Tripterygium wilfordii Hook F (TwHF) extracts (TEs) in the treatment of rheumatoid arthritis (RA); however, the results have been inconsistent. This meta-analysis is aimed to assess the safety of TEs and their effects on the treatment of RA. Randomised controlled trials (RCTs) comparing the effects of TEs and placebo (PBO) or disease-modifying antirheumatic drugs (DMARDs) in patients with RA were included. Weighted mean differences (MDs) were calculated for net changes by employing fixed-effect or random-effects models. After filtering, ten RCTs (involving 733 participants) were included in this study. The methodological quality of these studies was generally low. Compared with DMARDs, TEs alone produced a mild increase in grip strength (GS)  = 0.81; 95% confidence interval (CI): 0.14 to 1.48). The most common adverse effects (AEs) of TEs were gastrointestinal discomfort, menstruation disorders, and amenorrhea. In conclusion, TEs, as a sort of “herbal DMARD,” could be as effective as synthetic DMARDs in the treatment of RA. However, the efficacy of TEs in treating RA should be further estimated with better designed, fully powered, confirmatory RCTs that apply the American College of Rheumatology (ACR) improvement criteria to evaluate their outcomes.Clinical trials have reported the effects of  Rheumatoid arthritis (RA) is an autoimmune disease of unknown aetiology that is characterised by pain, stiffness, and swelling of peripheral joints . RA affeHowever, many patients discontinue the above treatments because of adverse events (AEs)  or poor Tripterygium wilfordii Hook F (TwHF), commonly known as thunder god vine, is a member of the Celastraceae family. It is a perennial vine-like plant that is abundant in south China [th China . Anti-inth China , 11, ankth China , 13, andth China . Additioth China , Crohn'sth China , and solth China .Tripterygium species, 95% are terpenoids [Among the approximately 380 secondary metabolites isolated from rpenoids . Triptolrpenoids , respectrpenoids .2 [in vitro and in vivo, it is easy to speculate that TEs are likely to be types of herbal DMARDs, which differ from synthetic DMARDs.Meanwhile, many studies have been dedicated to elucidating the potential molecular mechanisms underlying the anti-inflammatory and immunosuppressive effects of TEs , includi2  productiWhile the extracts of TwHF have been most frequently used for a long time in treating RA, there exist a number of issues. In this regard, most of this clinical information comes from uncontrolled clinical trials or from retrospective reports, and few multicentre clinical trials have been performed to confirm the effects of TEs in the treatment of RA. In addition, the scientific evidence verifying that TEs are as effective as other conventional treatments in treating RA remains to be further validated. In terms of security, the safety of a long-term TE intake for chronic RA is uncertain. Given these uncertainties, it is necessary to assess the pertinent trials to systematically review the potential effects and safety of the long-term application of TEs in the treatment of RA.To ensure the accuracy of our systemic review and meta-analysis, we designed and reported our results by employing a checklist of items that was as consistent as possible with the Preferred Reporting Items for Systemic Review and Meta-Analyses (PRISMA) statement.We searched the following digital databases to identify trials: PubMed, Embase, the Cochrane Library, and Clinical Trials.gov. In addition, we searched the Chinese databases, such as the CNKI Database, VIP Database, CBM Database, WanFang Database, and Chinese Clinical Trial Register. All of the databases were searched from their available dates of inception to the latest issue (January 2013).Tripterygium wilfordii Hook F,” “lei gong teng,” “thunder god vine,” or “yellow vine”  and “rheumatoid arthritis,” or “RA.” For the Chinese databases, free text terms were used, such as “lei gong teng” or “huang teng” (which means Tripterygium wilfordii Hook F in Chinese) and “lei feng shi guan jie yan” (which means rheumatoid arthritis in Chinese). A filter for clinical trials was applied. To collect an adequate number of trials, the reference lists of relevant publications were also searched to identify additional studies.Different search strategies were combined as follows. For the English databases, we used free text terms, such as “Randomised controlled trials (RCTs) were included regardless of blinding, publication status, or language. Studies were selected for analysis if they satisfied the following criteria: (1) the subjects took extracts of TwHF alone or with other DMARDs for at least 4 weeks; (2) the study was an RCT with a parallel or crossover design; (3) TEs were used as an active treatment intervention; and (4) people enrolled were diagnosed with RA, according to the 1987 guidelines of the American Rheumatology Association .“TEs,” in this review, mainly refer to the two root extracts of TwHF that have shown therapeutic promise, tripterygium glycosides tablets and tripterygium tablets. Therefore, studies using any TwHF-containing herbs or other herbal extracts were excluded. We also excluded case reports, reviews, retrospective studies, or studies without control groups. For obviously repeated studies, the authors of the reports were contacted to clarify any ambiguities. If the author could not be reached, the first published study was considered to be original. Studies were also excluded if the dose of TEs was not available. RCTs that lacked sufficient data to allow for the calculation of the net changes in outcomes and their variances from the baseline to the endpoint were also eliminated from our analysis. Two reviewers selected the articles independently. Based on the PRISMA requirements, a flow diagram of the study selection has been generated.The relevant data was extracted by two independent reviewers, and divergences were resolved by consensus or were arbitrated by a third reviewer. The validated Jadad instrument was adopted to assess each study's quality independently . The JadThe primary outcomes were tender joint count (TJC), swollen joint count (SJC), duration of morning stiffness (DMS), and grip strength (GS). The secondary outcomes consisted of rheumatoid factor (RF), erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP). AEs were also collected from the studies. For the trials that applied a three-armed group design, the outcomes of the groups were extracted if they met the inclusion criteria and were excluded otherwise. In case of vagueness or absence in the articles of the outcomes, the authors were contacted and related data has been extracted by consensus if the authors were unavailable.2 test, and Higgins I2 test. A fixed-effect model was employed when the studies in the group were sufficiently alike (P > 0.10); otherwise, a random-effects model was used. A Z score was calculated to test the overall effect, with significance set at P < 0.05. Publication bias was detected by funnel plots, Egger's regression asymmetry test, and Begg's test when the number of included trials ≥5 . We performed subgroup analyses to verify whether the use of TEs alone or with DMARDs had different effects on the outcomes.The effects of TE intake on patients with RA were calculated as differences between the treatment groups and the no TE control group, by employing Review Manager meta-analysis software, version 5.2. To ensure the credibility of the results, the net changes in all of the outcomes were calculated as the mean differences (TEs minus control) in changes (endpoint minus baseline) for parallel trials. We calculated weighted mean differences (MDs) or standard mean differences (SMDs) and 95% confidence intervals (CIs) for continuous data. MDs were used if the outcomes were evaluated in the same manner among trials, while SMDs were used if the same outcomes were evaluated by adopting different approaches. Heterogeneity was evaluated via the chi-square test, the tauTo minimise the clinical heterogeneity, we performed three subgroup analyses: TEs compared with a placebo (PBO); TEs compared with DMARDs; and TEs with DMARDs compared with DMARDs alone.The process of study selection is shown in The included studies were published as full texts between 1988 and 2011. All of the RCTs originated in China, except for one . Eight sTwo studies compared TEs with a PBO. Six studies randomised the participants to receive TEs alone versus a control of DMARDs. Two trials compared a cointervention of TEs and DMARDs  with a control of DMARDs alone. There were three types of TE preparations applied in the included trials, consisting of tripterygium glycosides tablets, tripterygium tablets, and an unknown TE capsule. Different doses of TEs were used in these trials. The TE intake ranged from 0.01 g to 1.8 g per day. Except for two trials in which the TEs doses were not less than 0.18 g, the doses of TEs in most of the included trials were moderate (≤0.09 g). The total daily TE intake was divided into one to three doses. One trial  reduced The duration of the interventions in the included studies also differed, ranging from four to twenty weeks. In the trial by Wang et al., the outcomes were detected at three time points: 20 weeks, 40 weeks, and 80 weeks . AnotherThe majority of the outcomes of the study , such asCompared with the four trials , 36, 37 P values exceeded 0.05 in three outcomes among the studies , and the 95% CI for the intercept included zero. However, these results cannot be considered convincing because there were fewer than ten trials.Egger's publication bias plots and Begg's test showed that there were no significant publication biases for three outcomes in which the numbers of the included trials were not less than 5. As shown in P = 0.01). The pooled results indicated a significant difference between TE-treated group and the PBO group, aside from RF . The significant difference was identified between TEs and PBO in terms of the SJC , DMS , and ESR . A small but significant increase in GS  was also found.Two trials (involving 92 patients) compared the therapeutic effects of TEs and a PBO , 27. TheP < 0.10). Consequently, a random-effects model was employed to pool the results. The pooled results displayed no significant differences between TE-treated group and the DMARDs group, aside from GS . However, no effects were found for TJC , SJC , DMS , RF , ESR , or CRP . Only one trial [Six trials (involving 513 patients) compared the therapeutic effects of TEs with those of DMARDs –36. The ne trial , ACR 50,P = 0.05). The pooled results showed no significant differences between the two groups in terms of ESR  or CRP . Unfortunately, none of the included trials reported its results: ACR 20, ACR 50, or ACR 70.Two trials (involving 128 patients) compared a combined therapy of TEs and DMARDs with DMARDs alone , 38. TheP = 0.071). In addition, the same trial [Eight trials reported outcomes for AEs. Seven trials , 36, 37 Although several systematic reviews and meta-analyses regarding the efficacy of TEs in the treatment of RA have been conducted, these systematic reviews achieved contradictory conclusions –43, whicCompared with a PBO, our results were consistent with those of Jiang et al.  in termsMany of our results were consistent with the findings of Jiang et al.  between As shown in The most common AEs with TEs were gastrointestinal discomfort, menstruation disorders, and amenorrhea, and they could be relieved with or without dose reductions. Due to different interventions, limited data, and the low quality of the included studies, the AEs were not ultimately combined. Identical to the synthetic DMARDs, the toxicity of TEs requires monitoring regularly to prevent AEs. Additionally, the doses of TEs should be controlled to avoid AEs.However, some limitations of this meta-analysis should be noted. First, nine of the included trials were conducted in Chinese populations, which implies a high risk of selection bias. This fact could have influenced the applicability of TEs to populations of other ethnic origins. Second, most of the studies published in Chinese were of poor quality regarding their designs, reporting, and methodologies. Only one multicentre RCT was identified , which aIn summary, TEs alone or combined with DMARDs might not be inferior to DMARDs in the treatment of RA. Based on their bioactivity, TEs, which function as a type of “herbal DMARD,” appear to have the same effects as those of synthetic DMARDs. Meanwhile, the AEs of TEs should be assessed periodically, as with synthetic DMARDs. Considering the low methodological quality of the randomised trials, more RCTs are needed before we can recommend TEs to replace synthetic DMARDs or to be combined with them.


