondary somatosensory cortices. The medial pain pathway travels through more medial cortical areas, including the anterior cingulate cortex (ACC), insula, amygdala, and hypothalamus. These two pathways are highly integrated, and both are indispensable for normal pain perception. Moreover, these areas are thought to be involved in sensory, motor, emotional, memory, and attentional processes.It is widely known that pain serves as a warning mechanism of danger to the individual: it interrupts, distracts, and demands attention. Moreover, attention deficit is one of the most frequently reported accompanying symptoms in people experiencing either acute or chronic pain.Many clinical studies have found that pain impacts attentional processes, and theOn the basis of many neuroanatomical and neuropsychological studies, Posner divided the human attention system into three independent networks: the alerting, orienting, and executive control networks. These networks have been distinguished at both the biochemical and cognitive levels, and have distinct neuroanatomical correlates-8. The aThe attention network test (ANT) can simultaneously measure the activity of all three networks, and evaluate their interrelationships, and allAcupuncture is an ancient eastern healing methodology, which is effective in the treatment of various brain disorders, such as psychiatric diseases,27, insoThe impact of acupuncture on attention, and its three independent networks, is also unclear. Acupuncture is sometimes accompanied by the sensation of pain; however, compared to painful stimulation, acupuncture appears to have a more complex neural mechanism. Is the effect of painful stimulation similar to that of acupuncture? Do painful stimulation and acupuncture modulate all of the three attention networks, or only one or two specific networks? The present study aimed to investigate and compare the impact of painful stimulation and acupuncture on attention using the ANT. We hypothesize that: (1) painful stimulation can impact attention; (2) acupuncture can impact attention; (3) the effects of acupuncture and painful stimulation on attention are similar.In order to reduce intersubject variability, participants consisted of a homogeneous group of 30 college students . In order to exclude any effects of practice, we recruited another 30 college students  as a control group to perform the ANT three times in a similar environment and on a similar schedule. All subjects were recruited from Anhui Medical University located in Hefei City, Anhui Province, China. All were right handed, and acupuncture naive. They all had normal speaking, writing, language expression, and cognitive skills. None had any history of serious physical disorders or of mental illness. Our study protocol was approved by the Anhui Medical University Ethics Committee, and written informed consent was obtained from all participants before the study.The experiment was divided into three blocks: baseline, after painful stimulation, and after acupuncture. During each block, all participants were administered the same ANT task. To exclude any interference of painful stimulation and acupuncture on the baseline block, each experiment began with the baseline block. Then, all participants were re-administered the ANT, immediately after either painful stimulation or after acupuncture. Lastly, the ANT was re-administered immediately after the remaining stimulus condition. In order to reduce possible influences on the results, participants were not informed of the order in which painful stimulation and acupuncture blocks would be performed, and in order to facilitate blinding, they were instructed to keep their eyes closed to prevent them from actually observing the procedures, and were asked to remain relaxed without engaging in any mental tasks. The sequence of painful stimulation and acupuncture was counterbalanced across all participants. There was a 5-min rest period after each ANT Figure .Unlike the painful stimulation and acupuncture blocks, during the baseline condition, all participants were administered the ANT task without any interruption. We designed the baseline block as the control condition.The acupuncture needles  were inserted in 2 non-meridian points . The needles were inserted vertically, to a depth of 30 mm Table . SubjectThe entire procedure took 10 min. We used the horizontally oriented visual analogue scale (VAS) to assess the degree of pain experienced,39, withP < 0.001). The procedure was performed by the same experienced and licensed acupuncturist on all subjects.The acupuncture needles  were inserted in 2 ST36 acupoints  . Participants viewed the stimuli shown on a computer screen, and responses were automatically collected via two response buttons. The stimuli consisted of a row of five horizontal black lines, with arrowheads pointing left or right, and the target was a left or right pointing arrowhead in the center, against a gray background. The target stimulus was flanked on either side by two arrows pointing either in the same direction (congruent condition), or in the opposite direction (incongruent condition), or by nothing . Participants were instructed to focus on a centrally located stationary cross throughout the task, and to respond as quickly and accurately as possible. The participant’s task was to identify the direction of the center arrow by pressing one button for the left direction with the index finger of their left hand, or a second button for the right direction with the index finger of their right hand. The target stimulus remained on the screen until the participant responded, but the maximum response time was cut off at 1700 ms. Cues consisted of an asterisk appearing for 100 ms, presented 400 ms before the presentation of the target. There were four cue conditions in the process: (1) no cue, the participant was shown a cross at the same location as the first stationary cross for 100 ms; (2) a center cue, an asterisk was presented on the central point; (3) a double cue, an asterisk was presented at two target locations simultaneously, above and below the central point; and (4) a spatial cue, an asterisk was presented at a target location either above or below the central point. The whole process of the ANT consisted of a 24-trial practice block, and three experimental blocks of trials. The presentation of trials was in a random order for each participant. Each experimental block consisted of 96 trials . The entire ANT was completed in 20 min  derived from the different experimental conditions to measure the efficiency of the alerting, orienting, and executive control networks. AlertinP < 0.05. To assess differences between individual conditions, a Student–Newman–Keuls (SNK) test was also used.Statistical analysis was performed using SPSS . The statistical significance of differences between the baseline, after painful stimulation, and after acupuncture conditions was evaluated by a one-way analysis of variance (ANOVA); the between-subject comparison was evaluated using an independent samples t-test, and the threshold for statistical significance was set at P < 0.001; flanker type, F  = 345.498, P < 0.001; interaction of cue conditions × flanker types, F = 8.626, P < 0.001; [ii] after painful stimulation: cue condition, F  = 167.751, P < 0.001; flanker type, F  = 382.327, P < 0.001; interaction of cue condition × flanker type, F = 18.639, P < 0.001; and [iii] after acupuncture: cue condition, F  = 250.158, P < 0.001; flanker type, F  = 415.649, P < 0.001; interaction of cue condition × flanker type, F = 20.530, P < 0.001).The mean RTs and