Pneumonia is a leading cause of morbidity and mortality among adults worldwide; however, the risk factors for community-acquired pneumonia in Africa are not well characterized.The authors recruited 281 cases of community-acquired pneumonia and 1202 hospital controls among patients aged ≥15 years who attended Kilifi District Hospital/Coast Provincial General Hospital in Kenya between 1994 and 6. Cases were admissions with an acute illness with ≥2 respiratory signs and evidence of consolidation on a chest radiograph. Controls were patients without signs of pneumonia, frequency matched by age, sex and hospital. Risk factors related to socio-demographic factors, drug use, clinical history, contact patterns and exposures to indoor air pollution were investigated by questionnaire, anthropometric measurements and laboratory assays. Associations were evaluated using a hierarchical logistic regression model.Pneumonia was associated with human immunodeficiency virus (HIV) infection , anemia , splenomegaly , recent history of pneumonia , history of pneumonia >2 years previously , coryza in the 2 weeks preceding hospitalization , current smoking , use of khat , use of snuff  and contact with several animal species. Presence of a Bacillus Calmette-Guerin (BCG) scar was associated with protection . The risk factors varied significantly by sex.Pneumonia in Kenyan adults was associated with global risk factors, such as HIV and smoking, but also with specific local factors like drug use and contact with animals. Intervention strategies should account for sex-specific differences in risk factors.The online version of this article (10.1186/s41479-017-0041-2) contains supplementary material, which is available to authorized users. Community-acquired pneumonia (CAP) is a common cause of morbidity and mortality worldwide. In Africa, CAP is associated with an in-hospital mortality of 6–15% among adults, as reported from hospital-based studies .Studies from high-income countries have identified several risk factors for CAP including smoking –7, age >Different environmental and socio-economic circumstances in sub-Saharan Africa are likely to give rise to different risks for pneumonia, including younger age at presentation, which has been observed . There iThis case–control study was conducted at Kilifi District Hospital (KDH), and Coast Provincial General Hospital (CPGH) in Kenya among patients who presented either to the outpatient clinic or the casualty department. Cases were adult patients aged ≥15 years who were admitted with CAP. CAP was defined as an acute illness (<14 days), characterized by at least two respiratory symptoms  and evidence of consolidation on a chest radiograph. The radiographs were read by a study physician and later confirmed, independently, by a consultant thoracic radiologist.Controls were adults aged ≥15 years who presented to the outpatient clinics of the same hospitals who did not meet the clinical case definition of CAP. They were frequency matched on age, sex and hospital of presentation in a ratio of 4:1 with cases. Controls with diagnoses that were strongly associated with the exposures of interest  were excluded.A target sample size of 1500 (300 cases: 1200 controls) was sought for the study. The study was powered to detect relevant odds ratios using a range of prevalence estimates for a wide variety of exposures included in the study , malaria parasites by microscopy, and sickle cell status. A full hemogram, glycosylated hemoglobin (HbA1C) test and blood grouping (ABO) were also performed.p-value of <0.1 to include in the intermediary multivariable model. Risk factors contributing significantly  to the intermediary multivariable models were subsequently included in a final multivariable model. Backward stepwise analysis was used in each of the multivariable analyses. In addition, prompted by the presence of sex-specific exposures (e.g. pregnancy) and several instances of effect modification due to sex, two sex-restricted models were developed following a similar hierarchical process.Associations with case status were analyzed using logistic regression, adjusting for the matching variables  in each model. Because this was the first study of risk factors for pneumonia in an unselected population in Africa, a wide range of potential exposures were explored. A hierarchical process was used to define the final model, whereby related exposures were first examined in intermediary models before the best representative exposures were selected for a final, multi-variable model. The intermediary models examined 5 categories of related variables Table . Within Some variables, e.g. BMI and presence of a scar following Bacillus Calmette-Guerin (BCG) vaccine, were introduced shortly after the study had begun, leading to some missing data .Between March 1994 and May 1996, 301 cases and 1202 controls were recruited. After review of the chest radiographs by the radiologist, 20 of the original cases were excluded as non-CAP. Among the 281 remaining cases, 177 (63%) were male and 22 (7.8%) were aged ≥55 years. The matching achieved a similar distribution of age, sex and route of recruitment across cases and controls  was more common among cases; cooking for oneself was more common among controls . Current smokers and ex-smokers had a 2-fold increased risk of pneumonia compared to never-smokers; recent ex-smokers had a 10-fold increase in risk  of alcohol consumers and 97% (312/321) of current smokers. Females were the largest consumers of snuff , but did not report consumption of 07 of alcExposure to animals was reported in 43% (519/1202) of the controls. Significant associations in the intermediary model included exposure to monkeys, chickens, ducks and goats, of which only the latter two remained significant in the final model  and khat, which are particular to this population.Smoking is a well-established risk factor for CAP , 16. TheCatha edulis Forsk, is a shrub whose leaves and twigs are chewed for their stimulant effect and there is no obvious biological explanation of this association. Overall, however, drug use appeared to be a major avoidable risk factor.Use of snuff and khat are novel associations found among women and men, respectively. Snuff use is a risk factor for oral cancer , while kHistory of coryza (representing URTIs) was associated with pneumonia . Viral UPatients with a previous history of pneumonia were at a higher risk of CAP in the current study, especially those whose initial episode occurred more than 2 years previously; in previous studies the risk was higher for more recent episodes . Childhomatatus (minibuses for public transport) and frequent visits to a nightclub, which are all likely to be indicators of higher SES, were associated with a reduced risk of disease despite also implying more human contact and therefore, potentially, a greater risk of infection.The authors found that low social economic status (SES), measured directly by level of income and indirectly by proxy measures like the materials used for house construction, was not associated with pneumonia. However, higher education, increased use of Indoor air pollution is a leading risk factor for respiratory diseases , includiAs in other studies from developed countries , 38, HIVMycobacterium tuberculosis was found in 9% [Evidence of BCG vaccination was associated with a 70% reduction in risk of pneumonia among men. The effect in women was smaller and non-significant. In the complementary study of pneumonia etiology conducted in the same cases, nd in 9% . Severalnd in 9% , 41. Fornd in 9% . These bnd in 9% . The WHOnd in 9% .The limitation of this study is that it is an analysis of historical data and therefore, due to changes in epidemiology in the ensuing years, the relative importance of some of the observations may have changed. First, several risk factors that were identified have changed in prevalence; for example, HIV-infection and malaria have both declined and smoking has increased. While this alters the public health importance of these factors and invalidates any attempt to calculate the current population-attributable fraction for pneumonia, it does not invalidate the etiological association.Second, temporal changes may have modified the effect of risk factors; for example, the introduction of anti-retroviral therapy reduces the risk of pneumonia in HIV-infected individuals , 46. ThiThe authors believe this is the only case–control study on the risk factors of CAP ever conducted in an unselected adult population in Africa. As the major risk factors were unknown at the outset, the study examined many different exposures simultaneously. Although this leads to a risk of false-positive associations, the purpose was to scan a broad range of potential risks that could be explored and confirmed in subsequent focused studies. As such, several key risk factors have been identified that are amenable to vaccination or to changes in lifestyle habits. Furthermore, in this setting the study has demonstrated that the risk factors for pneumonia among men and women were sufficiently different that they should be investigated and managed separately.This study was designed as a hypothesis-generating study. It has identified a number of potential risk factors that suggest that interventions that induce changes in lifestyle habits  may have a beneficial impact on the incidence of pneumonia in this population—these are worth considering in confirmatory studies. Previous history of pneumonia was the strongest risk factor of all in this study, suggesting a target for post-discharge vaccination.