Objective. To evaluate Health-Related Quality of Life (HRQoL), medication used, and Stock of Health Capital (SHC) in physically active elderly participants in Community Exercise Programs (CEPs) compared to a sedentary group. Methods. EuroQol standardized instrument was completed by physically active elderly  who participated in CEPs. Common items were compared to HRQoL data of 1,874 sedentary elderly people, taken from the Catalan Health Survey 2006 (CHS'06). Visual Analogue Scale (VAS) outcomes and medication used were assessed through parametric statistics. Dimensions of health conditions were compared, between sedentary people and physically active elderly participants in CEPs. SHC results were obtained combining the EuroQol scores and Life Expectancy (LE) values. An economic value of €34,858.70 was assigned to these years of LE. Results. Physically active subjects had better HRQoL values  than CHS'06 sedentary subjects . Medication used was different between physically active subjects  and CHS'06 sedentary subjects . SHC data for physically active elderly  were higher than for CHS'06 sedentary subjects . Regular physical activity increases functionality of the body's biological dimensions and is associated with lower mortality rates  . There iResearch evidence also shows an association between physical activity and psychological well-being, such as a reduction in depression and anxiety or increase in levels of self-esteem and positive affect .An individual's health has been traditionally measured on the basis of indicators of morbidity, mortality, and Life Expectancy. At present, there is a search for new, more dynamic ways to measure health, with an emphasis on the subjective dimension. The World Health Organization, in its institutional definition, already established this tendency when defining health as a state of absolute physical, mental, and social well-being, rather than just the absence of disease . The conGusi et al.  applied Furthermore, health can also be understood as an investment, when applying prevention measures. Health is, from this perspective, a kind of Human Capital . A persoIn Spain, SHC studies have been applied to population in Catalonia  by usingSo, the aim of the present study was to assess SHC, HRQoL, and medication used in a sample of physically active elderly subjects engaging in a community-based physical exercise program in comparison to a group of sedentary elderly in Catalonia, derived from the 2006 Catalan Health Survey.The sample consisted of a group of individuals, older than 60, who participated in exercise programs, including activities such as keep-fit, tai chi, walking, pétanque, and water activities. In total, 2,185 subjects took part in the study  from October 2004 to May 2007. Sampling was intentional, because it was known by the main researcher. Participants came from the four provinces of Catalonia . All the groups participated in Community Exercise Programs (CEPs) that had a common protocol of activities, intensity, and frequency.Data for the sedentary population was taken from the Catalan Health Survey (CHS) conducted in the year of 2006. This survey was organized by the Government of Catalonia . Data from CHS'06 were transferred by the Health Department of Generalitat. In total, there were 1,874 subjects . Data were classified according to health geographic region. Health care resources did not change along the period of study. A database was generated with the results from the elderly participating in the CEPs and from the sedentary subjects, with a total number of 4,061 participants. Age and gender differences were analyzed separately.Both surveys, the present one and the CHS one, were anonymous and voluntary.Measurement instruments were divided into three separate parts: sociodemographic data, objective health measures (number of illnesses and medication used), and HRQoL measure. Questionnaires were distributed and filled in individually by physically active elderly during group sessions with the supervision of a research assistant.descriptive system (ds), with five dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression.worst imaginable health state” and “best imaginable health state”;Visual Analogue Scale (VAS), with scores from 0 to 100, with end points labeled as “health costs. EuroQol has a system to transform DS into costs or preferences of population for all the health states.To assess HRQoL, the EQ-5D questionnaire was used , 15, as To calculate SHC, results from the EuroQol costs were used, multiplying results of preferences by Life Expectancy (LE). This value is labeled as QALY  . Subsequt-test. A statistical homogeneity test was not positive. An alpha level of 0.05 was selected to consider that the difference of means was significant. Data analyses were carried out using the statistical package SPSS, version 15.0 for Windows.Descriptive statistics were obtained for all the variables. Values corresponding to mean VAS of EuroQol, medication used, and SHC, in relation to gender and age, were analyzed using Student's P < 0.05) higher HRQoL (75.36 and 70.71) than CHS'06 sedentary men and women (58.35 and 50.59), in all the age groups analyzed , sedentary males (from 62.5 in 60-to-64-year-old to 52.56 in older-than-85 subjects), and sedentary females (from 56.17 in 60-to-64 group to 49.25 in older-than-85 group). This tendency is similar in physically active elderly males from 60 to 64 (76.81) to 75 to 84 (74.91), as shown in In the case of elderly men, physically active subjects have a significant lower mean for medication used with 1.89 units in comparison with sedentary men (4.34 units), in all the age groups analyzed. Physically active females showed a significant difference too (2.87) with sedentary women (4.21) in all the age groups .Women use more medication than men when being physically active and sedentary.Medication used increases with age in physically active elderly males (from 1.21 in the 60–64 group to 2.19 in older than 85), physically active elderly females (from 2.67 in 60–64 to 2.77 in 75–84 group), sedentary males (from 4.11 in 60–64 to 4.67 in 75–84), and sedentary females (from 4.21 in 60–64 to 4.52 in 75–84), as shown in The SHC of physically active elderly  is higher than the one of the sedentary subjects  in all the age groups .Men have higher SHC than women when being sedentary, but this tendency is the opposite when being physically active. Physically active females showed higher SHC than physically active males.SHC decreases with age in physically active males , physically active females , sedentary males , and sedentary females , as shown in Physically active male elderly subjects, when adjusted for gender, showed lower percentage of problems in all the dimensions. The dimension self-care  is the one with the lowest percentage of problems, whereas the dimension pain/discomfort  is the one with the highest percentage of problems in sedentary and physically active groups , in both physically active and sedentary subjects. The difference becomes progressively bigger with age. The first age group under analysis, from 60 to 64 years, showed that physically active subjects present a higher percentage of problems than the sedentary groups in the dimensions of pain/discomfort and anxiety/depression, but this relationship is reversed with age Tables  and 3. TThe introduction of the SHC perspective in our results allows us to complement the previous findings from an economic perspective. Physically active elderly showed a higher SHC than sedentary subjects, which demonstrates their greater health potential.The results showed that women's SHC is significantly higher than that of the physically active males, whereas in the case of sedentary subjects this relationship is reversed. We could interpret these results in the sense that physical activity improves women's health proportionally more in comparison with men.The elderly people that engage in regular physical activity show a better HRQoL than the sedentary subjects, after adjusting for age and gender. Differences are more obvious in the older age groups. This better HRQoL can be seen both in a global assessment and in the different dimensions. The dimensions of mobility, usual activities, and self-care show an important evolution in the number of problems from 75 years old onward in the two groups that were analyzed. The dimensions of pain/discomfort and anxiety/depression show a higher percentage of problems for physically active elderly in the younger age groups, but this relationship is reversed as age increases. The measures of medication used corroborate results from a subjective perspective, representing better health for those people that engage in physical activity.Positive assessments of physically active subjects, both from the perspective of VAS and DS, are directly correlated to a better SHC. As health improves with exercise, they have a higher LE; the SHC of physically active females improves in comparison to that of physically active males, who still have a lower LE than women.We cannot deduce causal relationships among the factors analyzed. From this perspective, further longitudinal studies are needed to answer these questions.Although results tend to relate an improvement in the health of subjects engaging in physical activity in comparison with sedentary subjects, it is noteworthy that in this study the subjects' health condition prior to measuring their HRQoL was not taken into account. In this respect, we think that further experimental research should consider this criterion or factor prior to intervention in order to confirm the present descriptive results.Finally, we should highlight that the use of a generalist measurement tool such as the EuroQol, which was validated in Catalonia, has allowed us to compare a sample of subjects in this population. However, the use of an instrument that is not specific for a certain age group does not help to discriminate whether the main cause for worse health is fitness. Studies that work with homogenous age groups should help to refine our results.