accuracy rates for each of the three conditions are summarized in Table We conducted an analysis of variance with repeated measures for accuracy as well, but there were no significant main effects of cue conditions or flanker type in the three conditions Table .P < 0.001). Our results show that participants were significantly more vigilant following painful stimulation or acupuncture than in the baseline condition , and the comparison between painful stimulation and acupuncture conditions revealed a significant difference . There was a significant main effect of the three conditions on the executive control network tasks  = 8.811, P < 0.01). Participants had less difficulties in resolving conflict after either painful stimulation or acupuncture than in the baseline condition , while there was no significant difference between the painful stimulation and acupuncture conditions . However, there were no significant differences between the three conditions on the orienting network tasks  = 2.398, P > 0.05). Thus, participants exhibit specific improvements in the performance of the alerting and executive control networks after either painful stimulation or acupuncture, but there was no impact on the function of the orienting network. There also was a significant main effect of the three conditions on the overall mean RTs  = 23.238, P < 0.01). Participants took significantly less time to finish the test following either painful stimulation or acupuncture than they did in the baseline condition . There was no significant difference between overall mean RTs after either of the two interferences . Additionally, there was no significant difference observed in response accuracy between the three conditions  = 0.811, P > 0.05) .We examined the relationship between the VAS and the scores of the three attentional network tests. No significant correlations were identified between the VAS and the three network scores for either the painful stimulation or the acupuncture condition  = 0.361, P > 0.05; [iii] Executive control: F  = 0.168, P > 0.05).There were no significant differences observed in alerting, orienting, and executive control networks between the three trials performed by the control group  = 0.070, P > 0.05; Orienting, T = 0.348, P > 0.05; Executive control, T = 0.071, P > 0.05); [ii] acupuncture condition: Alerting, T = 0.006, P > 0.05; Orienting, T = 0.921, P > 0.05; Executive control, T = 0.795, P > 0.05).There were no significant differences observed in the alerting, orienting, or executive control networks in a between-subject comparison of the pain stimulation and the acupuncture conditions , and acts to monitor and resolve conflicts between competing information. Previous studies on animals and humans have shown that the medial frontal cortex, and particularly the ACC, can greatly reinforce acute nociceptive responses; for example, formalin injections enhanced behavior with disgust experience,52. FurtIn our study, the orienting network was not affected by either painful stimulation or acupuncture. This is in agreement with the findings of several other studies. For example, no difference was found in the function of the orienting network from 6 years of age to adulthood, the findings indicating that the orienting network as assessed by the ANT remains stable during brain development, and chiIn our present study, the results confirmed that acupuncture can impact selective attention networks, enhancing the efficiency of the alerting and executive control networks; notably, when compared to painful stimulation, acupuncture had a significantly greater effect on the alerting network. This is contrary to our third hypothesis; however, the mechanisms underlying this difference have yet to be elucidated. While the neural mechanisms of acupuncture are unknown, it has been suggested that it may induce an increased release of endorphins, serotonin, norepinephrine, or γ-aminobutyric acid. AcupuncThere are a number of potential limitations to the current study. We included a 5-min rest period after each ANT; it is possible that this period was not long enough for subjects to rest well. Future studies could include a longer rest period between trials.In conclusion, the results of the current investigation support the existence of selective effects on the alerting and executive control attentional networks following either painful stimulation or acupuncture. To the best of our knowledge, this is the first study to concurrently assess the effects of both painful stimulation and acupuncture on the three attention networks, using the ANT. From a clinical/functional point of view, we confirmed that: (1) painful stimulation can impact attention; (2) acupuncture can impact attention; (3) the effects of acupuncture and painful stimulation are not identical. Further studies could combine the ANT with functional magnetic resonance imaging and positron emission computed tomography in order to more precisely investigate the neural mechanisms underlying the influence of painful stimulation and acupuncture on functional attention networks.The authors have declared that they have no competing interest.Conceived and designed the experiments: GL, JF, KW. Performed the experiments: GL, HJM, SH, YHT. Analyzed the data: GL, PPH. Wrote the paper: GL. All authors read and approved the final manuscript.


The research of multicomponent drugs, such as in Chinese Medicine, on both mechanism dissection and drug discovery is challenging, especially the approaches to systematically evaluating the efficacy at a molecular level. Here, we presented a network pharmacology-based approach to evaluating the efficacy of multicomponent drugs by genome-wide transcriptional expression data and applied it to Shenmai injection (SHENMAI), a widely used Chinese Medicine composed of red ginseng (RG) and Radix Ophiopogonis (RO) in clinically treating myocardial ischemia (MI) diseases. The disease network, MI network in this case, was constructed by combining the protein-protein interactions (PPI) involved in the MI enriched pathways. The therapeutic efficacy of SHENMAI, RG, and RO was therefore evaluated by a network parameter, namely, network recovery index (NRI), which quantitatively evaluates the overall recovery rate in MI network. The NRI of SHENMAI, RG, and RO were 0.876, 0.494, and 0.269 respectively, which indicated SHENMAI exerts protective effects and the synergistic effect of RG and RO on treating myocardial ischemia disease. The successful application of SHENMAI implied that the proposed network pharmacology-based approach could help researchers to better evaluate a multicomponent drug on a systematic and molecular level. Chinese Medicine, featured as having “multiple ingredients and multiple targets,” has been widely used to treat complex diseases for decades . So far,It would be promising to reveal a drug's efficacy via high throughput technology , such asRecently, network based analyses such as network pharmacology emerged and have become a powerful tool to systematically reveal complex biological relationships , 17. UnlPanax ginseng C. A. Mey, steamed and dry) and Radix Ophiopogonis  Ker-Gawl, root), is a Chinese Medicine that is widely used in clinically treating ischemic heart disease [In this study, for the first time, network pharmacology is introduced and applied to the evaluation of the efficacy of Shenmai injection (SHENMAI) in treating myocardial ischemia (MI). SHENMAI, composed of red ginseng . The HPLC fingerprinting assay was performed to estimate the batch-to-batch consistency of SHENMAI [SHENMAI no. 1107282) extracts of RG and RO, and