The competency for interacting with alcohol is a highly useful Educational Psychology model for preventing and for understanding the different behavioral levels of this interaction. Knowledge of facts, concepts and principles about alcohol use, self-regulated behavior, and attitudes toward alcohol are predictive of adequate interaction with alcohol. The objective of this study was to empirically evaluate this postulated relationship. A total of 328 Spanish adolescents participated, between the ages of 12 and 17. All were enrolled in 1st–4th year of compulsory secondary education, in the context of the ALADO Program for prevention of alcohol intake in adolescents. An ex post facto design was used, with inferential analyses and SEM analyses. Results show an interdependence relationship, with significant structural prediction between the behavioral levels defined and the level of alcohol intake, with principles, self-regulating control and attitudes carrying more weight. Analyses are presented, as are implications for psychoeducational intervention using preventive programs based on this competency model. Alcohol abuse in adolescents is an old problem  , procedural  and attitudinal . In the specific case of educational prevention of alcohol intake, this approach means delimiting the level of subcompetencies that adolescents possess at each level.An individual may be considered ise Roe, , 2003. Fise Roe, . This giconceptual subcompetency: adolescents' knowledge and their perception of the risk involved with alcohol is different from that of adults, and this in itself is a factor that predisposes toward some dangerous or inadequate behavior. All epidemiological studies agree that adolescent alcohol use in our day is abusive, and the authors conclude that this comes from adolescents' not understanding the real risks. For this reason it is very important to collect their opinions and what they conceive to be facts, concepts and principles in regard to alcohol. According to earlier research studies, adolescents' knowledge and principles center on reasons to justify the use of alcohol and the consequences of alcohol use , procedural knowledge  and attitudinal knowledge  will be mutually determined. Finally, they will determine the level of adjustment in interacting with alcohol.To determine any interdependence relationships between the low-medium-high level of each subcompetency with respect to the other subcompetencies, and to adjustment in interacting with alcohol. Consequently, Hypothesis 2 established that adjustment in interacting with alcohol (nonconsumption) will be determined by conceptual type factors (more principles than facts/concepts), procedural type  and attitudinal type, although the latter are mediated by procedural variables.To establish any structural predictive relationships between the different subcompetencies. In this case, n = 106), (2) surrounding neighborhoods, from a medium-low social stratum (n = 101) and (3) outlying, marginalized population areas with compensatory education, from a low social stratum (n = 121). The homeroom teachers from every group participated voluntarily in the experiment, having been invited by the School Psychology adviser of the local Teacher Development Center. Participating students were between the ages of 12 and 17 years  and were enrolled in compulsory secondary education (grades 7–10) at one of three public secondary schools. This age range was selected for methodological purposes, making it possible to form two groups, the 12- to 14-year-olds (n = 207), corresponding to the first stage of adolescence , and the 15- to 17-year-olds (n = 121), corresponding to the second stage of adolescence (adolescence per se). The final sample size from which all measurements were taken contained 328 subjects. Of these, 178 were male (54.3% of the sample) and 150 were female (45.7% of the sample). The mean age of the sample was 13.82 years, with a standard deviation de 1.19.The population under study were students from public secondary schools in a southern province of Andalusia (Spain). In order to include different types of schools in this investigation, schools were selected from three types of urban areas: (1) center of town, from a medium-high social stratum  = 2767.595; p < 0.001. Confirmatory Factor Analysis (CFA) showed adequate indicators for the Default model: χ2 = 1612.957, Degrees of freedom (779–117): 662, p < 0.001; all the variances are significant for p < 0.001; NFI = 0.865; RFI = 0.848; IFI = 0.914; TLI = 0.902; CFI = 0.913; RMSEA = 0.025; HOELTER model = 1095 (p < 0.05),1138 (p < 0.01). See Figure The scale SRQ, Self-Regulation Questionnaire  showed an index KMO = 0.985; Bartlett's Sphericity Test (df = 210) = 3603.882; p < 0.001. Confirmatory Factor Analysis (CFA) showed adequate indicators for the Default model: Chi-square = 408.448, Degrees of freedom (252–64):188, p < 0.001; all the variances are significant for p < 0.001; NFI = 0.894; RFI = 0.870; IFI = 0.940; TLI = 0.925; CFI = 0.9393; RMSEA = 0.022. However, this structure does not concur with others found in other samples  = 529.335, p < 0.001. Confirmatory Factor Analysis (CFA) showed adequate indicators for the Default model: Chi-square = 58.574, Degrees of freedom (44–24): 20, p < 0.001; all the variances are significant for p < 0.001; NFI = 0.903; RFI = 0.826; IFI = 0.34; TLI = 0.8; CFI = 0.2; RMSEA = 0.0; HOELTER model = 1349. See Figure The scale for We used the Escala de Ajuste en la interacción con el alcohol [Scale of Adjustment in interacting with alcohol], which contains four items (Alpha = 0.915). This scale belongs to the Inventario de Evaluación de conocimientos, actitudes e interacción con el alcohol , through an online utility created for this purpose . Specifically, these data correspond to the project baseline, having been collected in September-October, 2008. Previously, cooperation had been requested from the Teacher Development Center, from the students' parents and from the School Board, for their participation. The project was approved by the University Bioethics Commission (University of Almería). The students participated voluntarily. The parents were informed in writing. As the participants in the Project were minors, both the parents and school administrators gave written informed consent for the study. All data was collected in accordance with the principles of the Psychologist's Deontological Code and the Spanish Data Protection Act.Data collection instruments were applied over the course of the school year 2009-10, within the framework of the ex-post facto methodological design was used. Relationships were measured just as they occurred in the natural environment, without any treatment, using inferential and structural analyses based on the Presage-Process-Product Model  related to alcohol intake.Procedural subcompetency: Personal self-regulation skills, referring to planning and behavioral action control.Attitudinal subcompetency: Attitudes and values toward alcohol intake.Product variables, referring to interaction with alcohol,4. Adequate behavior in interaction with alcohol: no contact.direct effects in the form of beta coefficients: less than 0.05 is considered too small to be meaningful, above 0.05 is small but meaningful, above 0.10 is moderate, and above 0.25 is large. For indirect effects, we use Kenny's  were carried out using SPSS (v. 23.0) for Windows. For levels of the independent variable self-regulation, cluster analysis was used, obtaining three levels: low, medium and high. AMOS (v. 23.0) for Windows was used for the structural validity analysis of each inventory and for constructing the structural prediction model. To interpret the CFA and SEM model fit, we focused on the comparative fit index (CFI) and the root mean square error of approximation (RMSEA). CFI values equal to or more than 0.90 and 0.95 respectively were taken to indicate acceptable and close fit to the data  = 2.451 (Pillai), p < 0.01, n2 = 0.085, power = 0.897]. Partial effects were shown in attitude  and in adjustment in alcohol consumption . No significant effect appeared for the variables planning and control (components of self-regulation). See Table A main effect appeared, statistically significant, of the IV ge . Partial effects were a significant effect of level of self-regulation on knowledge of facts , on knowledge of concepts , on knowledge of principles  and on attitudes . Finally, a significant effect appeared in the variable adjustment in alcohol use . See Table A statistically significant main effect appeared for the IV on . Partial effects showed a significant effect of the level of attitude toward alcohol on knowledge of facts , on knowledge of concepts , and on knowledge of principles . Also, the level of attitude toward alcohol appeared with a significant partial effect on the degree of self-regulatory control . Finally, a significant effect appeared in the variable adjustment in alcohol use, but without clear directionality . See Table A main effect appeared, statistically significant, in the IV The results of structural analysis or pathway analysis (SEM) showed an acceptable model of relationships between variables (model 3). The relationship parameters of both models are set out below. See Table facts (F) was a significant positive predictor (0.63) of the latent variable Knowledge of concepts (C), and this variable is positively predicted (0.63) for latent variable knowledge of principles (P). In addition, the facts (F) variable (0.63) and the principles variable (P) are positively predicted (0.28) of latent variable interaction with alcohol (INT). Complementarily, the latent variable planning of behavior (PL) was a significant predictor (0.36) of the latent variable attitudes (A). At the same time, self-control of behavior (CONTR) was a positively predictor (0.18) of latent variable interaction with alcohol (INT). Complementarily, the latent variable attitudes (A) predicted a positive and significant relationship (0.20) with the latent variable interaction with alcohol (INT). All the variances of errors were significant (p < 0.001). Table direct effects of the variables inherent in the model.This predictive linear model establishes that latent variable Knowledge of multiple indirect predictions among the variables. This predictive linear model establishes that latent variable knowledge of facts (F) was a positive significant predictor (0.440) of the latent variable knowledge of principles (P), and a positive predictor (0.124) of latent variable interaction with alcohol (INT). The latent variable knowledge of concepts was a positive predictor (0.192) of the latent variable interaction with alcohol (INT). The latent variable knowledge of principles was a positive predictor (0.072) of the latent variable interaction with alcohol (INT).The model also contributed the existence of facts (F) was another indirect, positive predictor of items of C, P, and INT; the latent variable knowledge of concepts (C) was an indirect, positive predictor of items of C, P, and INT; the latent variable knowledge of principles (P) was indirect, positive predictor of items of INT.The latent variable knowledge of planning of behavior (P) was an indirect, positive predictor of items of attitudes (A) and interaction with alcohol (INT); the procedural and latent variable self-control of behavior (CONTR) was an indirect, positive predictor of items of interaction with alcohol (INT).The procedural and latent variable attitudes toward alcohol (A) was an indirect, positive predictor of items of interaction with alcohol (INT). See Table Complementarily, the attitudinal and latent variable The final model is graphically represented in Figure first objective of this study was to determine any interdependence relationships between the low-medium-high level of each subcompetency with respect to the other subcompetencies, and to adjustment in interacting with alcohol. Thus, Hypothesis 1 established that the low-medium-high level of conceptual knowledge , procedural knowledge  and attitudinal knowledge  would be mutually determined, and that finally, these levels would determine the level of adjustment in interacting with alcohol.The conceptual competence  determines the level of attitudes toward alcohol and the degree of adjustment in interacting with alcohol, that the level of procedural competence (self-regulation) determines the level of the principles and attitudes, and that the level of attitudinal competency (attitudes) differentially and inversely affects the level of knowledge about alcohol (facts and concepts), while directly affecting the degree of principles and of self-control. These results offer support for the competency model, by showing how each type of learning affects the others. One especially interesting result was that concept learning affected the degree of attitude acquisition, but not the degree of acquisition of self-control. However, the level of self-regulation did affect the learning of principles and attitudes toward alcohol. This represents more evidence on the importance of this behavioral level, corroborating that attitudes also affect the acquisition of principles and the degree of self-control. The second part of the hypothesis was also partially validated, showing that only the level of conceptual competence (principles) was accompanied by a higher level of adjustment. This result reinforces the idea that each variable analyzed, on its own, has a limited effect in determining the level of adjustment.This hypothesis was partially confirmed. Results provided evidence that the level of second objective was to establish any structural prediction relationships between the different subcompetencies, with Hypothesis 2 affirming that adjustment in interacting with alcohol (nonconsumption) would be determined both by conceptual type factors (more principles than facts/concepts), procedural type  and attitudinal type, although the latter are mediated by the procedural variables. In this case, the hypothesis was consistently fulfilled, with the appearance of a significant SEM model that showed different direct effects. Knowledge of facts affects concepts and these in turn affect the principles elaborated; knowledge of facts and of principles are the variables that most affect adjustment in interacting with alcohol. In addition, self-regulation affects adequate interaction via attitudes, and directly through self-control. Finally, attitudes also affect adjustment. However, the indirect effects are what has shown that all the levels of competencies—conceptual , procedural (planning and self-control) and attitudinal (attitudes)—are joint determinants in the degree of adjustment for nonconsumption of alcohol. These results are consistent with the prior evidence that has shown in part the importance of each of these variables : to have assimilated the information about alcohol and its effects on the immature adolescent brain , of attitudes and values : to have skills and meta-skills of self-regulated behavior  the acquisition of n Spear, ; (2) themethodological contribution, with respect to the type of analyses carried out. Going beyond the usual descriptive or classic association strategies, a two-fold strategy was applied in order to validate the causal relations consistently, using inferential analysis and structural path analysis. The inferential analysis has shown clear interdependence relationships between the levels of the variables. Path analysis, based on the previous inferential analyses, has corroborated the multidirectionality of the proposed causations, producing an empirical model of this competency consistent with the one proposed, and offering a structural foundation for future interventions  The concept of competence is multidimensional  are trained to a higher level of self-regulation and they are protected from environments with excessive information about alcohol. The opposite would occur in dysregulatory educational contexts , where adolescents are allowed to have more direct contact with alcohol consumption, and early alcohol intake, or dysregulation, is encouraged. These results are consistent with the effect of the educational context at school, as seen in a previous dissertation report  an eminently informational thrust, for learning facts and concepts about the problem ; and (2) the more developmental thrust, referring to learning behavioral principles, behavior management skills or self-regulation, and the motivational or attitudinal aspect. Conceptual, procedural and competence would be impregnated with a holistic model of education, approaching each level of competency as different and needing to be approached differently. This question therefore deserves some profound analysis. In the first place, one must reinforce the importance of principles in alcohol use—norms, standards and goals for behavior (Pons et al., self-regulatory behaviors—as a procedural meta-skill—is a must in educational programs for primary prevention of alcohol intake, given that this behavioral level has a clear effect on adjustment, as has been demonstrated in prior evidence from secondary and tertiary therapeutic programs (Fernández et al., These results corroborate the idea that limitations. First, the effect of gender and of year in school were not analyzed, in an effort to streamline the design and show the relationships presented here, given that these effects were reported in an earlier research report (Marcos, Theory of Self- vs. External-Regulation™ (de la Fuente, This study is not free of  Marcos, . However Marcos,  as is exIn the future, it would be desirable to perform research that incorporates the effect of other variables that recent research has identified as important in managing stress—an important aspect in adolescence, with all its personal, academic and social changes (González et al., JdlF: Research design, data analysis and results writing; IC: Coordinator of the R & D Project and the Program; MS: Research of the R & D Project and the Program; FP: Program implementation and data collection; AG: Manuscript Review and Writing; JF: Writing and review in English.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Depressed patients had risks of non-adherence to medication, which brought a big challenge for the control of tuberculosis (TB). The stigma associated with TB may be the reason for distress. This study aimed to assess the psychological distress among TB patients living in rural areas in China and to further explore the relation of experienced stigma to distress. This study was a cross-sectional study with multi-stage randomized sampling for recruiting TB patients. Data was collected by the use of interviewer-led questionnaires. A total of 342 eligible and accessible TB patients being treated at home were included in the survey. Psychological distress was measured using the Kessler Psychological Distress Scale (K10). Experienced stigma was measured using a developed nine-item stigma questionnaire. Univariate analysis and multiple logistic regression were used to analyze the variables related to distress, respectively. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to present the strength of the associations. Finally, the prediction of logistic model was assessed in form of the Receiver Operating Characteristic (ROC) curve and the area under the ROC curve (AUC). According to the referred cut-off point from K10, this study revealed that 65.2% (223/342) of the participants were categorized as having psychological distress. Both the stigma questionnaire and the K10 were proven to be reliable and valid in measurement. Further analysis found that experienced stigma and illness severity were significant variables to psychological distress in the model of logistic regression. The model was assessed well in predicting distress by use of experienced stigma and illness severity in form of ROC and AUC. Rural TB patients had a high prevalence of psychological distress. Experience of stigma played a significant role in psychological distress. To move the barrier of stigma from the surroundings could be a good strategy in reducing distress for the patients and TB controlling for public health management. Tuberculosis (TB) is a chronic infectious disease that influences not only physical health, but also the psychological and social well-being of patients. Psychological co-morbidity prolongs the course of illness, involves lengthier diagnostic procedures, increases treatment costs, and reduces treatment efficacy ,2,3. A mA Pakistani study found that up to 46% of TB patients had depression . SeveralWith regard to the studies about different variables related to distress in TB patients from different regions, some discovered that gender ,9, age, Stigma has been long studied by researchers, among whom Goffman’s work is more concerned with the stigmatizing consequences on the individual. According to this, when a disease label is attached to a patient, the label could have the power to spoil the sufferer’s identity . As to tChina is still among the countries with the highest burden of TB, despite the great progress that has been made in controlling TB over the past decades . In ChinThis study was part of a survey on rural TB patients in Shandong Province, which is located in eastern China with a population of nearly 100 million and unbalanced economic development: poor in the west and rich in the east. First, three regions based on the economic level were sampled by using multi-stage random sampling. Then, two counties in each sampled region were selected, and six rural towns in each sampled county were selected randomly. Therefore, 36 towns in the six sampled counties were chosen as the survey sites. In the end, patients were cluster-sampled from the 36 selected towns, where all the eligible TB patients were included as samples for the study. The sampling method has been described previously in another paper . In ChinThe developed questionnaire consisted of sociodemographic characteristics, medical conditions, questions to measure experienced stigma, and a scale to measure psychological conditions. Sociodemographic characteristics included age, gender, living with a partner (yes/no), school years, and self-reported household income (high/middle/low) in comparison to local level, while medical conditions were presented in the form of treatment duration, and self-rated illness severity (no/minor/moderate/severe). Based on the mean values, continuous variables: age, school years, and treatment duration were further dichotomized into binary variables: age groups (old/young), education levels (high/low), and treatment length (long/short), in case variables in the original format or in multi-categorized format showed no statistical significance in models.In this study, experienced stigma was conceptualized as individual experiences from treatment by family members, neighbors, and friends in daily life since the diagnosis was confirmed. Based on the item-response theory in identifying items that made maximal discrimination of respondents and literatures’ reviews about stigma scales ,24,25, tFor the stigma questionnaire in this study, the