Each day in the United States in 2007 there were almost 1.5 million home health care patients. This study examines the use of DSs and factors associated with their use in this population.Data were from the 2007 NHHCS - a nationally representative probability sample survey. Medical records of 4,683 current home health patients  were sampled from 677 participating home health agencies . Therapeutic classes analyzed were Nutritional Products (NP)  and Non-vitamin, Non-mineral Dietary Supplements (NVNMDS). Multivariate analyses were used to examine the independent roles of demographic and health factors with use of NP and NVNMDS, and the association of NP and NVNMDS with pain and pain management strategies. Variables in the multivariate analyses were age, sex, race, number of chronic conditions, whether the patient lived alone and/or had a caregiver, mobility, cognitive impairment, medication assistance and primary payor.In preliminary analyses 59% of patients had at least one type of NP and 7% had NVNMDS noted on their medical record. In multivariate analyses, use of NPs was associated with age, sex, payor and number of chronic conditions, and use of NVNMDS was associated with age and race. Neither NP nor NVNMDS were associated with reported pain or a standing order (SO) for pain management. NP, but not NVNMDS, were associated with an “as needed” (PRN) order for pain management.Patients who were older, female, with Medicare as primary payor and more chronic conditions were more likely to use NP. Older and white patients were more likely to use NVNMDS. Patients using NP were more likely to have a PRN order, but not a SO. Continuing analyses will include more detailed coding of DSs and analysis of concomitant use of DS with over-the-counter and prescription medications.


Background. Focus upon depression and prevention of its occurrence among adolescents is increasing. Novel ways of dealing with this serious problem have become available especially by means of internet-based prevention and treatment programs of depression and anxiety. The use of Internet-based intervention programs among adolescents has revealed some difficulties in implementation that need to be further elucidated. The aim of this study is to investigate the association between personality and adolescent depression and the characteristics of users of an Internet-based intervention program. Method. The Junior Temperament and Character Inventory (JTCI), the General Self-Efficacy scale (GSE) and the Centre for Epidemiological Studies-Depression scale (CES-D) have been administered to a sample (n = 1234) of Norwegian senior high-school students. Results. Multiple regression analysis revealed associations between depression and gender, and several JTCI domains and facets. In line with previous findings in adults, high Harm Avoidance and low Self-Directedness emerged as the strongest predictors of adolescent depressive symptoms. Further, in logistic regression analysis with the covariates JTCI, GSE and CES-D, the only significant variables predicting use/non-use were the CES-D and the temperament domain Reward Dependence. Conclusion. The results in this study revealed level of depressive symptoms as the strongest predictor of the use of the Internet based intervention and that personality might provide useful information about the users. The prevalence of depression in childhood is low, whereas adolescence is a period of life characterized by a substantial vulnerability to depression . AccordiFactors affecting development and predisposition to depression are numerous . Grant aThere is increasing evidence that psychiatric disorders have specific associations with underlying temperament and character traits among children and adolescents –13. The novelty seeking (NS), harm avoidance (HA), reward dependence (RD), and persistence (P). On the other hand, character refers to self-concepts and individual differences in goals and values, which in turn affect voluntary choices and intentions. According to Cloninger [self-directedness (SD), cooperativeness (C), and self-transcendence (ST). These aspects of personality interact to allow for adaptation to life experiences and also influence the vulnerability for emotional and behavioral disorders.  A model to assess temperament and character to describe underlying biogenic structures of personality had been developed by Cloninger et al.  resultinloninger , charactScores on the TCI have shown to be variant between depressed individuals and nondepressed . ElevateSince the adult version of the TCI might be unsuitable for use in an adolescent population, Luby et al.  develope So far, research on the relationship between JTCI and depression among adolescents is sparse. A few studies have reported associations between JTCI and psychopathology in adolescents –38. Schm Different relationships between temperament and character traits and mental health are suggested to exist in adolescents and adults . TherefoOne might expect that many depressed adolescent individuals will never formally seek help or contact with health services , renderiThe use of internet-based interventions among adolescent samples has revealed some difficulties in implementation . MotivatThe concept of self-efficacy refers to a person's “conviction, that one can successfully execute the behavior required to produce the outcomes”  and thuBeing able to depict the role of personality and adolescent depression in this context it is important to understand fundamental and underlying mechanisms in order to get a better understanding and treatment of it. If researchers can understand what underlies the development and vulnerability towards depression among youth, treatment can be modified to better target key factors. Internet-based interventions for depression are, compared to traditional face-to-face treatment, easy to present and to implement.The aims of the current study are twofold: firstly, to assess the predictive power of gender, age, and personality aspects  for the severity of depressive symptoms , and secondly, to explore the characteristics of users versus nonusers of an Internet-based intervention program (MoodGYM) using the variables JTCI (domain and facets), GSE, gender, and CES-D.Participants were recruited from four senior high schools in Troms County in Northern Norway as a part of a larger study with a four-arm randomized controlled trial design with repeated measures (pre- and post- intervention). Members of our research group visited the four participating schools for recruiting the participants. The recruitment process involved the delivery of a short informative lecture about mental health in general and a presentation of the MoodGYM program, followed by an invitation to the students to participate in the study. Students volunteering to participate signed a written consent form. If the students did not want to participate in the MoodGYM trial, they had the choice of participating in the preintervention survey only. As an incentive for becoming a participant, a lottery drawing was announced. There was an additional lottery for those participating in the MoodGYM trial.The data collection for the current study was part of the preintervention survey, which was conducted by computer in a classroom setting on the day of the information session. The students without access to a computer completed a paper version. Students willing to participate in the MoodGYM trial received username and passwords on e-mail within a week of recruitment for registration in the program. The use of MoodGYM was self-directed, without personal followup, and no time was allocated during school hours. Within 6–8 weeks, the research team returned to collect postintervention data.The regional medical research ethics committee approved the study. Data of use of MoodGYM were securely stored on a server at the Australian National University and were retrieved for information about use/nonuse for participants in the trial.MoodGYM is an internet-based self-help program based on the principles of cognitive behavior therapy (CBT). It has been developed at the Centre for Mental Health Research at the Australian National University in Canberra. The aim of this program is prevention and treatment of depression by means of five modules and a personal workbook . Each moLevel of depression was measured using a Norwegian version of the Centre for Epidemiologic Studies-Depression scale (CES-D) , developSelf-efficacy was measured using the Norwegian version of the General Self-Efficacy Scale (GSE) . The scaThe JTCI is a self-administered questionnaire containing 106 items scored on a five-point scale (1 to 5) ranging from “totally agree” to “totally disagree.” The Norwegian version of the JTCI was developed according to established guidelines following several steps based on the German version of the JTCI . This prP = .793, SD = .846, CO = .803, and for ST = .796.  The Cronbach alpha for the current study were for NS = .795, HA = .846, RD = .792, Demographic parameters were gender, age, and grade in high school.All statistical analyses were performed with the SPSS version 18 and 19 for Macintosh. To identify unique JTCI correlates and predictors of depressed mood, hierarchical regression methods were used. For the domain-level analysis, all JTCI domains were subjected to forced entry in the same analytic step and their unique contributions simultaneously evaluated. In the facet-level analysis all of the 29 facets scales were entered in the same model using forward entry.