the vehicle in the form of an injection, were supplied by 2 extractMale Sprague-Dawley rats (180–220 g) were purchased from Shanghai SLAC Laboratory Animal Co., Ltd. A rat model of myocardial infarction was induced by permanent occlusion of the left anterior descending coronary artery. Briefly, after anesthetized using diethyl ether, the rats were fixed with the hair over the heart picked, then underwent a left thoracotomy and were ligated on the left anterior descending coronary artery. The control (sham) group was given the same surgery but without ligation. SHENMAI and the vehicle were given via intraperitoneal injection for 7 days in rats with myocardial ischemia. In detail, 10 mL/kg of SHENMAI and the corresponding dose for RG and RO were given to the rats, respectively. The dosage of SHENMAI and its components used was calculated in accordance with clinical consumption and was confirmed by our preliminary study. On the eighth day, the rats were anaesthetized by intraperitoneal injection of 0.2 mL/100 g anesthetic, which was prepared by mixing diazepam and ketamine in the ratio of equality, for measuring echocardiography using a VisualSonics Vevo 770TM in vivo microimaging system equipped with an RMV-707B cardiovascular scanhead . Then the border between the infarct and noninfarct left ventricle area in the rat heart was harvested to extract mRNA for genome-wide transcriptomic analysis.Total RNA was extracted using TRIZOL Reagent  following the manufacturer's instructions and checked for a RIN number to inspect RNA integrity by an Agilent Bioanalyzer 2100 . Qualified total RNA was further purified by RNeasy mini kit  and RNase-Free DNase Set . Total RNA was amplified, labeled, and purified by using GeneChip 3'IVT Express Kit  following the manufacturer's instructions to obtain biotin-labeled cRNA. Array hybridization and wash were performed using GeneChip Hybridization, Wash and Stain Kit  in Hybridization Oven 645  and Fluidics Station 450  following the manufacturer's instructions. Slides were scanned by GeneChip Scanner 3000  and Command Console Software 3.1  with default settings. Raw data were stored on ArrayTrack , a java-t-test with a threshold of P value <0.01 and fold change >1.5 was applied to find out the significant genes according to the microarray expression profiles. In this study, the significant genes differentially expressed between Myocardial ischemia (MI) group and control group were used for further pathway enrichment analysis.MI network was constructed based on the MI enriched pathways and PPI knowledge. To define MI enriched pathways, a widely used approach of Welch Pathway enrichment analysis was then applied to find the significant enriched pathways of these DEGs. ArrayTrack  was usedIn this study, the nodes of the MI network are the genes involved in the MI enriched pathways, and the edges are the protein-protein interactions between these genes. Since protein-protein interactions (PPIs) for rats were relatively few in number that could hardly reflect the overall network relationships between genes  was used as a quantitative index to evaluate the network perturbation recovery from MI to normal state by treatment. To calculate the NRI, the regulating score (RS) was first calculated to evaluate the influence of MI and SHENMAI on each node in the network, which was calculated by the average ratio of expression data between MI/treatment and control samples formula . In form. These 27 pathways involved 10 metabolism pathways, 10 cellular process pathways, 4 human disease pathways, 2 environmental information processing pathways, and DNA replication. For instance, The adipocytokine signaling pathway (KEGG id: rno04920) showed a P-value = 0.026, and dilated cardiomyopathy (KEGG id: rno05414) showed a P-value <1.0e − 8. A detailed list of the 27 significant pathways used in this study is in Supplement Table S1 .A combined algorithm with simple According to the KEGG database, a total of 1478 genes were involved in these 27 significant pathways. The Orthologene database in ArrayTrack was used to convert these genes from rat to human. As a result, 905 genes have been found to have at least one interaction with other genes (including self-loops), and all the 2618 interactions were involved. R2 = 0.868), indicating that MI the network was scale-free like The MI network was constructed based on these genes and interactions, and was visualized by Cytoscape (version 2.8.0)  Figure . In thisThe number of up-and downregulating nodes in the giant component by MI was 177 and 106; the number of up-and downregulating nodes by SHENMAI was 112 and 60, respectively. The result showed that the number of regulated nodes by SHENMAI was smaller than in MI. Regulating score maps of SHENMAI and MI were drawn based on the regulating score of the MI group and SHENMAI treatment , middle.up, Rrdown, and Rrall, were 0.9096, 0.9057, and 0.7787, respectively. So, the NRI of SHENMAI was 0.865. The NRI was used to quantitatively evaluate the efficacy of the drug, based on the ability of the drug to recover the network from MI to normal. The NRI was a value between 0 and 1, and a higher NRI represented a good efficacy in treating MI in our study. As mentioned above, the ratio of recovery regulation of SHENMAI, RrP = 0.0002 and 0.0006).We also calculated the NRI of RG, and RO, which were solely used to treat MI. The NRI of SHENMAI, RG and RO were 0.865, 0.425, and 0.271, respectively . Both RGP < 0.05) related to MI controls. However, individual treatment of RG and RO did not show significance to impair the cardiac function. In our study, LV function was used as the golden indicator to evaluate the drug efficacy of SHENMAI, RG, and RO in the development of cardiac failure after myocardial ischemia by using echocardiography after 7 days of treatment. As shown in The overall trends in EF and FS indicators of SHENMAI, RG, and RO were consistent with the NRI in the network based analysis, which showed SHENMAI had the best and significant efficacy performance according to both the echocardiography study and network based analysis, while RG and RO showed insignificant efficacy according to the echocardiography result. The accordance of the echocardiography result and NRI indicated that network pharmacology based analysis could reveal drug effects on treating MI on a molecula level related to phenotype indicators.In this study, we presented a network-based approach to evaluating the efficacy of Chinese Medicine using genome-wide transcriptional expression data. By constructing a specified biological network of MI and analyzing the network regulation, we quantitatively evaluated the efficacy of the multicomponent drug SHENMAI in treating MI. The result indicates that SHENMAI has a significant efficacy in treating MI, which was represented by its ability to repair the MI network. Furthermore, comparative analysis of SHENMAI and its components RG and RO indicated that RG and RO have the synergistic effect on treating MI. This result was further validated by LV function via echocardiography experiments. Based on our study, we believe that evaluating the efficacy of Chinese Medicine on a systematic and molecular level will be a trend in future drug research.Supplement Table: Detailed information of 27 enriched pathways. KEGG pathway analysis tools embedded in ArrayTrack were used for pathway analysis, and pathway with Fisher p-value <0.05 was identified as the enriched pathway. 27 enriched pathways were eventually identified and their detailed information was listed in Supplement Table .Click here for additional data file.