total Cronbach’s α was 0.91, and the corrected item-total correlations were from 0.57 to 0.72, which indicated good reliability. Factor analysis extracted one factor with eigenvalue 5.14, which could explain 57.15% of the variance. The factor loadings ranged from 0.65 to 0.79.The five-point Likert Kessler Psychological Distress Scale K10) (Chinese version), which has 10-item questions measuring anxiety or depression and other psychological-related symptoms in the past four weeks , was use  and 95% confidence intervals (CIs) were used to present the strengths of the associations. Finally, the predictive capability of the logistic model was assessed adopting the Receiver Operating Characteristic (ROC) curve and the area under the ROC curve (AUC). The statistical significance p value was set at p < 0.05. Statistical Analysis System (SAS 9.2 version) software  was used in data analysis.After data collection, a database was set up using EpiData 3.1 . First, the level of psychological distress in accordance with the K10 definition was presented by sociodemographic characteristics, clinical conditions and experienced stigma. Second, univariate analysis was used to test the associations between the variables and psychological distress by adopting Pearson’s Chi-Square. Third, variables with In accordance with the sampling criteria, there were 372 patients in the sample frame, and among them, 342 tuberculosis eligible patients were included in this survey. Of these rural TB patients, 70.47% (241/342) of the surveyed were men. The average age was 53.57, ranging from 15 to 96, and 42.11% patients were above 60 years old. The patients had an average of 5.70 years of school education. With regard to marital status, 78.07% (267/342) of patients lived with a partner or spouse. 37.13% (127/342) of the patients ranked their household income to be below the local average level. The mean length of treatment was 3.11 months; while 73.68% (252/342) patients rated their illness severity as moderate or severe . Moreovep < 0.05) in relation to psychological distress. Meanwhile, marital status seemed to have no association with distress in this study  of the surveyed patients were categorized as having psychological distress. Women, older patients, patients with less schooling, and patients with a lower household income had higher percentages of psychological distress. However, further univariate analysis using the Chi-Square test showed that only school education and household income were statistical significant variables (is study .p < 0.0001) to psychological distress, while the treatment length (p > 0.05) was not. As for experienced stigma, 45.32% (155/342) patients had a high level of experienced stigma, and experienced stigma was found to be significantly associated with psychological distress as well, according to the Chi-Square test (p < 0.0001). In summary, univariate analysis revealed that school years, household income, illness severity, and experienced stigma were variables with statistical significance p < 0.05  in the multiple logistic model  or severe  in contrast to no or minor symptoms, and a high level of experienced stigma  compared to low level of experienced stigma , were siic model .The ROC curve is a plot of sensitivity (distress predicted to be distress) versus (1-specificity) (non-distress predicted to be distress), which could be used to measure and visualize the predictive capability of the logistic regression model by using experienced stigma and illness severity. Meanwhile, the area under the ROC curve (AUC) could be used as a model measure of goodness of fit. Having TB could impose a psychological burden on patients. In this study, TB patients in rural areas showed a high percentage of psychological distress by using K10, which could not be ignored. This study also found that experienced stigma was significantly associated with psychological distress among rural TB patients, and so was illness severity. The K10 and stigma questionnaire proved to have good reliability and validity. Both experienced stigma and illness severity could well predict psychological distress among TB patients in the logistic model.It is quite understandable that the degree of illness severity could make patients worried and frustrated, and this could result in distress. One study found that illness perception could predict depression in patients with heart disease . These fThere has been a scarcity of TB stigma assessment in quantitative methods , especiaThere is some evidence that gender, age, household income, and school years are significant variables to mental health in populations living in certain social settings, or coming from certain cultural backgrounds ,38,39, bEach study has its weaknesses, and for this study, this was cross-sectional, as related variables could not be inferred to as being causal, and would need further observation in a longitudinal study. Second, this study was conducted in rural areas, and findings could be explored for urban inhabitants or migrants in the cities. Moreover, the effects of stigma on distress may be underestimated among the complicated cases who were excluded from the study. Finally, other variables such as self-esteem may have mediating effects in mental health, and are worth further exploring in future studies.So far, China has conducted many health care measures to help TB patients, and this has contributed to the success of TB control. According to the World Health Organization (WHO) definition of health, there is no state of health that does not include mental health, implying that health must include psychological health. This is the same for the psychological health of TB patients. This study contributed to the characterization of the relation between stigma and psychological distress among rural TB patients, and this was the first exploration in this field in China.Rural TB patients presented a high level of psychological distress; both K10 and the stigma questionnaire proved to be good tools for measurements. Experienced stigma was significantly associated with psychological distress, which implied the necessities of reducing TB related stigma through intervention studies about attitude or behavior changes in public, and self-efficiency in patients.


The prosocial tendencies measure (PTM; Carlo and Randall,  Prosocial behavior is a “voluntary behavior intended to benefit another” , positive and negative affect (assessed in subset 2), neuroticism, extraversion, openness, agreeableness, conscientiousness  as well as their aspects (assessed in subset 3) were examined as correlates of the PTM-R subscales to evaluate sources of validity evidence. The rational to choose these constructs are very diverse. The reason to choose empathy was the relation of prosocial acts in third person economic games and empathy  were recruited via online questionnaire. Most of the participants were recruited during a university course from students of the course and filled in an online questionnaire. The questionnaire was presented with SoSci Survey  for answering questions. For more details about the data quality criteria, see Leiner  filled in an online version of the questionnaires.For this study, 285 student participants  fulfilled the data quality criteria.For this study, 360 participants were recruited and 339 participants  fulfilled the data quality criteria. The sample was diverse in terms of age and education, with the mode in students and young workers with academic background.In this study, 326 participants were recruited and 294 participants .The instruments used were the translated version of the PTM-R  and bayesian information criterion (BIC) for the comparison with the one-factor model. X2model, a fit index that should not be significant, is reported along with Root Mean Square Error of Approximation (RMSEA), indicating good fit if RMSEA ≤ 0.06  is reported, as well as Tucker-Lewis index indicating good fit the higher they are, with previous recommendations being higher than 0.95 , that should be ≤0.08  differences between groups are trivial in nature.The measurement invariance test was performed with the software package semTools , the SDS-CM (subset 1), PANAS Scales (subset 2), NEO-FFI (subset 2), and the BFAS (subset 3) as well as the Bonferroni adjusted correlations of the subscales of the PTM-R, the E-Skala (subset 1), the SDS-CM (subset 1), PANAS Scales (subset 2), NEO-FFI (subset 2) and the BFAS (subset 3) were also computed. Additionally, Bonferroni adjusted correlations between the PTM-R subscales and the amount of money offered in the one-shot dictator game were computed in subset 3.This study was carried out in accordance with the recommendations of “Ethical guidelines, The Association of German Professional Psychologists”  with written informed consent from all subjects. All subjects gave written informed consent in accordance with the Declaration of Helsinki. The protocol was not approved by any additional ethics committee, for it was simply a translation and combination of different self-report questionnaires in one study, combined with short self-reports or a dictator game. If the participants took part in the dictator game, a cover story was used, but they were told about this deception as soon as the task was over, as it is common practice in psychological experiments.F(1/1065) = 67.42, p < 0.001, partial η2 = 0.06], altruism  and compliant prosocial behavior  for women, and a higher score in public prosocial behavior in men .The means, standard deviations, and ranges for the subscales of the PTM-R are presented in Table ESM1. Participants scored highest on the altruistic prosocial behavior subscale, followed by compliant prosocial behavior, dire prosocial behavior, emotional prosocial behavior and anonymous prosocial behavior. The lowest scores were observed for public prosocial behavior. Multivariate ANOVA revealed a gender difference, showing a higher score in emotional prosocial behavior [Correlation of the subscales can be seen in Table r = −0.49), as well as the positive correlations between dire and emotional prosocial behavior (r = 0.40), compliant and dire prosocial behavior (r = 0.30) and compliant and emotional prosocial behavior (r = 0.35).The exploratory factor analysis led to a six-factor solution  = 542.38, p < 0.001; RMSEA = 0.053; CFI = 0.903; TLI = 0.886; SRMR = 0.058. Fit indices for the model in lavaan were identical except for CFI = 0.910, TLI = 0.904, SRMR = 0.0561, and RMSEA = 0.049 with 90% confidence interval 0.044–0.054. TLI and CFI did not support the model proposed, but RMSEA and SRMR indicate that this model had a good fit. The X2 did also not support the model, however it can be argued, that the sample size was very high, so “trivial differences between the sample and the estimated population covariance matrices are often significant because the minimum of the function is multiplied by N-1”  = 1,720.8, p < 0.001, with the target model having a better fit and X2. Also, AICsix−factor model = 31,809 compared to AICone−factor model = 33,500 and BICsix−factor model = 32,070 compared to BICone−factor model = 33,697.For the confirmatory factor analysis, the fit indices for the target model reported by onyx software were: r = −0.90) and emotional prosocial behavior (r = 0.32) were observed. While correlations between public prosocial behavior and altruism have also been observed for the original version of the PTM-R , compliant and dire prosocial behavior (r = 0.62) and compliant and emotional prosocial behavior (r = 0.31) were in line with the findings of the original