α level and for significance tests involving the seven domains and the 29 facet scores on the JTCI. This adjustment resulted in a critical α level of .0071 (.05/7) and .0017 (.05/29), respectively.Bonferroni adjustment was applied to the critical Direct logistic regression was run to assess the impact of nine independent variables  on the likelihood that participants in the study would use MoodGYM or not.Another direct logistic regression assessed in more detail the impact of JTCI facets on users versus nonusers of MoodGYM. The model contained thirty-two independent variables .F = 84.32, P < .001 with a mean of 15.78 and 11.00, respectively  and 635 females (51.3%) with a mean age of 16.8 (range = 15–20). Women scored significantly higher on CES-D than men ectively . The totr = .56, P < .01) and SD  yielded the strongest association with depressed mood. Somewhat lower significant associations were obtained for P, while small ones emerged with NS , RD , CO , and ST . When CES-D scores were correlated with the seven JTCI domains all coefficients emerged as significant . HA  = 118.88, P < .001. The JTCI explained an additional 40.2% of the variance in depression, R square change = .402, F change  = 131.42, P < .001. In the final model the following measures were statistically significant: gender , and after Bonferroni correction: NS , HA , RD , SD , and CO .A hierarchical multiple regression analysis was applied to assess the power of gender, age and personality to predict depressive symptoms (CES-D). A preliminary analysis was conducted to disclose any violations of assumptions. Gender and age were entered into step one, explaining 6.5% of the variance in depression . After tP < .001). Significant facets, after Bonferroni correction, were SD4 (self-striving) , SD2  , HA1 (anticipatory worry) , and RD4 (independence) .A more detailed analysis was performed on facet level of the JTCI domains to check for their ability to predict depression. For this analysis, facet scale scores were entered into the hierarchical regression analysis at the second step in the model using forward selection after age and gender were forcedly entered in step one. Nine of the 29 facet scales emerged as unique and significant predictors. Together with gender and age, they explained 52.8% of the variance in CES-D scores . Gender Direct logistic regression was performed to assess the impact of a number of factors on the likelihood that participants in the study would use MoodGYM or not. The number of users in this sample was not optimal, with only 51 (7.3%) participants actually logging in and using the MoodGYM program.χ2 = 20.71, P < .05, indicating that the model was able to distinguish between participants that used and those who did not use MoodGYM. The model as a whole explained between 3.2 (Cox and Snell R square) and 7.9% (Nagelkerke R square) of the variance in use/nonuse and correctly classified 45.2% (an improvement of 37.8% from the model where only the constant is included) of the cases. Further, the Hosmer and Lemeshow test has a significance level of .584, thus indicating that the model prediction does not significantly differ from the observed. The Wald criterion showed (P < .05), and indicated that those who reported a higher level on CES-D were more likely to use MoodGYM than those who scored lower on CES-D, controlling for all the other factors in the model. This means that for every point a participant increased on the CES-D score, the odds of using MoodGYM increased with 5% (O.R. = 1.05). The odds ratio of .953 for RD (reward dependence) indicates that for every additional point on RD the odds were 4.7% less for the participants to use MoodGYM, controlling for other factors in the model. The model contained ten independent variables . The overall model was significant n showed  that onlTo investigate in more detail the traits of MoodGYM users, a direct logistic regression was performed to assess the impact of the JTCI facets on the likelihood that participants in the study would use MoodGYM or not.χ2 = 59.92, P ≤ .001, indicating its ability to distinguish between participants who used versus not used MoodGYM. The model as a whole explained between 8.3 (Cox and Snell R square) and 20.3% (Nagelkerke R square) of the variance in use/nonuse and correctly classified 60.9% (an improvement of 53.5% from the model where only the constant is included) of the cases. Furthermore, the Hosmer and Lemeshow test yielded a significance level of .241, thus indicating that the model prediction does not significantly differ from the observed. The Wald criterion demonstrated (P < .05) indicating that female students have a 26.5% increase of odds for using MoodGYM. Findings are reported in The model contained thirty-two independent variables . The overall model was significant nstrated  that sevThe findings from this study underline the potential importance of personality in adolescent depression. The JTCI factors harm avoidance and self-directedness, yielded the strongest associations. In the regression model, JTCI domains explained additional 40.2% of the variance in CES-D after having controlled for age and gender. NS, HA, RD, SD, and CO emerged as significant correlates in explaining depression among adolescents, which is slightly different from an adult population , 16, 23.The facet level analysis reveals a more detailed picture of traits affecting depressed mood. The second regression model shows that the JTCI facets explain 46.4% of the variance in CES-D. The following facets emerged as significant associations with CES-D: SD4 (self-striving), SD2 , HA1 (anticipatory worry), and RD4 (independence). Cloninger et al.  describeThe present study was conducted among a younger sample that might affect which domains and facets emerge as specific. The results from the facet level analysis reflect adolescents with elevated depressive symptoms as individuals lacking the ability to work towards long-term goals, which in addition, worry and expect the worse in situations even when there is support and assurance available. They resemble withdrawn, independent individuals, who apparently are insensitive to social pressure, which at first glance might display them with a strong personality, not vulnerable to depression. This finding might be a combined effect of the other facets and seems like a natural response when individuals struggle with their self-image at the same time as they worry and expect negative outcomes and do not cope adequately with embarrassment. A subject with such a personality will most likely not express true feelings. The challenges concerning adherence of online CBT users deserve further investigations , 47. Des In order to give a more detailed description of the users of MoodGYM, a second logistic regression was done including the same predictors, but based on the JTCI facets. Here, gender was the strongest predictor, indicating that female students are more likely than male students to use this kind of intervention. The level of depressive symptomatology also predicted its use, reflecting that depressed individuals might actively use this kind of program. The facet sd3 (resourcefulness) also emerged as a strong predictor of use, indicating that the users are resourceful and effective individuals, focused on solving problems and are perceived by others as competent and productive. On the other hand, they score lower on p4 (pragmatic) , describThis gives a picture of the MoodGYM users as effective and strict rule-followers, working effectively in order to achieve goals, at the same time as they seem similar to independent individuals reluctant to take into account what others do or mean. These individuals' worry of failure might function as worry of failure might function as a facilitator towards goal-directed behavior, at the same time as it reflects their vulnerability to depression. They also seem to be like resourceful individuals who are underachieving, holding a pragmatic view upon what they are doing. These aspects, together with the level of depression symptoms and gender, moderately predict use of MoodGYM, indicating that there could exist other important factors that will better predict its use. The assessment of the characteristics of internet-based intervention users is an intriguing aspect of online delivery healthcare research that needs further investigation. The fact that only a few students used the MoodGYM program might indicate that this kind of intervention is most appealing to and effective in individuals with specific characteristics. The delineated characteristics of MoodGYM users might aid us in the further development of internet-based programs, their implementation and last but not least facilitate uptake and adherence. Data collection occurred in a classroom environment, not ensuring sufficient privacy for the participants. Further, the effect sizes reported are small. Also the variables failed to explain a larger portion of the variance, indicating that definite conclusions of both predicting use/nonuse and depression cannot be drawn. A relatively small number of MoodGYM users (7.3%) also compromise the study. Further, the large sample size also raises concern about unreliable responses. To minimize the possible effect, repeated “data-washing” was made, and this effect is assumed to be minimal. Finally, this group of adolescents had not been specifically asked to take part in a treatment intervention, which may also affect the outcome and possibly the low rate of adherence to the intervention. Since this investigation represents part of a larger study on identifying and exploring different aspects of MoodGYM after its introduction in Norway, its results should be regarded as preliminary.