The interplay between different types of potentially traumatizing events, posttraumatic symptoms, and the pathogenesis of PTSD or major dissociative disorders (DD) has been extensively studied during the last decade. However, the phenomenology and nosological classification of posttraumatic disorders is currently under debate. The current study was conducted to investigate differences between PTSD patients with and without co-occurring major DD with regard to general psychopathology, trauma history, and trauma-specific symptoms.Twenty-four inpatients were administered the Clinician-Administered PTSD Scale for DSM-IV (CAPS) and the Mini-Structured Clinical Interview for DSM-IV Dissociative Disorders (MINI-SKID-D) to assess DD and PTSD. Additionally, participants completed questionnaires to assess general psychopathology and health status.Symptom profiles and axis I comorbidity were similar in all patients. Traumatic experiences did not differ between the two groups, with both reporting high levels of childhood trauma. Only trauma-specific avoidance behavior and dissociative symptoms differed between groups.Results support the view that PTSD and DD are affiliated disorders that could be classified within the same diagnostic category. Our results accord with a typological model of dissociation in which profound forms of dissociation are specific to DD and are accompanied with higher levels of trauma-specific avoidance in DD patients. Since Pierre Janet described the phenomenon of dissociation at the beginning of the 20th century Janet, , researcIn general, the link between dissociative symptoms and PTSD has been studied in various populations  and based on the reviewed literature, we hypothesized that a difference will be found between patients with PTSD and patients with additional DID in terms of symptom complexity, trauma history, and comorbid disorders. These predictions in general are in accordance with the theories and recent research contributions reviewed above. Both Schauer and Elbert  as well  and baseParticipants were 24 patients of an inpatient clinic in Bielefeld, Germany. Consecutively admitted patients were evaluated during a period of 3 months. All patients were comparable regarding the amount of treatment and time since admission to the clinic and between 18 and 60 years. Exclusion criteria were established by the clinic . Our aim was to assess subjects with a history of traumatic life experiences and either (1) PTSD without any comorbid DD, (2) PTSD with comorbid DD, and (3) DD without PTSD. Due to the specialization for trauma-related disorders, every patient who was administered to the study within the period of assessment presented PTSD. Hence, it was not possible to recruit a “dissociation-only” group.dissociative amnesia as it is a very common condition in PTSD patients) and were labeled “PTSD group.” The diagnoses in both subgroups are shown in Participants were divided into two subgroups on the basis of structured clinical interviews. The “DD” group consisted of patients with a DSM-IV diagnosis of at least one major DD (DID or DD not otherwise specified [DDNOS] and PTSD. The other group included those patients who received the diagnoses of a current PTSD as described in the DSM-IV but without a comorbid diagnosis of any major DD (except of All participants provided written informed consent after the aims and procedure of the study was explained to them. Participants filled out the questionnaires within 2 days of being admitted to the clinic and were interviewed by an experienced clinician. Interviews were carried out by one of the authors (P. W.) during two sessions on consecutive days within the first 2 weeks of admission. In the first session, the Clinician-Administered PTSD Scale  was used for the diagnosis and quantification of PTSD.Dissociative symptoms were assessed using the German version of the MINI-SCID-D  = 6.29, p<0.001, phi = − 0.52. Moreover, a distinct difference was found regarding “duration of the worst event” showing that subjects in the DD group reported a longer duration compared to the PTSD-only group (Hedge's g=1.21).t(18) = 3.17, p<0.001. =35.00, SDDD=8.54 vs. MPTSD=21.18, SDPTSD=7.96, F = 13.97, p< 0.005), whereas there were no significant differences with respect to re-experiencing and hyperarousal  = 0.07, p=0.80, phi = 0.06, substance use disorders χ2 = 1.16, p=0.28, phi = 0.24, psychotic disorders (none), eating disorders χ2 = 1.16, p=0.28, phi = 0.24, or anxiety disorders χ2 = 0.40, p=0.53, phi = 0.14. The mean number of MINI diagnoses did not differ significantly between the two groups.On the FDS, the DD groups did not report more dissociative symptoms than the PTSD group whereas on the MID, the DD group reported significantly more dissociative symptoms than the PTSD group. Group differences on the BDI and SOMS were examined by means of an ANOVA. As shown in U tests revealed that the DD group had received more psychotherapeutic treatments during the past 10 years and that the duration of the intervention was longer than in the PTSD group  had more frequent therapeutic experiences and reported longer periods of incapacity for work due to mental health problems. In addition, even though both groups did not differ with respect to overall PTSD severity, patients with comorbid DD had a higher score on trauma-related avoidance.In general, our findings are consistent with current etiological theories regarding the differentiation between PTSD and DD. Given the impact of various childhood traumata on the pathogenesis of psychopathology (i.e., Egeland, Our finding that the groups did not differ with respect to type and frequency of traumatic experiences questions the predictive power of these factors in the distinction of both disorders. Whereas several authors suggested that more severe early childhood trauma would be reported in DID or DDNOS compared to PTSD patients (i.e., Steele et al., A careful interpretation of the results of the present study could be that the chronicity of traumatic experiences might be more important than the trauma type in the development of DD and PTSD. Compared to patients with PTSD only, those with co-occurring DD reported significantly more trauma-specific avoidance behavior as assessed by the CAPS (Blake et al., Our finding that PTSD patients with DD reported longer and more psychotherapeutic treatments is in line with previous notions that, given the complexity of symptoms, the diagnosis of DID is usually made in the course of longer time periods of therapy (Gast, Rodewald, Kersting, & Emrich, Alternatively, the duration and number of therapeutic treatments could be a cause for the development of dissociative symptoms (Piper & Merskey, Even though our findings are encouraging, they should be interpreted carefully as we did not assess quality of early and later parental relations, attachment types and emotional support. These are factors that can buffer or worsen the experience of a potentially traumatizing event. The current study is also limited by a very small sample size; therefore, caution must be applied to the interpretation and generalizability of findings. Thus, our results might be affected by type 2 errors. Even though effect sizes validate the absence of differences between both groups to some extent, the presence of non-differences cannot be verified by means of statistical testing. Moreover, since all participants were inpatients we cannot rule out, that they had a much higher level of psychopathology than those in outpatient treatment, leading to an absence of group differences. However, given that no study has systematically investigated these diagnostic groups so far, the present findings might help to better understand the complex relationship among trauma, PTSD, dissociation, and DD. Future studies are recommended to compare large numbers of patients with PTSD, those with DD, and ideally patients with both PTSD and DD also. Major clinical implications regard possible avoidance tendencies of PTSD patients with co-occurring DD. As discussed above, larger avoidance tendencies may results in longer therapy or longer therapies could be associated with a higher probability to induce avoidance in the patient. As a consequence, interventions should try to address possible avoidance strategies of these patients. Moreover, therapists should be aware of their patient′s disposition to develop and get engaged in avoidance behavior.In conclusion, bearing in mind the limitations of the present study, our results show that PTSD and co-occurring DD are similar with respect to the overall severity of trauma symptoms as well as comorbid features. In addition, both diagnostic groups were comparable on a variety of characteristics related to trauma history therefore suggesting that they might share a common etiology. The fact that co-occurring dissociation was specifically linked to increased trauma-related avoidance as well as to longer therapeutic treatments might support the idea that DD may reflect a well-learned and automated avoidance mechanism in response to stressful and overwhelming trauma symptoms. This might result in a particularly complex overall presentation of psychopathology with higher levels of impairment that should be addressed by adequate therapeutic approaches taking into account both the similarities but also the differences in treating PTSD only as compared to PTSD and a co-occurring DD.