version of the PTM-R again. Also, for altruism, as in the original version, there was no correlation with anonymous and dire prosocial behavior. For the rest of the latent factors, there was a negligible or weak positive correlation, as could be also found in the original English version of the questionnaire, with the exception that anonymous and dire prosocial behavior showed a moderate positive correlation (r = 0.35).The model of the confirmatory factor analysis is shown in Figure Measurement invariance to the original English dataset was determined via Δ-CFI. For the metric or factor loading invariance Δ-CFI = 0.007 and Δ-RMSEA = 0.001. Hence metric invariance was given following Chen  and CheuThe means, standard deviations, and ranges for the subscales of the PTM-R are presented in Table ESM1. Cronbach's alpha of the validating constructs empathy, cognitive sensitivity, emotional sensitivity, emotional concern, cognitive concern and social desirability can be seen in Table The means, standard deviations, and ranges for the subscales of the PTM-R are presented in Table ESM1. In sum, the reported altruistic behavior confirmed findings of the entire dataset. The relation to other constructs like neuroticism, extraversion, openness, agreeableness and conscientiousness, as well as trait positive and negative affect can be seen in Table The means, standard deviations, and ranges for the subscales of the PTM-R are presented in Table ESM1. Reported prosocial behavior confirmed findings of the complete dataset. The relation to other constructs like neuroticism, extraversion, openness, agreeableness and conscientiousness can be seen in Table In the study of Rodrigues et al. , where tmean age = 23.325, SD = 3.422, range = 19–31) participated in this study , is executed if one does not have the need to be polite. This more rational approach to prosocial behavior is yet negatively related to social desirability, maybe also indicating a more rational choice making and utilitarianism Mill,  or prefeEmotional prosocial behavior tendencies measured with the German version of the PTM-R are related positively to neuroticism, agreeableness and extraversion. This shows the necessity of having the sensitivity for the problems of others, denoted by neuroticism and the tendency to actually approach others in such emotional situations, showed by extraversion for emotional prosocial behavior. Additionally, this prosocial behavior category correlated with all subtypes of empathy (see subset 1), showing the high empathic drive of this type of prosocial behavior tendency.Dire prosocial behavior, which also correlates with all empathy-related subscales measured in subset 1, however is just correlated with the aspect compassion. This fits the concept of dire prosocial behavior, because one can be motivated to help in a crisis by compassion. As no other aspect or concept is related with this kind of prosocial behavior, the motivation to show this behavior seems to be solely driven by the compassionateness.The compliant prosocial behavior tendencies measured with the German version of the PTM-R, in contrast, are not related to all aspects of empathy, but only to emotional concern. Being also correlated with agreeableness, this shows the reciprocal and interactive nature of this prosocial behavior category. Looking at the aspects of agreeableness related to compliant prosocial behavior, one can see that compassion and politeness are correlated with this kind of prosocial behavior. This leads to the assumption, that there is a common basis for this kind of prosocial behavior and altruism, for they are sharing the same correlational pattern for the big five aspects measured with BFAS. Finally, the anonymous prosocial behavior is not correlated with any aspect of the big five personality aspects, but it is correlated with emotional and cognitive empathic concerns.Regarding the correlations of the prosocial tendencies with other personality traits assessed in this study, one can identify empathy, cognitive and emotional concern, cognitive and emotional sensitivity and agreeableness as positive correlates of prosocial behavior. These findings fit the argument that empathy may be a driving force in some prosocial behavior categories  with statements in general) could take an influence on the correlations within the items of the different prosocial tendency categories as well as on the correlations between the different prosocial tendency categories. So, for every prosocial behavior category, the Cronbachs' alpha is likely to be lower if reversed items would be used, as well as the correlations of the underlying constructs may be overestimated in some cases where positive correlations were found, but also underestimated when negative correlations were found. However, as there are similar relations of the subscales of the PTM-R that are highly correlated with each other with other constructs measured with less biased instruments , Translation of PTM-R, writing of manuscript, data preparation and analyses. NU: Translation and retranslation of PTM-R, correction of manuscript, conceptual advice. PM: Data collection (Germany), correction of manuscript, methodological and conceptual advice. GC: Author of PTM-R: support of translation, data collection (USA), correction of manuscript, conceptual advice and input. JH: Conceptual and methodological advice and input, correction of manuscript, translation of PTM-R.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Dietary alteration of the gut microbiome is an important target in the treatment of obesity. Animal and human studies have shown bidirectional weight modulation based on the probiotic formulation used. In this study, we systematically reviewed the literature and performed a meta-analysis to assess the impact of prebiotics, probiotics and synbiotics on body weight, body mass index (BMI) and fat mass in adult human subjects. We searched Medline (PubMed), Embase, the Cochrane Library and the Web of Science to identify 4721 articles, of which 41 were subjected to full-text screening, yielding 21 included studies with 33 study arms. Probiotic use was associated with significant decreases in BMI, weight and fat mass. Studies of subjects consuming prebiotics demonstrated a significant reduction in body weight, whereas synbiotics did not show an effect. Overall, when the utilization of gut microbiome-modulating dietary agents (prebiotic/probiotic/synbiotic) was compared to placebo, there were significant decreases in BMI, weight and fat mass. In summary, dietary agents for the modulation of the gut microbiome are essential tools in the treatment of obesity and can lead to significant decreases in BMI, weight and fat mass. Further studies are needed to identify the ideal dose and duration of supplementation and to assess the durability of this effect. Akkermansia muciniphila, which appears to protect the host against the invasion of pathogens, the breakdown of gut barrier defenses, systemic inflammation, endotoxemia, atherogenesis, lipogenesis and insulin resistance and its consequences [Firmicutes relative to Bacteroidetes phyla [Firmicutes phyla are known to be more efficient extractors of highly caloric short-chain fatty acids from fiber relative to Bacteroidetes [Bacteroidetes with weight loss and Firmicutes with the development of obesity [Firmicutes phyla of gut microbes [Current data estimate that approximately 600 million people around the world are obese, with an additional 1.9 billion overweight people ,3. The dequences ,13. The equences ,15. Theres phyla ,17. Bactroidetes . Previou obesity ,20,21. Fmicrobes . Lactobacillus and Bifidobacterium, which, when ingested, provide health benefits, either directly or through interactions with the host or other microorganisms [The ability to engineer a favorable metabolic environment by dietary modulation makes the gut microbiome an attractive target in the war against obesity  22,23,2,25. Dietrganisms . The comrganisms . The userganisms . In this study, we aimed to review the literature systematically for evidence from randomized controlled trials on the impact of prebiotics, probiotics and synbiotics on weight, BMI and fat mass in adult human subjects and to analyze the overall effect based on pooled data from these trials. This study was registered in the International Prospective Register of Systematic Reviews (PROSPERO 2017 CRD42017075883) and the protocol is available for download at .The search strategy was based on input from the authors, key articles and the pearl growing of terms based on preliminary search results. There were no restrictions placed on publication dates or language. All searches were executed on 16 August 2017 from the following databases: Medline (PubMed) , Embase All interventional trials (randomized or non-randomized) utilizing prebiotics/probiotics/synbiotics in supplement or food-based form in adult human individuals (18 and older) with BMI ≥ 25 (overweight and obese) were included, while studies with children or pregnant patients were excluded. The use of any food or supplement influencing the gut microbiome  was considered as the exposure, and weight, BMI and fat mass changes in individuals following dietary intervention were the primary outcomes.The titles and abstracts of the studies were reviewed independently by two individual reviewers based on the inclusion and exclusion criteria. Consensus resolved any disagreement(s) when needed by input from a third reviewer. Articles deemed to have met the aforementioned criteria were then subjected to a full-text review. Data extraction was completed by two extractors. A third author served as a referee for resolving the disputes and cross-checking the data extractions. The risk of bias assessment was done using the Cochrane Collaboration tool for the assessment of the risk of bias of randomized controlled trials .Details regarding year, study design, population, randomization, blinding, intervention and placebo agents, duration of follow up and baseline and follow up BMI and body weight and fat mass were systematically extracted from the included studies. The differences in the mean change from baseline in BMI/body weight/fat mass comprised the primary measure of treatment effect. The meta-analyses were performed by computing the difference in mean changes using the random effects model with an inverse variance in Revman 5.3 . The primary outcome measure was the difference in mean change in BMI/body weight and fat mass comparing pre-/pro-/syn-biotics to placebos.p-values) were used to determine the SD [X2) and I2 were used to measure the heterogeneity among studies. Subgroup analyses stratified for the dose of probiotic and duration of treatment were performed to explore heterogeneity. Funnel plots and an Egger’s test of regression for funnel plot asymmetry were conducted to assess publication bias in the included studies.The included studies reported a mix of change from baseline and baseline/final value. When a change from baseline was reported in a study without the standard deviation (SD) of change, the presented statistical analyses comparing change , standard errors (SE), e the SD . When one the SD ,37. The n = 6) assessing fat mass, followed by bioelectric impedance  and body composition analyzer . A total of 8009 studies (7989 from library electronic search and 20 from references) were identified, from which 4721 studies remained after duplicates were removed . Two autp < 0.001. The mean difference for any agent was also significant for a reduction in body weight , and p < 0.001) in 18 evaluable