Background. Neonatal hyperbilirubinemia (HB) may cause severe neurological damage, but serious consequences are effectively controlled by phototherapy and blood exchange transfusion. HB is still a serious health problem in economically compromised parts of the world. The long term outcome has been regarded favorable based on epidemiological data, but has not been confirmed in prospective follow-up studies extending to adulthood.Methods. We studied the long term consequences of HB in a prospective birth cohort of 128 HB cases and 82 controls. The cases are part of a neonatal at-risk cohort (n = 1196) that has been followed up to 30 years of age. HB cases were newborns ≥ 2500 g birth weight and ≥ 37 weeks of gestation who had bilirubin concentrations > 340 µmol/l or required blood exchange transfusion. Subjects with HB were divided into subgroups based on the presence (affected HB) or absence (unaffected HB) of diagnosed neurobehavioral disorders in childhood, and compared with healthy controls. Subjects were seen at discharge, 5, 9 and 16 years of life and parent’s and teacher’s assessments were recorded. At 30 years they filled a questionnaire about academic and occupational achievement, life satisfaction, somatic and psychiatric symptoms including a ADHD self-rating score. Cognitive functioning was tested using ITPA, WISC, and reading and writing tests at 9 years of life.Results. Compared to controls, the odds for a child with HB having neurobehavioral symptoms at 9 years was elevated (OR = 4.68). Forty-five per cent of the HB group were affected by cognitive abnormalities in childhood and continued to experience problems in adulthood. This was apparent in academic achievement (p < 0.0001) and the ability to complete secondary (p < 0.0001) and tertiary (p < 0.004) education. Also, the subgroup of affected HB reported persisting cognitive complaints e.g., problems with reading, writing and mathematics. Childhood symptoms of hyperactivity/impulsivity (p < 0.0001) and inattention (p < 0.02) were more common in HB groups, but in adulthood the symptoms were equal. The affected HB had lower scores in parameters reflecting life satisfaction, less controlled drinking, but not increased substance abuse.Discussion. Our results indicate that neonatal HB has negative consequences in adult age. A prospectively collected cohort with strict inclusion criteria enables to control most of the bias factors involved with retrospective data. The control and HB groups were remarkably similar at birth in terms of medical data, and the growth environment of the children, as well as the parents’ social groups, education, size of family, type of housing at birth and at 9 years of age. Our findings bear resemblance to disorders of the fronto-striatal network, and also symptoms of the ADHD spectrum were frequent in the HB group suggesting a link of HB to other neurodevelopmental disorders. Neonatal hyperbilirubinemia (HB) is a well-recognized risk for severe neurological disability and death . While in = 1948) found no linear association between neonatal bilirubin levels and intelligence test scores or school achievement at 17 years of age, but the risk for low intelligence test scores was higher among full term males  with serum bilirubin levels above 342 µmol/l  as the only birth risk factor whose adult outcome is compared to healthy, typically developed controls similarly followed-up. Our aim was to study if the cognitive and behavioral problems discovered in childhood continue in adulthood, and if they affect the educational, occupational, and social functioning as well as health and wellbeing of the adult subjects.n = 372), birth weight under 2000 grams (n = 317), jaundice with bilirubin > 340 µmol/l (n = 368), severe respiratory difficulties necessitating external ventilation (n = 161), neurological symptoms (n = 195), maternal diabetes (n = 95), infant hypoglycemia (n = 104), and severe infection (n = 36); 19% had more than one risk factor  neonates had at least one predefined risk: APGAR score lower than 7 at 5 or 15 min  or more were required. Children who had received blood exchange transfusion because of rapidly increasing serum bilirubin values were also included. Those who died during early childhood and those with severe disabilities (incl. kernicterus) were excluded from follow up . Addition = 145).The control subjects, also prospectively studied from childhood, were born in the same hospital during the study period, attended the same schools, and were free of any perinatal risk factors. For the present study those with gestational age at or above 37 weeks, birth weight at or above 2500 g and full assessment information from 9 years of age are included . All participants gave their written consent to the study.The family’s social and economic status, maternal risk factors, genetic traits, medical data about delivery and delivery complications was recorded prospectively. The socio-economic status was defined as the father’s occupational level . Psychosocial distress score was formed to include poor housing conditions, divorces, relocations, alcohol abuse, unemployment, family conflicts, domestic violence, imprisonment, severe diseases or mental problems in family. Body-mass index was calculated as an indicator of the general health and development of the child.The cognitive and behavioral problems in childhood were assessed when the children were 5 and 9 years of age. This coincides with periods before and after entering school (at the age of 7 in Finland). The assessment methods have been described in detail elsewhere . To summA questionnaire was filled out by parents both at ages 5 and 9 regarding the parents’ work situation, existing developmental problems or disabilities within the family, the child’s home environment, development and skill acquisition, illnesses, school achievement and problem behaviors. The existing problems within the family that were probed were: delayed speech, delayed motor skills, clumsiness, reading and spelling difficulties, other school problems, inattention or short temperedness, squint, impaired hearing in childhood, mental retardation, mental illnesses and seizures, present or absent in other family members. In addition, the questionnaire at 5 years included 28 questions regarding the activity level, motor skills, communication and emotional affectivity of the child rated in a three point scale. At 9 years of age a questionnaire was also sent to the teachers concerning school achievement and the need of remedial teaching or a special class. Additionally, the teacher was asked to perform an evaluation of the pupil’s behavior and personality in class using 24 adjective pairs  with a five point rating between the extremes, as well as five open-ended questions for additional information.Based on the comprehensive assessments with measures described above, the children were classified into either having or not having different developmental disorders. The decisions were agreed upon at a clinical case conference between a pediatrician, child neurologist, a psychologist, and a speech therapist, who had performed the assessments. The results of these 5 and 9 year assessments have been published previously . The diaLong term outcome at the age of 30 years was assessed with an extensive questionnaire prepared for the purposes of this study. Educational outcome was measured by questions regarding school achievement . Occupational achievement was measured with a question about the type of present employment . Social functioning was assessed with a combined score measuring social satisfaction (three items) and social contacts (two items), higher value indicating more dissatisfaction. Life satisfaction, satisfaction with social relationships and satisfaction with social support received were measured with a 5 point scale (from very satisfied to very unsatisfied) and the social contact items included reported difficulty in making friends or maintaining social relationships (yes/no). General health was measured with a combined score of subjective health , the number of doctors’ appointments , the use of medication for physical illnesses, and the presence of headaches or gastro-intestinal complaints (yes/no). The incidence of past traumas, fractures and concussions was also noted. Substance use  were also included in the questionnaire as indicators of health and well-being. In addition to categorical variables, an alcohol consumption score was constructed by combining items of regularly drinking more than once a month , excessive use expressed by family members (yes/no), excessive use estimated by self (yes/no) and reported incidences of driving while intoxicated (yes/no). The psychiatric status was measured with a combined score of reported psychiatric problems , and the use of prescribed sedatives or hypnotics. The behavioural outcome was measured with the ADHD Current Symptoms Scale as well as the ADHD Childhood Symptoms Scale where each of the 18 DSM-IV  diagnostOf the cases fulfilling the criteria of the present study, 128 HB cases (54%) and 82 controls (57%) returned an adequately completed questionnaire at the age of 30 years. See Statistical analysis was performed using the STATISTICA analysis software . For conn = 70) and affected (n = 12) groups. The odds ratio was calculated as OR = 4.68  for a subject with HB of belonging in the affected group as compared to controls.There were 57 HB cases with at least one neurobehavioral disability used for classification at 9 years of life (the affected-HB group) and 71 with no disabilities (the unaffected-HB group). The controls were similarly classified into unaffected  but in univariate ANOVAs only the 5 min apgar differed between the groups, with the control group actually being the lowest. There was a slight but statistically not significant over representation of girls in the control group (57%) and boys in the affected (61%) and unaffected (55%) HB group.No difference between the affected-HB and unaffected HB-groups was found in parity, the percentage of small-for-date, mother’s smoking habits during pregnancy, maternal diabetes, the number of X-ray investigations during pregnancy, past miscarriages, maternal blood pressure, mother’s weight gain during pregnancy, glycosuria, toxemia, mother’s marital status or the hereditary traits . Among all cases with HB, 54 received phototherapy and 79 had blood exchange transfusions (in six cases more than one transfusion). The number of treatments was equal in the affected-HB group  and the unaffected-HB HB group . Neither were there any significant differences in the start time, duration of HB or the peak bilirubin value. ABO blood group incompatibility was present in 40 cases and Rh incompatibility in one. The treated and non-treated HB subjects were equal in terms of cognitive testing, school performance, and other assessments at 9 years of age indicating that treatment decisions did not explain the measured outcome differences.There were no differences in the children’s hospitalizations, traumas, or other somatic complaints and diseases in follow-up. The body-mass-index BMI of the child was similar in the three groups at age 9 years see . The groThe family’s socio-economic status was the highest and the social distress scores the lowest in the unaffected HB group differentiating it from the affected HB group but not from the control group in pair-wise comparisons. The affected-HB group did not differ from the controls. The significance levels were low and considering the multiple tests performed, the