Prior studies that have concluded that disk degeneration uniformly precedes facet degeneration have been based on convenience samples of individuals with low back pain. We conducted a study to examine whether the view that spinal degeneration begins with the anterior spinal structures is supported by epidemiologic observations of degeneration in a community-based population.361 participants from the Framingham Heart Study were included in this study. The prevalences of anterior vertebral structure degeneration (disk height loss) and posterior vertebral structure degeneration (facet joint osteoarthritis) were characterized by CT imaging. The cohort was divided into the structural subgroups of participants with 1) no degeneration, 2) isolated anterior degeneration (without posterior degeneration), 3) combined anterior and posterior degeneration, and 4) isolated posterior degeneration (without anterior structure degeneration). We determined the prevalence of each degeneration pattern by age group < 45, 45-54, 55-64, ≥65. In multivariate analyses we examined the association between disk height loss and the response variable of facet joint osteoarthritis, while adjusting for age, sex, BMI, and smoking.2), but not smoking.As the prevalence of the no degeneration and isolated anterior degeneration patterns decreased with increasing age group, the prevalence of the combined anterior/posterior degeneration pattern increased. 22% of individuals demonstrated isolated posterior degeneration, without an increase in prevalence by age group. Isolated posterior degeneration was most common at the L5-S1 and L4-L5 spinal levels. In multivariate analyses, disk height loss was independently associated with facet joint osteoarthritis, as were increased age (years), female sex, and increased BMI (kg/mThe observed epidemiology of lumbar spinal degeneration in the community-based population is consistent with an ordered progression beginning in the anterior structures, for the majority of individuals. However, some individuals demonstrate atypical patterns of degeneration, beginning in the posterior joints. Increased age and BMI, and female sex may be related to the occurrence of isolated posterior degeneration in these individuals. The importance of spine stability is a central paradigm in spine care. Maintenance of spine stability, through decreasing excessive or abnormal spinal movement, is the rationale for many commonly used treatments ranging from 'lumbar stabilization' rehabilitation to spinal fusion surgery . The spiOver time, however, the sequence of spinal degeneration has often been viewed from a more limited standpoint, with the perspective that anterior structure changes affecting the intervertebral disk largely precede- and lead to- posterior structure changes affecting the facet joints . The notMany prior studies of the degenerative cascade that have concluded that disk degeneration uniformly precedes facet degeneration have been based on convenience samples of individuals with LBP ,9,11,12.We conducted an ancillary study to the Framingham Heart Study. The Framingham Heart Study began in 1948 as a longitudinal population-based cohort study of the causes of heart disease. 5209 men and women living in Framingham, Massachusetts were enrolled in the Original study cohort. Beginning in 1971, 5,124 children of the Original cohort members and their spouses were enrolled as the Offspring cohort . In 2002Study participants were imaged with a MDCT scanner using methods that have been described previously . EvaluatDHL was graded using a system developed for research by Videman et al., and has been widely used in prior studies -23. UsinFJ OA was graded using criteria designed for research purposes that have been used in multiple studies ,26, and Inter-observer reliability was calculated between the physiatrist and the radiologist at the start of the reading process. All CT scans were interpreted for each parameter at spinal levels L2-L3, L3-L4, L4-L5, and L5-S1. Recalibration of physiatrist to radiologist was performed at multiple points during the reading process, either by direct interaction with the radiologist or by the review of images previously interpreted by the radiologist. To evaluate for reader-drift, we planned in advance to periodically reassess reliability at regular intervals. Inter-observer reliability using the weighted κ statistic varied between 0.70 and 0.84 for DHL (n = 50), and between 0.68 and 0.84 for FJ OA (n = 46).any DHL at one of the L2-S1 spinal levels. All statistical analyses were performed using SAS software, .Analyses focused on the individual participant, rather than on the individual spinal level. This analytic approach addresses the fact that changes at one level are thought to lead to multilevel changes over time , and acc435 individuals were evaluated for DHL and FJ OA by CT scan. 45.5% of individuals were female, and the mean age of the sample was 58.0 ±13.1 years. 6.0% of individuals had a lumbosacral transitional level, 8.3% had spondylolysis, and 3.2% had prior lumbar spinal surgery; these individuals (n = 74) were excluded from subsequent analyses, leaving 361 participants in the analysis. Individuals who were excluded were older than those who were not excluded , but were not materially different with respect to sex and BMI (data not shown).The study sample is described in Table Table 2 (OR 1.09 [95% CI 1.03- 1.16]) were also independently and significantly associated with posterior structure degeneration, but smoking was not. When interaction terms were added to the model, there were no significant interactions between moderate DHL and these covariates.In order to account for potential confounding, and to permit investigation of effect modification, the predictor variable of anterior degeneration- as well as the covariates of age, sex, BMI, and smoking- were included in multivariate logistic regression models using the response variable of posterior degeneration. These results are presented in Table Repeating the multivariate logistic regression, and using our secondary definition of anterior degeneration (any DHL), anterior degeneration remained significantly associated with the presence of posterior degeneration. Age, female sex, and BMI were also independently and significantly associated with posterior structure degeneration, but smoking was not. When interaction terms were added to the model, the interaction of BMI with any DHL was statistically significant (p = 0.02), suggesting a greater effect of increased BMI when any DHL was present.The current study is consistent with the view that, for a majority of individuals, degeneration begins with the anterior spinal structures. However, a minority of individuals  across the age spectrum exhibits a pattern of isolated posterior degeneration without substantial loss of disk height, occurring most frequently at the L5-S1 and L4-L5 spinal levels. For these individuals, the factors of age, sex, and BMI may explain, at least in part, the development of posterior structure degeneration without concurrent changes in the disk.In some patients the changes seen during the course of the progressive degenerative process affect mainly the facet joints' [Kirkaldy-Willis described spinal degeneration as the result of a complex interaction between the intervertebral disks and facet joints, which begins with precipitating events that could take place in any component of the three-joint complex. He stated clearly, ' joints' . Our fin joints' . Eubanks joints' , and herThis study has the advantage over prior studies in that we sampled a community-based population, included a large number of subjects, and used well-described and reliable measures for the pathoanatomic features of interest. In addition, our analysis was unique from others examining this question in that we used multivariate techniques. This is especially important because factors such as age are known to have strong positive associations with both DHL and FJ OA, creating the possibility of substantial confounding. We were able to demonstrate associations between key covariates and FJ OA, independent of the main association of interest between DHL and FJ OA.Some limitations pertain to this study. First, the cross-sectional nature of this study limits firm conclusions about causality. Second, although aspects of quantitative measurement were contained within the categorical scales of DHL and FJ OA used in this study, these scales were not truly quantitative. Some prior studies have had better resolution for detecting changes in disk degeneration when quantitative scales were used . HoweverThe observed epidemiology of lumbar spinal degeneration in the community-based population is consistent with an ordered sequence beginning in the anterior structures, for a majority of individuals. However, some individuals demonstrate atypical patterns of degeneration, beginning in the posterior joints. Increased age and BMI, and female sex, may