study arms. Fat mass reduction was evaluated in 11 study arms and was statistically significant with a mean difference of −0.60 kg , p < 0.001. There was a significant heterogeneity among the study arms for BMI, weight and fat mass (I2 > 50%) for any dietary modulation agent (prebiotic/probiotic/synbiotic). When stratified and based on study duration , only studies with a duration >12 weeks showed a significant reduction in BMI and body weight (p < 0.001).When any dietary modulation agent (prebiotic/probiotic/synbiotic) was compared to the placebo in 19 evaluable study arms , the meay weight . Howeverp < 0.001). The overall effect of probiotics on body weight reduction was significant, with an overall mean difference of −0.65 kg , p < 0.01) in the 13 study arms that were evaluated. Overall, a significant reduction in fat mass was also seen, with eight study arms using probiotics, leading to a mean difference of −0.94 kg , p < 0.001). There was significant heterogeneity in the study arms for BMI and body weight with I2 > 50%. However, for fat mass, the included probiotic study arms exhibited no heterogeneity (I2 = 0%). The effect of probiotics on BMI was evaluated in 14 study arms . Overall9 colony forming units (CFUs), medium dose 1–30 × 109 CFUs and low dose <1 × 109 CFUs) showed a greater mean decrease in BMI for the study arms with high dose probiotics , p < 0.001) compared to low dose probiotics , p = 0.04) (p < 0.001) and body weight , p < 0.001). When stratified by single vs. multispecies probiotic p < 0.001), body weight , p = 0.04) and fat mass , p < 0.001). Studies using Lactobacillus as a single strain showed a significant reduction in BMI , p < 0.001) and the greatest reduction in body weight , p < 0.001) and fat mass , p < 0.001) (p = 0.001). A subgroup analysis stratified by the dose of probiotic used (high dose >30 × 10 = 0.04) . However = 0.04) , studies< 0.001) . Howeverp = 0.07) in the five study arms evaluated (p = 0.04). Fat mass was evaluated in three prebiotic study arms with no significant change. Similar to probiotics, the prebiotic study arms for BMI and weight showed a significant heterogeneity (I2 > 50%); however, this was not significant for fat mass. Prebiotics only had a marginal effect on the reduction of BMI, with a mean difference of −0.27 , valuated . However2 > 50%). There were only three study arms using synbiotics to assess change in BMI and weight. No studies evaluated change in fat mass , and theThe risk of bias among the studies was assessed using the Cochrane Collaboration tool for the assessment of the risk of bias of randomized controlled trials . There wp > 0.05). The funnel plots created for the visual analysis of publication bias are presented in There was no significant publication bias identified in the analysis for the effect of any dietary modulation agent (prebiotic/probiotic/synbiotic) on BMI, weight and fat mass using regression for funnel plot asymmetry  and diet, which could influence the success of a prebiotic since its action is primarily the creation of a favorable environment for the growth of specific bacteria. The alteration of the gut microbiome is not restricted to dietary supplements alone. Alteration of the gut microbiome can also occur through the introduction of diets that favor different microbiota. A reduction in Mollicute predominance and an increase in Bacteroidetes has been demonstrated in obese humans with weight loss on a carbohydrate- or fat-restricted diet [Mollicute lineage of the Firmicutes to increase with an associated decrease in Bacteroidetes [Lactobacillus, Bifidobacterium and other species in animal husbandry where it has been used for weight gain in livestock and where the careful selection of strains is of paramount importance in the treatment of obesity [Prebiotics have been shown to reduce appetite, improve insulin sensitivity and improve lipid metabolism in animal and human studies ,67. Prebted diet . Similarroidetes . It is i obesity . Lactobacillus showing efficacy for reduction in BMI, body weight and fat mass can help guide consumers in a confusing and unregulated marketplace of probiotic supplements. However, further studies will be needed to confirm this finding. The finding of significant weight and BMI reduction in studies using low to medium dose probiotics over a long duration is highly relevant, since it suggests the potential effectiveness of long-term supplementation of over-the-counter probiotic supplements or fermented foods in the treatment of obesity compared to high dose probiotic supplements. Our findings of a single agent probiotic species such as 2 > 50% for several of the analyses. It is possible that the use of different methods for fat mass and body composition determination contributed to heterogeneity in the analysis of the effect of dietary interventions on fat mass. This was offset to some extent by the use of a random effects model of meta-analysis. We also performed a subgroup analysis stratified by dose and duration of supplementation to decrease heterogeneity and increase interpretability. However, regional variations in local food, differences in baseline gut microbiota in different geographical regions of the world and absence of baseline and post-intervention microbiome data for all the studies make any pooled analyses of dietary interventions for modulating the gut microbiome inherently heterogeneous. Moreover, the sustainability of probiotic interventions on the ecology of the gut microbiome may also vary, and further studies are needed to assess the sustainability of weight loss induced by these agents. Our study has several strengths. We extensively reviewed the literature from several databases in order to make this meta-analysis the most comprehensive to date. Moreover, we restricted our population to adult humans with a BMI ≥ 25, thereby selecting the population of greatest interest, as compared to previous quantitative reviews, which included all studies regardless of BMI. We also performed separate analyses for probiotics, prebiotics and synbiotics, as well as a combined analysis to increase the specificity of our findings. However, this study also has a few limitations. While there was a large number of studies assessing the effects of probiotics, the analyses of prebiotic and synbiotic agents were restricted to a relatively small number. There was also significant heterogeneity in the studies with IIn conclusion, dietary agents for modulation of the gut microbiome are essential tools in the treatment of obesity and lead to significant reductions in BMI, body weight and fat mass when compared to placebo. Further studies are needed to determine the ideal formulation for supplementation and to identify specific populations of overweight patients who would benefit most from gut microbiome modulation, in addition to assessing the durability of this effect.


To examine whether hypoesthesia and chronic pain are related in patients with MS.  Sixty-seven MS patients with pain and 80 persons without MS were included. Sensory functioning was tested by bedside neurological examination. Touch, joint position , temperature sense, and pain  were tested. Pain intensity was measured by the Colored Analogue Scale (CAS Intensity) and the Faces Pain Scale (FPS); pain affect was also measured by CAS Affect and Number of Words Chosen-Affective (NWC-A). Mood was assessed with the SCL-90 anxiety and depression subscales and the Beck Depression Inventory (BDI).  A significant negative relationship was found between pain intensity and the function of the dorsal column-medial lemniscal pathway, but not with the spinothalamic tract.  In addition to the already known relation between hyperesthesia and pain, hypoesthesia for touch and joint position also seems to be related to chronic pain in MS patients. Chronic pain is a common symptom in multiple sclerosis (MS) . Betweendecline in sensory functions, for example, hypoesthesia to touch [A lesion in the brain or spinal cord may express itself in sensory disturbances. It is well known that MS is characterized by sensory disturbances reflected in both hyper- and hypoesthesia . Hyperesto touch –11. The to touch . Compareto touch . HoweverCompared with the role of the spinothalamic pathway in pain, little is known about the role of the dorsal column-medial lemniscal pathway in chronic pain in MS . In examThe cumulative goal of the present study was thus to examine a possible relationship between chronic pain intensity and affect, and a decline in sensory functioning in patients with MS. Such a relationship may be clinically relevant as it implies that the presence of chronic pain in MS may be reflected by both hypo- and hyperesthesia. This study hypothesizes that, depending on the types of sensory dysfunction, that is, temperature, pain, light touch, and position sense, hypoesthesia may also be indicative of chronic pain intensity, pain affect, or both.The present cross-sectional study was part of a larger study examining the relationship between pain and cognition in patients with multiple sclerosis , 17.From the larger study, we included in the present study 67 MS patients who suffered from chronic pain. MS patients were recruited from a center, specialized in MS and other neurodegenerative disorders in the Netherlands, or enrolled from the personal environment of the researchers. In each case, an official diagnosis of MS was made by a neurologist, according to the criteria of Poser or McDonald criteria , 19. We Both the MS patients and the control participants were screened for education. Education was divided into five categories: elementary school not finished (score = 1), elementary school (score = 2), lower secondary school (score = 3), higher secondary school (score = 4), and higher vocational training for 18+/university (score = 5).Both groups suffered from arthrosis/rheumatoid arthritis, musculoskeletal disorders (e.g. neck-shoulder pain), migraine, osteoporosis, and peripheral neuropathic pain. Peripheral neuropathic pain was due to metatarsalgia, carpal tunnel syndrome, low back pain with irradiation, and meralgia paresthetica. Probably, our participants did not suffer from central neuropathic pain reflected in an absence of allodynia. Chronic pain was defined as pain occurred during a period of 3 months or longer .Within the scope of the present study, we listed analgesics  and medication that might be related to sensory disturbances: sedatives , antipsychotics , antidepressives , anxiolytics , and neurological disorders .Comorbidities that might cause sensory disturbances, that is, diabetes, transient ischemic attack (TIA), migraine, and epilepsy, were listed (for a full list of comorbidities see ).Participants (patients and controls) were excluded if they had a history of neoplasms, cerebral traumata, alcoholism, normal pressure hydrocephalus, disorders of the central nervous system other than MS, or disturbances of consciousness.The local medical ethical committee gave their approval for the present study . The patients were asked to give oral and written consent after they had been extensively informed about the aim and procedure of the study. After permission, the neuropsychological, the sensory function, and the pain perception tests were obtained. The patients were able to discontinue their participation at any time during the current study.Sensory function was tested by a bedside neurological examination. In particular, it was tested whether the sensory function of the MS patient was normal (score = 2) or decreased (score = 1) on two levels: dorsal column-medial