findings are not considered meaningful.p < 0.0001). In pair-wise comparisons the affected-HB group differed from the controls in all tests conducted; the unaffected-HB group differed from the controls only in spelling test (p < 0.003). The frequency of remedial instruction in preschool and school until nine years of age had been 86% in affected-HB, 44% in unaffected-HB, and 28% in the control groups (p < 0.0001).The performance of the groups in the Illinois Test of Psycholinguistic Abilities (ITPA), the Reading and spelling tests as well as the Wechsler Intelligence Scale for Children (WISC) performed at the age of 9 years is presented in The results show that despite similar medical history and growth pattern, many children in the HB group managed less well in the psychological tests than the control group. This is in line with a previous cross-sectional study of this cohort . In thatIn contrast to our observations, studies reporting childhood outcomes of HB have mostly found no significant consequences . In our p < 0.004). The proportion of subjects who had received the diploma at the end of the secondary education (after 12 years of school) was 30% in the affected-HB group, 70% in the unaffected-HB and 75% in the control group (p < 0.0001). Within the HB group, the relative risk of not completing secondary education was more than two-fold  for a person with affected-HB compared to an unaffected-HB.All but 2 subjects in all groups combined had graduated from first level education (the first obligatory nine years). However, 11% of the affected-HB subjects reported having required remedial teaching or a special class during those nine school years, in contrast to only one child in the control group and none in the unaffected-HB group  = 29.1, p < .0001, the affected-HB group having the lowest grades and differing from the other two groups in pair-wise comparison (p < .0001)  was significantly different in the three groups 001) see .p < 0.0001). When other forms of tertiary education (applied universities) were also included, the relative risk of not completing tertiary education was still elevated  for a person with affected-HB compared to an unaffected-HB.The proportion of subjects who by the age of 30 had completed an academic degree was 11% in the affected-HB group, 32% in the unaffected-HB and 31% in the control group (p < 0.006).At 30 years of age 86%, 93% and 90% of the groups  were working or studying full time, showing a similar outcome. At the other end of the spectrum, however, 11% of the affected-HB, 3% of the controls and none of the unaffected-HB groups were unemployed .Marital status and number of offspring was equal in all groups. Still, social dissatisfaction score was higher see  in the aThe general health problem score was similar in the three groups and there were no differences in the reported incidences of traumas, fractures and concussions.Alcohol consumption was more uncontrolled in the affected-HB group compared to the controls in pair-wise comparison. Particularly, past episodes of driving while intoxicated were reported by 20% of the affected-HB group but only by 6% and 9% in the unaffected-HB and control groups respectively. The use of illicit drugs was similar in the three groups, 10% of all reported having used at any time in the past.The results indicate higher alcohol consumption in the affected-HB group. Similar tendencies in association with developmental deficits have also been observed previously . Excessip < 0.004). The affected-HB group scored higher for childhood inattention compared to both the unaffected-HB and the control groups (p < 0.001), and also higher for childhood hyperactivity/impulsivity compared to the controls (p < 0.01). The unaffected-HB group scored higher in childhood inattention compared to the controls (p < 0.002). The difference was not significant for the current symptoms rating scales.Ongoing cognitive problems, all symptoms combined, were more frequent in the affected-HB group compared to the two other groups . SixteenNo differences in number of self-reported psychiatric problems between the groups were found. The use of sedatives or hypnotics was reportedly similar in all groups.The results indicate that the various learning disabilities found in a subgroup of the HB cases in childhood continue into adulthood. In our study, 23% of the affected-HB subjects reported persisting cognitive complaints at the age of 30 years, reading difficulties being reported most frequently. This is in line with the previous results at 9 years of age . In addiOur aim was to study long term consequences of neonatal hyperbilirubinemia at 30 year-old adults followed up from birth. To exclude the confounding effects of preterm birth, we included only newborns ≥ 2500 g birth weight and ≥ 37 weeks of gestation. The subjects with neonatal hyperbilirubinemia were divided into subgroups based on the presence (affected HB) or absence (unaffected HB) of diagnosed cognitive or behavioral disabilities in childhood, and compared with healthy controls. Our results indicate that neonatal HB has negative consequences in adult age. Nearly half of the HB group were affected by cognitive abnormalities in childhood and continued to experience problems in adulthood. This was apparent in academic achievement and the ability to complete secondary and tertiary education. Also, the subgroup of affected HB reported persisting cognitive complaints, e.g., problems with reading, writing and calculus. Childhood symptoms of hyperactivity/impulsivity and inattention were more common in HB groups, but in adulthood the symptom levels were equal. The affected HB still perceived lower levels of subjective wellbeing as well as social adaptability, and reported more poorly controlled drinking; findings that may reflect a more profound tendency of poor adjustment.The strength of our study is that our control and HB groups were remarkably similar at birth in terms of medical data and absence of risk factors, other than HB. Our base cohort’s limit for inclusion in the low birth weight group was 2000 g and inclusion to any group did not have a fixed limit of weeks of gestation. Consequently, there were a few neonates both in the control and the HB groups, whose gestational age was 35–36 weeks and/or birthweight between 2000 and 2500 g. In order to avoid any further bias we also excluded these borderline cases. The growth environment of the children was also very similar in the groups, as the parents’ social status, education, size of family, type of housing were comparable at birth and at 9 years of age. Further, the children were born in the same hospital, lived in the same metropolitan area, and attended the same schools. We also tested for attritional bias, and found none. Therefore we think that confounding factors are well controlled without need for statistical modeling. Our results should be well generalizable in otherwise uncomplicated HB cases, even in the era of more modern therapeutic possibilities.A limitation in our study is that a questionnaire is a rather insensitive tool that has sampling and data processing challenges . HoweverThe symptoms we found, e.g., decreased social adjustment, symptoms of the ADHD spectrum, and the ability to achieve goals when in an instructive environment  but not when independent planning and execution of tasks are required  bear resemblance to impairment of the fronto-striatal system. The pathogenesis of encephalopathy by unconjugated bilirubin is poorly understood but it seems to involve oxidative stress, a disruption of the blood–brain barrier and the consequent damage of neuronal cells . Brain pWe conclude that neonatal HB is a recognizable cause of adult age neurobehavioral problems, severe enough to have negative occupational and quality of life effects.


Candida prophylaxis in ICU is still a matter of debate. Oral chemoprophylaxis has been advocated to reduce the incidence of Candida colonisation and infection.We performed a randomised trial studying a single drug (nystatin) versus control in surgical/trauma ICU patients. Multiple-site testing for fungi was performed in each patient on ICU admission (T0) and subsequently every 3 days . The primary evaluation criterion was the time course of the corrected colonisation index.Candida colonisation: the most frequently colonised body sites were the stomach and the pharynx. The most frequent isolated species was Candida albicans. The corrected colonisation index was similar in the two groups at T0 (P = 0.36), while a significant statistical difference was observed between the treatment and control groups at T6 , at T9 , at T12 , and at T15 . The same results were obtained in the subgroup of patients already colonised at ICU admission.Ninety-nine patients were enrolled. At admission, 69 patients exhibited This trial shows that nystatin prophylaxis significantly reduces fungal colonisation in surgical/trauma ICU patients, even if already colonised.NCT01495039ClinicalTrials.gov:  Candida species are now among the leading pathogens in ICUs in both Europe and the United States [The challenge posed by nosocomial fungal infections in critically ill patients has become increasingly apparent over the past 20 years. d States -6. The id States . Moreoved States . Candidad States . CandidaCandida species is the leading risk factor for infection, and several elements support the assumption that multiple- site colonisation is a prerequisite for subsequent infection [Colonisation by nfection -12. Sevenfection .Candida colonisation index (CI) and found a strong correlation between colonisation intensity  and invasive infections [Assuming the risk of death is similar in multiple-site colonised surgical patients and in those with proven candidiasis , severalfections . The samfections .Candida species colonisation both in medical and surgical patients that were not colonised at admission to the ICU [For these reasons, oral chemoprophylaxis has been advocated for ICU patients, and in particular for surgical ICU patients, with the aim to reduce the incidence of heavy colonisation and infection , althoug the ICU . Since c the ICU ,18 a conWe therefore decided to perform a randomised controlled trial to evaluate the time course of CCI in a surgical/trauma ICU population, including those colonised at admission, undergoing nystatin prophylaxis.We performed a randomised, open-label, single-centre study with blinded assessment of the objective primary evaluation criterion. We studied a single drug (nystatin) versus control. The study was approved by the Ethics Committee of the Policlinico Hospital, Bari, Italy and was conducted in accordance with the Helsinki Declaration .The study was performed from November 2008 to August 2009 . The primary evaluation criterion was the time course of the CCI; the secondary evaluation criterion was occurrence of a fungal infection.Candida infection, prophylactic or curative antifungal treatment within the last 2 months, contraindication to oral drug administration, known allergy to nystatin or its derivatives, and prior inclusion in the study.The patients or their next of kin provided informed consent for participation in the study. The inclusion criteria were: surgical patients admitted to our ICU > 18 years of age and expected to require invasive mechanical ventilation for more than 48 hours. The exclusion criteria were: pregnancy, proven Candida infection were identified and recorded as previously suggested ) [6 U/day administered three times daily via the nasogastric tube; group N) or no nystatin