be related to posterior degeneration in these individuals. Longitudinal studies are needed to better understand the importance of segmental level biomechanics in degeneration, and ideally should include not only these important covariates, but also examination of genetic factors.The authors declare that they have no competing interests, except for the following:JGJ is a member of the GE Healthcare Advisory Board for Comparative Effectiveness and a consultant for HealthHelp, a Radiology Benefits Management company. AG was previously a scientific advisor for Facet Solutions.PS was involved with study concept and design, acquisition of data, analysis of data, interpretation of data, and drafting of the manuscript. AM was involved with study design and acquisition of data. DJH was involved with study concept and design, analysis of data, interpretation of data, and manuscript preparation. JGJ was involved with study design and interpretation of data. JR was involved with study concept, design, and interpretation of data. AG was involved with study design and acquisition of data. LL was involved with analysis of data and interpretation of data. JNK was involved with study design, analysis of data, interpretation of data, and manuscript preparation. All authors were involved with critical revision of the manuscript for important intellectual content and approved the final version of the manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2474/12/202/prepub


Introduction. Constipation is a common adverse drug reaction. Objective. Study associations between drugs and constipation in nursing home residents. Design. Cross-sectional study. Material and Methods. Nursing home residents above 60 years of age were included. Demographics, diet, physical activity, activity of daily living, nutritional status, use of drugs, and diseases were recorded. Constipation was defined as functional constipation or constipation-predominant IBS according to the Rome III criteria and/or regular use of laxatives. Drugs were classified according to the Anatomical-Therapeutic-Chemical Classification System (ATC), and anticholinergic effect was noted. Results. In all, 79 men and 188 women with a mean age of 85.4 (SD 7.1) years were included. The prevalence of constipation was 71.5%. Use of drugs in general, including polypharmacy, was not associated with constipation. Reduced activity of daily living , other antidepressants (N06AX) , and benzodiazepine derivatives (N05BA)  were significantly associated with constipation; drugs with markedly anticholinergic effect , natural opium alkaloid (N02AA) , and propionic acid derivatives (M01AE)  showed a trend. Conclusion. In elderly with constipation, focus should be on specific groups of drugs and nonpharmacological factors, not on drugs in general. Chronic functional constipation affects 17–40% of the elderly and reduces quality of life [Gastrointestinal symptoms including constipation are common adverse drug reactions . Drugs hIn general, the use of drugs is high in elderly in nursing homes –13. FraiThis cross-sectional study aimed at finding the impact of drugs on constipation in elderly in nursing homes.In 2008-2009, this cross-sectional study was performed in nursing homes in the counties of Oppland and Hedmark, Norway. Registered and auxiliary nurses with good knowledge of the residents collected data from the medical records and got information from the residents and their next of kin. A blood sample was collected.Residents above 60 years of age living in nursing homes for more than 8 weeks and without organic gastrointestinal diseases that could cause constipation were included in the study.The following variables were recorded: age, gender, weight, height, smoking habits, use of alcohol, somatic and psychiatric diseases, physical activity , activity of daily living (Katz' Activity of Daily Living (ADL) index (score 0 (very dependent)–6 (independent)), nutritional status  [Constipation was defined according to the Rome III criteria for functional constipation  except ft-test, Mann-Whitney U test, Fisher's exact test, and Chi-square for trend. Three multivariable analyses (stepwise backward logistics regression) were performed with constipation as dependent factor and either number of drugs, drugs with markedly anticholinergic effect, or groups of drugs at ATC-level 4 with P ≤ 0.2 in bivariate analyses as independent variables. In addition, variables presumed to be associated with constipation , and other variables associated with constipation with P ≤ 0.05 in the bivariate analyses were included in the analyses. The cut-off point for groups of drugs was set to P < 0.2 to avoid loss of any group of drugs since this was the primary aim of the study. The cut-off point for other variables was P < 0.05 to reduce the number of covariates in the calculations. Since a drug is highly associated with the disease under treatment, both the group of drugs and the disease were included if one of them was associated with constipation with P ≤ 0.2 in the bivariate analyses. The one with the lowest impact on the outcome in the multivariable analyses was removed. Age and gender were maintained in all analyses, and number of drugs and the anticholinergic effect were maintained in the respective analyses, independent of degree of significance. Other variables were removed one by one in the backward regression analyses until only variables with P < 0.1 remained in the equation. Foreseeable interactions were controlled for.Associations between constipation and the recorded variables were analyzed with Student's P values ≤ 0.05 were regarded as statistically significant and P ≤ 0.10 as a trend. PASW Statistics 18 was used for the analyses. The power to detect a statistically significant difference (α ≤ 0.05) of 1.4 in the mean number of drugs used by subjects with and without constipation was 80%.Multiple imputation for missing data was performed with all variables included in the analyses . Two-sidThis study was approved by the Regional Committee for Medical and Health Research Ethics, Central Norway, and by Privacy Ombudsman for Research at Oslo University Hospital and performed in accordance with the Declaration of Helsinki. All residents or their next of kin gave written informed consent to participate. Residents giving consent themselves were informed by the nursing staff. Next of kin or legally acceptable representative to residents unable to provide informed consent were given oral and written information during a visit to the nursing home or by post and phone before giving informed consent.Out of 24 invited nursing homes, 13 participated. In the participating nursing homes, 267 out of 647 residents (41.3%) participated in the study. Other antidepressants (N06AX) was significantly associated with constipation, and vitamin B12 (B03BA) and thyroid hormones (H03AA) with less constipation.Tables Other antidepressants and benzodiazepine derivatives (anxiolytics) (N05BA) were significantly associated with constipation; natural opium alkaloids (N02AA) and propionic acid derivatives (M01AE) showed a trend. Vitamin B12 and thyroid hormones were associated with less constipation. Analyses performed on original and imputed data did not differ in principal.Constipation was more prevalent in this study (71.5%) than in most corresponding studies –6. CompaThe main finding was that use of drugs in general, including polypharmacy, was not significantly associated with constipation in this nursing home population with a high prevalence of constipation and polypharmacy. Most studies, reviews, and guidelines focus on drugs and polypharmacy as risk factors for constipation in elderly , 14, 24.The prevalence of use of drugs with markedly anticholinergic effect was three times higher in subjects with constipation than in those without. The constipating effect of drugs with anticholinergic effect has been reported in several studies and in reviews, and the nonsignificant finding in this study is probably due to low power since rather few subjects used this type of drugs –7, 9, 25Other antidepressants, which have also been associated with constipation in other studies, and benzodiazepine derivatives were significantly associated with constipation [Propionic acid derivatives (M01AE) and natural opium alkaloids (N02AA) showed a trend; the ORs were 7 and 5, respectively. The high ORs show that the prevalence of constipation was much higher in users than nonusers of these drugs and the lack of statistical significance was probably a type II error due to few users. The constipating effect of these drugs is known from several studies and reviews [A few groups of drugs were associated with constipation. tipation , 26. Pro reviews , 26.Thyroxin hormones and vitamin B12 and less constipation have previously not been described. However, thyroxin has been associated with diarrhoea [To our knowledge, the significant associations between iarrhoea .Reduced activity of daily living