lemniscal function (by testing joint position and touch) and function of the spinothalamic cortical pathway (by testing temperature sense and pain). The classification from Svendsen and colleagues was used to assess the spinothalamic cortical pathway and dorsal column-medial lemniscal pathway .This pathway mediates fine touch and joint position. Fine touch was tested by applying a cotton wool on the dorsal side of the right and left hand, forearm, and upper arm. Joint position was tested by passively stretching or bending one finger of the patient. The patient was asked which finger has been stretched or bended. Three fingers of each hand were moved. Fine touch or joint position were considered to be disturbed if the participant failed, by giving one or more incorrect answers, to indicate whether they were touched or gave an incorrect answer concerning the position of the joint. During all of these tests the patients kept their eyes closed .This pathway mediates pain and temperature. Pain was tested by applying a pinprick with a needle with either a sharp or blunt end on the dorsal side of the participant's right and left hand, forearm, and upper arm. Temperature sense was evaluated by making a distinction between warm and cold. The investigator touches the dorsal side of the right and left hand, forearm, and upper arm with a small plastic bottle filled with either cold or hot water. The patient kept their eyes closed during the test. If the participant gave one or more incorrect answers, sensory function was considered to be disturbed .Two CAS scales were applied: one measures the intensity of pain (CAS Intensity) and the other measures the affective/emotional components of pain (CAS Affect) . The CASThis is the affective part of the McGill Pain Questionnaire (Dutch version) and is composed of 5 groups . Each grThis scale consists of seven different faces with different expressions. Each face represents an increased feeling of pain , 25. TheTwo pain domains were composed: (1) pain intensity, which is composed of the CAS Intensity and the FPS, and (2) pain affect, which is composed of CAS Affect and the NWCA. The MS patients were asked to indicate their level of pain during the last week. This way of measuring the level of pain is reliable, according to a study of Forouzanfar and colleagues .The extent to which patients were suffering from pain is presented in the Results section.As pain may be associated with depression and anxiety , three qThe scores of these three scales were first converted into z-scores. Subsequently, a reliability analysis resulted in a Cronbach's alpha of 0.84. Next, we made a composite domain score “mood.”The pain scales  and sensory tests  were administered in one session. First, the pain scales were conducted from the patient, after which the sensory functions were assessed.t-tests, and Mann–Whitney U tests were applied to analyze data between groups. As some cells had a low cell count, statistical significance was established by means of Fischer's exact tests (two-tailed). The relationships between chronic pain, the dorsal column-lemniscal pathway, and the spinothalamic tract were analyzed by hierarchical linear regression analyses: one model predicting pain intensity and one predicting pain affect. In the first step, mood was added as a predictor; in the second step, the dorsal column-medial lemniscal pathway; and in the third step, the spinothalamic tract was entered. Adjusted R2 and R2 are reported as measures of model fit and ΔR2 as a measure of the effect of sensory functioning  on pain while controlling for mood. The level of significance was set at p < 0.05.We used the SPSS-PC program for the data analyses. Chi-square tests, t (145) = 1.46; p=0.15).The mean age of the MS patients  did not differ significantly from the mean age of the control group  .The distribution of gender within the group of MS patients is as follows: 66.2% women and 33.8% men. Within the control group, the distribution of gender was 66.3% women and 33.8% men  = 0.55; p < 0.59).The mean level of education of the MS patients is 3.57 (SD = 0.76). The mean level of education of the control group was 3.50 .With respect to depression and anxiety, MS patients showed significant higher scores than the controls .23.9% of the MS patients had decreased sensibility to touch. Disturbances in joint position were found in 25.8% of the MS patients. Both sensory functions were significantly more disturbed in MS patients than in the control group  and a group of patients without sensory disturbances. We were interested whether, compared to MS patients without sensory disturbances, those with sensory disturbances suffered more from comorbidities that might have caused those sensory disturbances. As can be seen in U tests show that MS patients suffer significantly more from pain intensity and pain affect, compared to controls  were examined by means of chi-square test and Fisher's exact test. The results show that concerning analgesics, only cannabis differed significantly between both groups; MS patients with sensory disturbances used significantly more cannabis than those without sensory disturbances. No significant differences between both groups were observed concerning the other medications that might be related to sensory disturbances . Adding the functioning of the dorsal column-medial lemniscal pathway explained an additional 10% of variance in pain intensity (Model 2). There was no significant change in explained variance in pain intensity, after adding the function of the spinothalamic tract (Model 3) .The results of a hierarchical regression analysis show a significant relationship between mood and pain affect, explaining 9% of the variance in pain affect (Model 1). No significant relationships were found between pain affect and the function of the dorsal column-medial lemniscal pathway (Model 2) and between pain affect and the function of the spinothalamic tract (Model 3) .The goal of the present study was to examine a possible relationship between hypoesthesia and chronic pain in MS patients. The main finding relates to our observation of a significant negative relationship between pain intensity and hyposensitivity concerning light touch and joint position  . This fiThe rationale is that chronic pain, known to be present in MS , may be The main finding yielded related questions. One of these include whether MS patients with sensory disturbances differed from those without sensory disturbances concerning comorbidities that might provoke sensory disturbances. This appeared not to be the case . A similCompared with controls, the use of baclofen, paracetamol, and cannabis was significantly higher in our MS patients . The higOur finding concerning the relationship between hypoesthesia and pain intensity in MS patients may be clinically relevant. In cases of hyperesthesia, a patient may respond quite vividly to light touch, for example, due to a considerable increase in pain , even whsymptoms instead of major depressive disorders [Our results further show that compared with controls, MS patients had higher scores on scales measuring mood, more specifically depression and anxiety . The relisorders . We obseisorders . Feisteiisorders  emphasizisorders . They alisorders .The present study has several limitations. Firstly, we were unable to perform quantitative sensory testing (QST) to examine sensory function in MS patients in an objective way. This is because our study was based partly on Svendsen and colleagues' study , which eβ fibers  or by laser-evoked potentials that are transmitted by Aδ fibers (nociceptive) [In addition to QST, a neurophysiological examination in a study on pain in MS could be conducted, for example, by measuring somatosensory-evoked potentials that are transmitted by thick-myelinated Aceptive) .Another limitation of the present study is that we did not observe central neuropathic pain in our patients. Central neuropathic pain might occur in 50% of the MS patients . Althougwithout chronic pain in the present study. Such a control group would have been appropriate to examine the clinical and neuropathological characteristics of MS patients who do suffer from chronic pain.A final limitation is that we did not include an MS group could be an indication of chronic pain in MS patients.The present study indicated a negative relationship between hypoesthesia, for light touch and joint position, and pain intensity in MS patients who suffer from chronic pain. As a consequence, the clinician should be aware of the fact that, although hypoesthesia need not per se be related to chronic pain, it


Hypertension is a risk factor for cognitive impairment in older age. However, evidence of the neural basis of the relationship between the deterioration of cognitive function and elevated blood pressure is sparse. Based on previous research, we speculate that variations in brain connectivity are closely related to elevated blood pressure even before the onset of clinical conditions and apparent cognitive decline in individuals over 60 years of age. Forty cognitively healthy adults were recruited. Each received a blood pressure test before and after the cognitive assessment in various domains. Diffusion tensor imaging (DTI) and resting-state functional magnetic resonance imaging (rsfMRI) data were collected. Our findings confirm that elevated blood pressure is associated with brain connectivity variations in cognitively healthy individuals. The integrity of the splenium of the corpus callosum is closely related to individual differences in systolic blood pressure. In particular, elevated systolic blood pressure is related to resting-state ventral attention network (VAN) and information processing speed. Serial mediation analyses have further revealed that lower integrity of the splenium statistically predicts elevated systolic blood pressure, which in turn predicts weakened functional connectivity (FC) within the VAN and eventually poorer processing speed. The current study sheds light on how neural correlates are involved in the impact of elevated blood pressure on cognitive functioning. Hypertension is highly prevalent in the aging population and the prevalence of it increases with age , respectively. Compared to investigations of WM lesions at the macrostructural level , and the average values were used.To assess the cognitive functions of our subjects, six domains were measured in the current study: processing speed, working memory, selective attention, divided attention, visuospatial skills and executive functioning.Processing speed. A composite score of processing speed was obtained by adding the raw scores of the Digit Symbol Coding and Symbol Search according to the Wechsler Adult Intelligent Scale Third Edition—Taiwanese version  was used  comprising Parts A and B was used  was used, comprising Form V items in the following order: 16, 9, 6, 2, 12, 30, 7, 17, 19, 28, 20, 21, 26, 24 and 22  and were then entered into the DSI studioThe DTI data that were corrected for eddy current and motion distortions were also entered into the FSL to obtain FA maps. Tract-Based Spatial Statistics  with the three resting-state frontoparietal networks  were performed on the blood pressure measures controlling for age, gender and education. Partial correlations between blood pressure measures and SW were investigated, controlling for age, gender and education. A general linear model (GLM) approach was used to identify how blood pressure measures could be related to brain connectivity at the voxel level. Specifically, systolic, diastolic, or pulse pressure