prophylaxis as control (group C).Reasons for admission, demographic characteristics, immune status, and the Sequential Organ Failure Assessment score were recorded on admission. The duration of mechanical ventilation, the duration of antibiotic and corticosteroid therapy, the length of stay in the ICU, the route of nutrition , and mortality were also recorded. In cases of residual gastric volume > 500 ml/24 hours or vomiting, the patient was excluded from the analysis. Risk factors for 000/mm)) . PatientMultiple-site testing for fungi included tracheal secretions, swab, stomach contents, pharyngeal, rectal and groin skinfold swabs, urine, and blood. These tests were performed in each patient at ICU admission (T0) and subsequently every 3 days throughout the ICU stay . The specimens were placed in a dry medium and taken to the Mycology Laboratory. Group assignment was not indicated on the specimens, so the mycologists were therefore blinded to treatment allocation. Each specimen was directly microscopically examined and cultured on Sabouraud media. The attending physicians were not aware of the results of the colonisation samples, and therefore no empirical or pre-emptive antifungal therapy was in place in enrolled patients.Candida species (except blood) and the total number of sites tested. The CCI was calculated for each time point as the product of the CI multiplied by the ratio of the number of distinct nonblood body sites showing heavy growth to the total of body sites growing Candida species. Fungal infection was defined as either the presence of candidaemia or the identification of Candida species in a normally sterile body site, associated with severe sepsis and negative tests for bacteria. During the study period, adverse events related to the study drug were monitored .Colonisation was assessed for each body site specimen, and yeasts were identified. Fungal colonisation was defined as the presence of the same yeast on one or more of the six distinct body sites tested (blood sample excepted). The CI was calculated for each multiple-site testing as the ratio between the number of distinct body sites colonised by t test was used to compare normally distributed continuous variables, and the Mann-Whitney U test was used to analyse variables not normally distributed. All P values were two-tailed. Statistical significance was set at P ≤ 0.05. For an estimated rate of fungal colonisation reaching approximately 60% in ICU patients, 49 patients per group had to be enrolled in the study to show a 50% reduction in fungal colonisation, with an α error of 5% and a β error of 20%.Continuous variables are expressed as the mean ± standard deviation or median (interquartile range). Categorical variables were compared by chi-square test or Fisher's exact test. Student's Of 260 patients assessed for eligibility, 128 were randomised to the two study groups. Of these randomised patients, 99 completed the study : 49 patients were randomised to group N and 50 patients to group C , followed by antibiotic therapy (n = 82) and parenteral nutrition (n = 56). The duration of mechanical ventilation as well as the ICU stay were similar between the two groups  while 30 patients were not colonised (15 patients in both groups). The most frequently colonised body sites were the stomach and the pharynx , followed by the trachea (27%) and the rectum (20%). There were no differences between the two groups at this time. The most frequent isolated Candida species at T0 was Candida albicans (71%), followed by Candida glabrata (14%) and Candida krusei (1%). Figure P = 0.36), while a significant statistical difference was observed between group N and group C at T6 , at T9 , at T12 , and at T15 .At admission, 69 patients exhibited  trachea 7% and thP <0.00009) at T6, and this difference persisted over time. At the end of the study period, the percentage of positive rectum samples significantly decreased in group N (from 12 to 8%) while it increased from 28 to 55% in group C (P <0.0001). A significant reduction of positive urinary samples was also noticed in group N (from 10 to 0%) compared with group C , No difference was detected in pharyngeal samples  as opposed to the control group . At T6, however, group N showed a statistical significant reduction of CCI , and this difference persisted at T9 , at T12 , and at T15  , but this significance did not persist over time and the very low number of the patients did not allow any analysis.Among patients colonised at admission, no statistical difference in CCI was found between the two groups at T0 and T3  or a shift to less susceptible or resistant non-albicans species (C. glabrata or C. krusei), increased costs, and adverse events [Invasive candidiasis infections are associated with an increased morbidity and mortality in ICU patients (30 to 40%), depending on the severity of underlying disease, the reatment . Early areatment . This isreatment ,22. Somee events ,24. Moree events ,26.Candida species, including C. glabrata and C. krusei. Although most species of Candida isolated in ICU patients remain susceptible to azoles, indiscriminate use of such drugs may lead to the spread of C. krusei and C. glabrata, intrinsically resistant to and dose-dependently sensitive to azoles, respectively [Candida species is limited to Candida lusitaniae and to some strains of Candida guillermondii, and resistance seldom develops during treatment [In this context, the use of nystatin may present a rationale alternative . Nystatiectively . In contreatment . MoreoveCandida species colonisation [Candida species colonisation. Since colonisation can be observed on admission to the ICU in almost 50% of patients [Nonabsorbable polyenes are integrated in most selective decontamination of the digestive tract regimens, and a recent meta-analysis showed that they significantly reduce fungal carriage and overall fungal infections, but without impact on fungemia . This menisation . This trpatients ,18, a coThe present trial showed that oral nystatin prophylaxis started on the day of admission is significantly effective in reducing heavy fungal colonisation, even in baseline colonised patients. This finding was presumably related to the efficacy of oral nystatin to significantly reduce the proportion of positive gastrointestinal sites , as shown in the treatment group. Accordingly, the CCI regularly decreased over time in patients receiving nystatin, whereas it tended to increase in controls. No adverse events developed during the study period, confirming that this polyene is a safe choice in the surgical ICU population. Interestingly, nystatin prophylaxis also reduces colonisation in the urinary tract, which is now advocated as the easier and simpler marker for heavily colonised patients . A possiCandida colonisation, this is usually not true for trauma patients. When we analysed the subgroup of trauma patients, however, we noted that almost 50% of them were colonised at admission to the ICU - suggesting that, in many cases, fungal colonisation can be community acquired and not only hospital related. Further trials are needed, in our opinion, to investigate this hypothesis.In the present study, almost 70% of included patients were colonised at admission. This was a surprising finding. While neurosurgical and abdominal surgery patients have several comorbidities and risk factors  that may predispose to subsequent Candida colonisation is very common among ICU patients, reaching 60% in non-neutropenic critically ill patients [Candida species overgrowth on mucosal and skin surfaces [Candida colonisation can be statistically associated with a higher frequency of clinical manifestation or even higher mortality [patients , and is patients ,13 sincesurfaces  and transurfaces ,33. Candortality . Based oortality .Candida infection can be drawn from our study because none of the included patients, even if heavily colonised, developed the infection. A probable hypothesis to explain this unexpected result is that, in our ICU, a rigid surveillance policy of central venous catheters was undertaken, including strict asepsis during insertion, careful medication, and early removal as soon as possible (median 3 days). This approach, together with a rapid interruption of parenteral nutrition in favour of the enteral route, could justify why no episode of Candida infection was documented during the study period. Moreover, the number of patients with abdominal surgery is low, especially in comparison with neurosurgical patients. This factor could be important because abdominal surgery is a risk factor for invasive candidiasis more than other types of surgery. This trial, finally, was designed to investigate the effect of nystatin prophylaxis on fungal colonisation during the ICU stay and not to detect any reduction in fungal infection, which would have required a larger number of patients.Unfortunately, no definitive conclusion regarding the effect of nystatin prophylaxis on Other limitations of the present study included the single-centre, open-label design and the small sample size. The inclusion criteria adopted , however, selected a homogeneous population of ICU patients, treated by the same staff adopting the same protocols to prevent infection - assuring, in our opinion, consistent and reliable results. Larger trials are warranted to elucidate the impact of nystatin prophylaxis on the infection rate and mortality in critically ill patients.The present trial shows that nystatin pre-emptive therapy in surgical/trauma ICU patients significantly reduces fungal colonisation, even in those colonised at admission. Moreover, when CCI is not calculated, we suggest nystatin use in those patients expected to require a long intensive care stay. This approach could contain antifungal therapy costs. Further clinical data are needed, however, to better identify patients who might warrant antifungal prophylaxis using drugs with low risk of resistant stain emergence, in order to drastically reduce fungal-related morbidity and mortality.• The incidence of nosocomial candidemia has dramatically increased and has been associated with high overall (35 to 80%) and attributable (30 to 40%) mortality.• An early and adequate antifungal treatment is independently associated with a reduction of hospital mortality.• Oral nystatin prophylaxis started at the day of admission is significantly effective in reducing fungal colonisation, even in baseline colonised ICU patients.CCI: corrected colonisation index; CI: colonisation index; group C: control group; group N: nystatin group; T0: day of admission to the ICU; T3: third day of ICU stay; T6: sixth day of ICU stay; T9: ninth day of ICU stay; T12: 12th day of ICU stay; T15: 15th day of ICU stay.The authors declare that they have no competing interests.MG participated in the design of the study, acquisition of data, drafted the manuscript, and performed statistical analysis. GC participated in the design of the study and acquisition of data. LD participated in the design of the study and performed statistical analysis. NB drafted and revised the manuscript for important intellectual contents. IA participated in the design of the study, acquisition of data, and drafted the manuscript. AS, AF, and CC participated in the acquisition of data. MTM contributed to analysis and interpretation of data. FB conceived the study and approved the final version to be published. FP drafted the manuscript, contributed to analysis and interpretation of data, and revised the manuscript. All authors read and approved the final manuscript.