was highly statistically significantly associated with constipation. Inactivity and dietary factors are explanations of this association, which is reported also in other studies and reviews , 9, 28. The participating rate was lower than desired. Exclusion of 11 out of 24 nursing homes probably occurred by chance. The low participation rate in participating nursing homes (41.7%) might have influenced the external validity. Informed consent was easier to obtain from residents able to provide informed consent themselves than from the next of kin. This might explain why the prevalence of dementia was somewhat lower than in some other studies. The most frail and dement residents might therefore have been underrepresented , 11, 12.More information than normally in clinical studies was based on information from the nurses, next of kin and the medical journals, and less from the residents themselves, since the majority of the participants had cognitive impairment. This might have reduced the validity of the data, but use of deputies was inevitable.Groups of drugs were analyzed at ATC-level 4, which are drugs with similar chemical structure and uniform side effects. Analyses on ATC-level 5 would have resulted in too small groups, and ATC-level 3, or higher combine drugs with different side effects.P = 0.05–0.10) have been reported because the associations might be of clinical significance, and the lack of statistically significance might be due to low power (few users of these drugs). The constipating effect of some groups of drugs used by few subjects might have been missed.The power of the study allows the exclusion of an effect of drugs in general, including polypharmacy, on constipation. The study also indicates an unfavourable effect of drugs with markedly anticholinergic effects (OR 3.7). Some associations between groups of drugs and constipation with high OR but not statistically significant associations (benzodiazepine derivatives, other antidepressants, natural opium alkaloid, propionic acid derivatives, and drugs with markedly anticholinergic effects, in addition to nonpharmacological interventions like activity of daily living.Use of drugs in general, including polypharmacy, was not associated with constipation in elderly in nursing homes, but some specific groups of drugs were. Therefore, in elderly with constipation, focus should be on specific groups of drugs and not drugs in general. This study indicated that focus should be on


In view of the rapid geographic spread and the increasing number of confirmed cases of novel influenza A(H7N9) virus infections in eastern China, we developed a diffusion model to spatiotemporally characterize the impacts of bird migration and poultry distribution on the geographic spread of H7N9 infection.Three types of infection risks were estimated for 12 weeks, from February 4 to April 28, 2013, including (i) the risk caused by bird migration, (ii) the risk caused by poultry distribution, and (iii) the integrated risk caused by both bird migration and poultry distribution. To achieve this, we first developed a method for estimating the likelihood of bird migration based on available environmental and meteorological data. Then, we adopted a computational mobility model to estimate poultry distribution based on annual poultry production and consumption of each province/municipality. Finally, the spatiotemporal risk maps were created based on the integrated impacts of both bird migration and poultry distribution.In the study of risk estimation caused by bird migration, the likelihood matrix was estimated based on the 7-day temperature, from February 4 to April 28, 2013. It was found the estimated migrant birds mainly appear in the southeastern provinces of Zhejiang, Shanghai and Jiangsu during Weeks 1 to 4, and Week 6, followed by appearing in central eastern provinces of Shandong, Hebei, Beijing, and Tianjin during Weeks 7 to 9, and finally in northeastern provinces of Liaoning, Jilin, and Heilongjiang during Weeks 10 to 12.In the study of risk caused by poultry distribution, poultry distribution matrix was created to show the probability of poultry distribution. In spite of the fact that the majority of the initial infections were reported in Shanghai and Jiangsu, the relative risk of H7N9 infection estimated based on the poultry distribution model predicted that Jiangsu may have a slightly higher likelihood of H7N9 infection than those in Zhejiang and Shanghai, if we only take the probability of poultry distribution into consideration.In the study of integrated risk caused by both bird migration and poultry distribution, the higher risk in southeastern provinces occurred during the first 8 weeks, and that in central eastern provinces appeared during Weeks 8 to 12, and that in northeastern provinces since Week 12. Therefore, it is necessary to regulate the poultry markets as long as the poultry-to-poultry transmission is not so well understood.With reference to the reported infection cases, the demonstrated risk mapping results will provide guidance in active surveillance and control of human H7N9 infections by taking intensive intervention in poultry markets. Please see Additional file The emergence of a novel influenza A(H7N9) virus have drawn the global concerns about the possibility of a new influenza pandemic in human society ,2. UntilDue to the rapid geographic spread and the increase of confirmed cases, it would be necessary and desirable to estimate the risks of H7N9 infection in different provinces/municipalities of eastern China. However, at present it remains quite challenging to build comprehensive transmission models for H7N9 virus because the mode of transmission has not yet been well understood. For example, based on a report by European Certre for Disease Prevention and Control on April 19, 2013, there is no evidence of sustained human-to-human transmission. Moreover, based on an official statement from the Chinese Ministry of Agriculture, only 39 samples are positive for the H7N9 virus among 47,801 tests samples taken from live animal markets, farms, and slaughter houses. This implies that there is even no convincing evidence of sustained poultry-to-poultry transmission. Therefore, in this paper, we consider the possibility that infected birds/poultry in one region cause infections in another due to bird migration and/or poultry distribution. Specifically, we use the likelihood of bird migrating to (or the relative quantity of poultry being distributed to) certain provinces/municipalities to infer their risks of human infection.In this paper, we present a diffusion model to infer the geographic risks of H7N9 infection by spatiotemporally characterizing both bird migration in eastern China and poultry distribution in mainland China. Specifically, we pay attention to investigating three types of risk: (i) the risk caused by bird migration, (ii) the risk caused by poultry distribution, and (iii) the integrated risk caused by both bird migration and poultry distribution. First, to determine the impacts of bird migration, we develop a method for estimating the likelihood of bird migration from one location to another. Then, to quantify the impacts of poultry distribution on H7N9 spread, we adopt a computational mobility model to estimate the poultry distribution among provinces/municipalities in mainland China based on their annual poultry production and consumption volumes. Accordingly, for each type of infection risk, we aim to infer the potential spatiotemporal patterns of H7N9 infection. Finally, we discuss the limitations and potential extensions of our models in more complicated transmission situations.In order to characterize bird migration from south regions to north regions during spring season, we consider 12 provinces that belong to bird migration routes of eastern China . In the To estimate the poultry distribution in mainland China, we collect the data on the annual poultry production and consumption of each province/municipality from China Animal Husbandry Yearbook 2012 and China Statistical Yearbook 2012 .K: In this paper, we pay special attention to the geographic spreading of H7N9 infection in eastern China. Because at the present time there is no convincing evidence of sustained human-to-human or poultry-to-poultry transmission, we do not attempt to build a comprehensive model for H7N9 transmission. Nevertheless, we focus on inferring the risk of H7N9 infection in different locations by characterizing the impacts of bird migration and poultry distribution from one location to another. Our model is based on the concept of reproduction matrix I represents the number of infections, and K characterizes the migration of birds and/or distribution of poultry in mainland China. Note that in Wallinga et al’s study [K is known as the “next generation matrix” for deterministic models [where ’s study , the repc models , and “mec models .K is twofold. First, the poultry distribution matrix among 