was entered as a regressor, together with age, gender and education as covariate regressors on all subjects’ FA maps masked by the mean FA skeleton, or resting-state FC data masked by the significant IC. Using the randomize function in FSL, permutation tests based on 5000 permutations were performed with a 0.05 significance level after correcting for family-wise error (FWE) using threshold-free cluster enhancement (TFCE). To further correct for multiple testing of the components involved in the resting-state frontoparietal networks, a significance level of 0.005 was adopted for analyzing FC. The region of interest (ROI) approach was then applied and the mean values of regional FA and FC within significant clusters of the corresponding contrast were retrieved and partially correlated with the cognitive measures—including composite score of processing speed, composite score of working memory, interference index of SCWT, interference index of CTT, visuospatial performance on JLO and executive functioning captured by TOL—controlling for age, gender and education. Moderation analyses were performed to examine whether the associations between FA or FC and cognitive measures were dependent on the blood pressure measures. A parallel mediation model was then established to examine how brain variables might mediate the relationship between blood pressure measures and cognitive function in the subjects. Finally, serial mediation analyses were performed based on the findings from the moderation and parallel mediation analyses. Moderation and mediation analyses were performed using PROCESS macroF = 0.042, p = 0.838; diastolic: F = 0.166, p = 0.686; pulse pressure: F = 0.000, p = 0.991). The average value of each measure was used for the subsequent analyses.Blood pressure measures did not differ between pre- and post-assessment  = 0.005, p = 0.943).Among all subjects, 17 of them were on drugs for hypertension treatment. The average duration was 124 months , and no significant age difference between those on drugs and others was detected . They did not correlate with scores of MMSE and GDS even when controlling for age, gender and years of education. Systolic pressure was related to diastolic and pulse pressure positively, controlling for age, gender and years of education (systolic and diastolic: R(35) = 0.642, p < 0.001; systolic and pulse pressure: R(35) = 0.804, p < 0.001; diastolic and pulse pressure: R(35) = 0.060, p = 0.724).None of the blood pressure measures were related to age, years of education, or scores of MMSE or GDS  = −0.606, p < 0.001). Their composite scores of working memory were positively correlated with their performance in JLO (R(35) = 0.392, p = 0.016). Their total moves and total time spent in TOL were correlated with each other (R(35) = 0.409, p = 0.012).Subjects’ composite processing-speed scores were negatively correlated to their total time spent in TOL (R(35) = −0.334, p = 0.044) and pulse pressure (R(35) = −0.337, p = 0.041) were negatively correlated with the composite score of the processing speed. Trending associations were observed in systolic pressure with the Stroop interference index (R(35) = −0.293, p = 0.079) and with the total time spent in the TOL (R(35) = 0.315, p = 0.057). Trending associations were also observed between pulse pressure and total moves (R(35) = 0.281, p = 0.093) and with the total time spent in the TOL (R(35) = 0.311, p = 0.061). Diastolic pressure did not correlate with any cognitive functions , and none of the blood pressure measures were correlated with the composite score of working memory, the CTT interference index, or the visuospatial performance on JLO .Both systolic (R(35) = 0.34, p = 0.04) and pulse pressure (R(35) = 0.373, p = 0.023) were positively correlated with SW  = 0.089, p > 0.05).At the topological level, both systolic  and in the left posterior thalamic radiation , whereas diastolic pressure was only negatively associated with the FA in the left PTR . No significant clusters were associated with pulse pressure in the WM along the main tracts.Structurally, systolic pressure was negatively associated with FA largely in the splenium  and diastolic pressure was negatively associated to the FC of the left STG (LSTG) with the VAN  with the ventral attention network  = 0.345, p = 0.036).Structurally, the FA within the cluster of the left PTR  was positively correlated with the composite processing-speed scores (R(35) = 0.398, p = 0.015) and the composite score of processing speed (R(35) = 0.359, p = 0.029) and negatively correlated with total time spent in the TOL (R(35) = −0.342, p = 0.038).Functionally, the FC of the RSTG with the VAN was positively correlated with the Stroop interference index . The association between the FA within the cluster of the left PTR and the composite scores of working memory was moderated by pulse pressure . The association between the FA within the cluster of the splenium of the corpus callosum and the total moves used in TOL was moderated by systolic and pulse pressure . The association between the FA within the cluster of the left PTR and the total moves used in TOL was also moderated by pulse pressure . The association between the FA within the cluster of the splenium of the corpus callosum and the total time spent in TOL was moderated by systolic pressure . The association between the FA within the cluster of the splenium of the corpus callosum and the total time used in TOL was moderated by pulse pressure .Structurally, the association between FA within the cluster of the splenium of the corpus callosum and composite processing-speed scores was moderated by systolic Figure , diastolR2 = 0.07, b = −0.06, SE = 0.03, p = 0.043). The association between FC of LSTG with VAN and the Stroop interference index was moderated by pulse pressure . The association between FC of LSTG with VAN and the CTT interference index was moderated by systolic pressure .Functionally, the association between FC of RSTG with VAN and composite processing-speed scores was moderated by pulse pressure  the impact of blood pressure  on the link between structural connectivity and FC and processing speed, or (ii) the impact of structural connectivity on the link between blood pressure and FC and processing speed. Importantly, our serial mediation analyses revealed that the lower FA of the splenium of the corpus callosum statistically predicted higher systolic pressure, which in turn allowed for the statistical prediction of weakened FC of the RSTG in the VAN and eventually poorer processing speeds in healthy subjects . Details of the models that were tested are presented in Figures Our study provides preliminary evidence that elevated blood pressure is associated with detectable brain connectivity variations in adults without apparent cognitive impairment and that elevated blood pressure is related to slower information processing. To investigate the brain changes that are associated with elevated blood pressure at the topological and connectivity levels, we have investigated SW, WM integrity as captured by FA, and FC within three resting-state frontoparietal networks. In this study, we confirmed our hypothesis that brain changes at the topological  level and connectivity  levels are related to elevated blood pressure. Importantly, the FC of the RSTG with the VAN of cognitively healthy subjects mediates the impact of elevated blood pressure on information-processing speed, with a preserved corpus callosum predicting more favorable blood pressure levels. Together, our results have suggested that the impact of elevated blood pressure on specific cognitive functions and the brain occurs earlier than the onset of clinical conditions.At the topological level, our study identified alterations in the structural topology of the brain in relation to elevated blood pressure. From our behavioral findings, individuals with higher blood pressure tended to have slower information-processing speeds with an upward shift of the SW property of their structural brain networking. SW captures the balance of network segregation and integration via clustering and short paths  was weakened in the elderly with higher blood pressure. The association between weakened frontoparietal network connectivity and higher blood pressure described in our study, parallels the results of a recent study reporting an alteration in the frontoparietal network of hypertensive individuals (Li et al., Based on the mediation analysis, the weakened connectivity of the RSTG in the VAN could largely explain the predictability of high systolic blood pressure on slower information processing speeds in cognitively healthy adults. The frontoparietal system—comprising three subsystems the FCN, the DAN, and the VAN (Yeo et al., Additionally, the splenium of the corpus callosum is a major interhemispheric commissure with extensive connections linking the visual areas and the parietal and posterior cingulate regions (Knyazeva, Finally, trending associations were observed in systolic pressure with Stroop interference index and with the total time spent in the TOL. It is plausible that we did not have sufficient statistical power to detect significant correlations. Moreover, reaction time in perceptual and decision tasks is a basic indicator of information processing speed (Anstey et al., Our analyses have provided preliminary evidence concerning how blood pressure, structural and FC, and cognitive function might be related to each other on a relatively small sample of adults aged 60–70 years without apparent cognitive decline. We have applied multiple comparisons corrections for voxel-wise analyses to statistically control for errors from multiple comparisons, but the findings should be interpreted with caution and should be regarded as preliminary. Interpretations were made based on correlation, regression and mediation analyses. Owing to the nature of the cross-sectional design, we could not confirm the causality of the relationship without longitudinal data but could only make inferences from the statistical analyses. Therefore, a prospective longitudinal study on the relationship between the brain of cognitively healthy individuals and their blood pressure is needed. Lastly, the blood pressure measures were obtained from participants only before and after the cognitive assessment; the data could be improved by measuring blood pressure multiple times across a period to have a better approximation of participants’ blood pressure levels.This study has used a multi-modal neuroimaging approach to investigate how elevated blood pressure may be related to alterations in brain connectivity before the onset of clinical conditions and apparent cognitive decline. Our results have demonstrated the close relationships among elevated blood pressure, changes in brain topology and connectivity, and cognitive function. Although prospective studies are needed to validate our findings, our study has provided findings and shed light on how the functional brain is involved in the impact of elevated blood pressure on cognitive aging.TMCL conceptualized the research idea and planned the study. EP-WM collected the data. NMLW and EP-WM analyzed and interpreted the data. NMLW wrote the manuscript. All authors read and approved the final manuscript. All authors had access to the data, and all authors agreed to submit the article for publication.This study was supported by KKHo International Charitable Foundation and The University of Hong Kong May Endowed Professorship in Neuropsychology awarded to TMCL.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.