Few studies demonstrate effectiveness of therapies for oral rehabilitation of patients with cerebral palsy (CP), given the difficulties in chewing, swallowing and speech, besides the intellectual, sensory and social limitations. Due to upper airway obstruction, they are also vulnerable to sleep disorders. This study aims to assess the sleep variables, through polysomnography, and masticatory dynamics, using electromiography, before and after neuromuscular electrical stimulation, associated or not with low power laser  and LED (= 660 nm) irradiation in CP patients.50 patients with CP, both gender, aged between 19 and 60 years will be enrolled in this study. The inclusion criteria are: voluntary participation, patient with hemiparesis, quadriparesis or diparetic CP, with ability to understand and respond to verbal commands. The exclusion criteria are: patients undergoing/underwent orthodontic, functional maxillary orthopedic or botulinum toxin treatment. Polysomnographic and surface electromyographic exams on masseter, temporalis and suprahyoid will be carry out in all sample. Questionnaire assessing oral characteristics will be applied. The sample will be divided into 5 treatment groups: Group 1: neuromuscular electrical stimulation; Group 2: laser therapy; Group 3: LED therapy; Group 4: neuromuscular electrical stimulation and laser therapy and Group 5: neuromuscular electrical stimulation and LED therapy. All patients will be treated during 8 consecutive weeks. After treatment, polysomnographic and electromiographic exams will be collected again.This paper describes a five arm clinical trial assessing the examination of sleep quality and masticatory function in patients with CP under non-invasive therapies.The protocol for this study is registered with the Brazilian Registry of Clinical Trials - ReBEC RBR-994XFSCerebral Palsy. Stomatognathic System. Electromyography. Transcutaneous Electric Nerve Stimulation. Phototherapy. Sleep Disorders. Polysomnography. Cerebral palsy (CP) refers to disorders of motor development, rising from the primary brain injury, are permanent and changeable character, causing secondary musculoskeletal abnormalities and limitations in activities . Recent Currently, the children with CP are classified according to their functional independence in gross motor function. Through Gross Motor Function Classification System (GMFCS) for CP , the claIt is known that the main alteration present in children with CP is the motor impairment, which causes several modifications rose from encephalopathy, with consequent changes in body biomechanics. In addition, the child may have intellectual disorders, sensitive, visual and hearing, which added to the motor changes, task constraints and the environment, have repercussions in different ways in their functional performance ,7-11.Besides the difficulties in locomotion previously described, as a result of the lack of motor coordination, orofacial alterations are also common in these individuals. These disorders are followed by pain, joint noise and irregular or deviated jaw function . IndividIn general, important functions such as mastication, speech and swallowing are compromised, due to tongue thrusting, cheeks and lips incompetence, resulting in salivary incompetence, presence involuntary bite reflex, asymmetric positioning of the neck, making it difficult to maintain the posture of the head, as well as lack of dynamic balance of the masticatory muscles -16. SomeThis study aims to assess the sleep variables and masticatory dynamics by means of PSG and EMG, respectively, prior and after neuromuscular electrical stimulation, associated or not with low power laser irradiation  and LED (= 660 nm) in patients with cerebral palsy. It is expected that Laser e LED biostimulation will promote the morphophysiologic recovering of muscle fibers and the decreasing of inflammatory process that will be observed through the achievement of muscular physiology within normal patterns established in this study. It is hypothesized that oxyhemoglobin desaturation, caused by pauses in breathing during sleep, can lead to harmful function in neuromuscular system in individuals with CP. We also hypothesize that electrical stimulation, led therapy and laser therapy will contribute to balance the muscular function, adjusting to physiologic patterns of muscular activity, in rest and isometric positions ,18. The This is a randomized, five arms clinical trial Figure  conducteAdult individuals between 19 and 60 years old with CP will be recruited from the Training Program in Dentistry for Persons with Disabilities, Department of Biosciences and Oral Diagnosis, School of Dentistry, São Paulo State University, Sao Jose dos Campos, SP, Brazil.It will be included hemiparetic, quadriparetic or diparetic CP subjects, with partially preserved cognitive function, ability to respond to verbal commands, and informed consent signed by patient or patient’s responsible to voluntary participate in the study. The exclusion criteria are patients underwent to orthodontic or functional maxillary orthopedic treatment and therapies to reduce spasticity (eg. botulinum toxin) at least 6 months before the study.After the evaluation of the eligibility criteria, the subjects will be randomly distributed into the five intervention groups. Randomization numbers will be generated using envelopes which will contain a card stipulating to which group the subject will be allocated. It will be used sealed and opaque envelopes to ensure confidentiality.The sample size, obtained by means of statistical power analysis revealed that with 10 subjects in each group, an 90% power to detect a clinically relevant difference would be present at the alpha level of 0.05.Anamnesis will be obtained in order to assess chief complaint, onset, frequency, evolution of the problem, consulted professionals, treatments, results and prescription of drugs, medical and family history, parafunctional habits and psychogenic aspects.A specific part of the questionnaire will approach sleep breathing disorders, including snoring, choking during sleep, drooling, nightmare experience, movement during sleep and mood after waking. For the clinical examination, dental occlusion, tooth wear, tooth loss, Mallampati evaluation  and tonsFor the EMG record, it will be used an eight-channel electromyography equipment  Figure  [Figure The average data will be expressed in RMS (Root Mean Square) which qualitatively expresses the record of electrical activity of muscles under study .It will be used a mandibular force transducer  Figure .The sEMG, referring to the masseter, temporallis, supra-hyoid, bite force and range of mandibular opening shall be provided in four distinct phases. Phase 1- initial data collection (Groups 1 to 5); Phase 2- treated groups (Groups 1 to 5) after 1 week of electrical stimulation with or without laser and LED therapy; Phase 3-treated groups (Groups 1 to 5) after 4 week of electrical stimulation with or without laser and LED therapy and Phase 4-treated groups (Groups 1 to 5) after 8 weeks after the last electrical stimulation with or without laser and LED therapy.Data obtained will be compared among each group to verify the effectiveness of the proposed therapies to improve the masticatory muscle activity in patients with CP.After the evaluation and diagnosis, patients will be randomly divided into 5 groups (n = 10). Groups 2 to 5 will be treated with lasertherapy or LED theraphy, combined or not with electricalstimulation twice a week for eight consecutive weeks, following the protocol of .2. Groups 3 and 5 will be irradiated with a light emitting diode (LED), emitting a wavelength band of 630 ± 5 nm, with a constant power 40 mW, and the maximum laser beam diameter of 0.38 cm2. Both will be operated in continuous mode and should be used in contact with the target tissue, providing an irradiance or intensity of 0.40 mW/cm2. The incidence of fluency range for each point of application will be of 12.0 J/cm2, and the irradiation time of 30 seconds for each predetermined point.The craniofacial complex will be irradiated in 12 areas, being 1. posterior region of the temporomandibular joint (TMJ) with open mouth, reaching the auriculo temporal nerve; 2. area prior to the sigmoid notch, insertion area of the lateral pterygoid muscle (upper beam) at the neck of the condyle and disk; 3. articular interface between condyle and fossa with open mouth; 4. angle of the jaw; 5. anterior temporal muscle; 6. middle portion of the temporal muscle; 7. posterior portion of the temporal muscle; 8. upper, middle and bottom of the sternocleidomastoid muscle; 9. anterior portion of occipitofrontal muscle; 10. posterior portion of the occipitofrontal muscle; 11. superficial portion of the masseter; and 12. supra-hyoid muscles. In groups 2 and 4, these anatomical structures will be irradiated with a laser diode of gallium arsenide and aluminum-GaAlAs , emitting at a wavelength of 660 nm, with a constant power 40 mW, and a maximum beam diameter of 0.38 cmNMES is a noninvasive technique, without systemic effects, is not addictive and has no undesirable side effects. This technique consists on the application of mild electrical stimulation through electrodes placed on the surface of muscles. It induces action potentials in motor nerve, causing activation of motor units . EffectsNeuromuscular electrical stimulation (Neurodyn III) equipment will be used. In this study, a protocol will be applied based on Nunes  recommenA full-night PSG  will be In order to ensure data quality, dentists in charge of EMG exam, as well as the speech-therapist in charge of oral movements and sleep technician in charge of the data acquisition of polysomnography will receive specific training. Periodic external monitoring will be performed to verify the adequate polysomnnographic examination. The results of the preoperative and postoperative exams will be analysed by blinded evaluators.t-test or Wilcoxon tests as appropriate. Comparisons between groups will be performed using Student t test or Mann–Whitney U according to the distribution. All tests will be 2 tailed, and p values of less than 0.05 will be assumed to represent statistical significance. All analyses will be performed using SPSS ver. 16.0.Data will be presented as means ± standard deviation, when applicable. For comparison of continuous variables prior and after polysomnography and specifics therapies, it will be used the paired Student This study will evaluate the effects of lower power laser, neuromuscular electrical stimulation, LED therapy, as well as neuromuscular electrical stimulation plus LED therapy and neuromuscular electrical stimulation plus laser therapy on the masticatory muscles activity in adults with CP, by means of surface electromyography. We believe that electrical stimulation may act in the modulation of muscle hyperactivity/hypoactivity, adjusting them to a level close to normality. Also, we expect the LED and laser morphophysiological favor recovery, which will be observed clinically by the absence or reduction of pain. In addition, polysomnography will be used to evaluate the sleep variables and to detect sleep-breathing disorders, and we believe that the sleep quality will be improved after therapies application.The authors declare that they have no competing interests.All the authors contributed to the conception and design the study. LCG and MFG provided the idea for the study, established the hypothesis and wrote the original proposal. SRFB is a speech therapist of the patients and made a contribution to evaluate and collect the data of the oral motor function. LCG, MYM, CTH and CPG made a contribution to acquisition and interpretation of EMG data. IRS, EFO, and ISD made a contribution to acquisition and interpretation of PSG data. LCG and LC significantly contributed to statistical analizys. SRN is a medical doctor, sleep specialist, made a contribution to literature research and shall make polysomnographics reports. ICA and JBOA were involved in critically revising the manuscript. CSO, LVFO and MFG supervised this study, participated in its design and coordination and, revised the manuscript that led to the final approval of the current submission. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2474/13/71/prepub