31 provinces/municipalities are deterministic, which is estimated based on statistical data about poultry production and consumption in each province/municipality. Second, bird migration is dependent on many time-varying factors . Therefore, we treat bird migration as a stochastic process to calculate the likelihood of bird migration. Accordingly, we investigate three types of potential risk caused by either bird migration, poultry distribution, or both of them.The estimation of In view of the lack of accurate data for characterizing bird migration along the migration routes in eastern China, we adopt a computational approach to inferring the likelihood of bird migrating among different regions from the available environmental and meteorological data.N to denote the total number of considered provinces and i or j to represent the index of each province. During the spring season , birds in eastern China mainly migrate from south to north. Here, we use mij to describe the likelihood of bird migration between two provinces i and j. In order to estimate mij, we consider three factors that may affect bird migration: (i) wetland area Li, (ii) traveling distance dij, and (iii) temperature Ti. Specifically, we consider the likelihood for bird migration between two provinces are proportional to the area of wetlands, and inversely proportional to the traveling distance. In addition, bird migration occurs in certain regions with suitable temperature In what follows, we use mij between provinces i and j as follows: Analogous to the gravity law of mobility patterns ,13, we candVar describes the variance between the temperatures Ti and Tj with suitable temperature μ is a scaling constant. The matrix M with the elements of mij is the overall likelihood matrix that describes the probability of bird migration among different regions.where si and consumption ci of each province/municipality i, i.e., i∈S|si−ci>0}), we calculate the probability of one unit of poultry flowing from i to any j∉S as follows: We estimate the poultry distribution among different provinces/municipalities based on their annual production and consumption. First, we normalize the production ’s study , we treaci and cj represent the normalized consumption of poultry in locations i and j, respectively; cij refers to the total normalized consumption in locations within the circle of radius rij certred at i (excluding the consumption in i and j). Here, rij is the adjacent distance of different provinces/municipalities in mainland China. Then, we calculate the relative impacts wi of each i∈S to others as follows: where K, each element kij∈K can be calculated as kij=wjpji.Based on the definition of reproduction matrix i at time window t−1 migrating to j at time window t can be calculated as follows: There are two steps to integrate the impacts from both bird migration and poultry distribution on each province/municipality. First, based on the estimated bird migration matrix, we calculate the probability of migratory birds that will be in a specific region during a specific time window . Specifically, the probability of birds located in j to l at time window t can be calculated as follows: Second, after calculating the integrated probability of bird migrating from different regions  reported their observations of bird migration. And predicted the peak would appear in late Aprild.The estimated spatiotemporal patterns of bird migration be well matched with the observations of the public news released by local media, reporting the appearance of migratory birds in their regions. For example, researchers reported that the migratory birds nesting in Yangtze River Delta region  would leave for north in earlier February until mid/late MarchBased on the poultry production and consumption in 31 provinces/municipalities of mainland China, we can estimate the probability of poultry distribution from one province/municipality to another. Based on the estimation, we can further examine the impacts of each province/municipality on the geographical spread of H7N9 infection. In this paper, since the majority of the confirmed infections in the early stage were reported in Shanghai and Jiangsu province, we assume that virus may come from these two regions. Because Shanghai’s annual consumption is larger than its annual production, Shanghai does not distribute poultry to other regions. Therefore, we show the relative risks of H7N9 infection estimated only by poultry distribution, e.g., from Jiangsu  on the diagonal; A is a diagonal matrix representing the per contact probability of acquiring infection at each location; B is a matrix referring to the poultry distribution and bird migration from one location to another; C is a diagonal matrix with the location-specific per contact of probability of transmitting infection on the diagonal. Further, if we do not know the epidemiological properties of H7N9 virus for poultry, we can assume that the diagonal values of matrices A (or C) are identical, i.e., the acquisition probability of H7N9 and the force of infection are the same for the poultry at different locations. By doing so, we can study the stable state of the model after the transmission period is finished without considering human interventions. Moreover, we can also suggest appropriate intervention strategies based on the properties of the reproduction matrix [Here, n matrix .At the present time, we still do not have enough information to build comprehensive transmission models for H7N9, for instance: (i) the source of the transmission has not yet been confirmed, (ii) the mode of transmission has not yet been well understood, and (iii) there is even no convincing evidence of sustained poultry-to-poultry transmission. Due to these limitations, in this paper, we only consider a diffusion model by assuming that there is no human-to-human and poultry-to-poultry transmission. Specifically, we use the geographic diffusion of birds or poultry (due to either migration or distribution) to infer the risk of H7N9 infection. In doing so, the estimated risk may not exactly reflect the confirmed cases of human infection. This is because human infections may depend on many other issues, such as the human movement from one region to another, and the mode of birds-to-poultry, poultry-to-human, and bird-to-human transmission. Moreover, the estimated potential risk in each region is earlier than the reported human infections. This is because it may take a period of time for an infected individual develop symptoms. Once more information is available, we are ready to address the above-mentioned limitations by designing more accurate models.Up to time when this paper is written on April 22), the number of cases of H7N9 infection is still increasing in eastern China. The source and the mode of transmission have not yet been confirmed. Some preliminary studies have suggested that influenza A(H7N9) virus may spread when humans contact with poultry population or poultry products . Experts have proposed that bird migrations during the spring season in eastern China may play a significant role in the emergence of infection cases in different regions. In view of these reasons, in this study, we have estimated the relative risks of influenza A(H7N9) virus by incorporating the information about both bird migration and poultry distribution in eastern China. Particularly, we produced the potential risk map based on the integration of bird migration and poultry distribution, at least three types of risk for human infection with influenza A(H7N9) virus (Figures 2, the nuBy characterizing the geographic patterns of bird migration and poultry distribution in eastern China, we have outlined three types of potential risk of human infection for different regions from February 4, 2013 to April 28, 2013. The results demonstrated in this study can provide new tools for public health policy makers to perform the active surveillance and control of H7N9 infections.aSource: http://sh.eastday.com/m/20121130/u1a7029021.html; http://news.sina.com.cn/o/2013-02-27/074026371385.shtmlbSource: http://henan.china.com.cn/news/china/201304/ 278532HXCZ.html; http://hebei.sina.com.cn/news/s/2013- 04-10/110844208.html; http://www.ha.chinanews.com/html/ yiliaoweisheng2012/dajiankang/2013/0416/15394.htmlcSource: http://ent.xinmin.cn/2013/04/13/19712929.html; http://news.sina.com.cn/c/2013-04-13/184526817748.shtml; http://kx.zxxk.com/Article/238489.htmldSource: http://epaper.hilizi.com/shtml/bdcb/20130413/ 23965.shtml; http://liaoning.nen.com.cn/system/2013/04/ 11/010314017.shtml; http://www.dongbeiya.org/ShowArticle. aspx?ID=4127The authors declare that they have no competing interests.JL and XZ conceptualized the paper, BS and SX prepared the first draft, and GY, JL, and XZ participated in the drafting and editing of the paper. All authors read and approved the final manuscript.Multilingual abstracts in the six official working languages of the United Nations.Click here for file