P < 0.05). With the optimal cut-off value, Kaplan-Meier analysis showed that MTC patients with LNR≥76.5% were significantly associated with poorer OS (log-rank test: P < 0.0001), and LNR≥40.7% were significantly associated with poorer DSS (log-rank test: P < 0.0001). LNR was an independent prognostic factor of poorer survival in MTC patients after adjusting for other variables by multivariable Cox analysis . Our results demonstrated that LNR could predict clinical outcomes in patients with stage IV MTC, and 76.5% was the optimal cut-off value of LNR to predict OS. LNR, as a function of the nodes positive and the nodes examined, could provide suggestions on the postoperative prognosis of patients with stage IV MTC.To assess the prognostic value of lymph node ratio (LNR) in patients with stage IV thyroid cancer based on the Surveillance, Epidemiology, and End Results (SEER) database. A total of 4,940 eligible patients were included for the analysis. Kaplan-Meier survival analysis and Cox proportional hazard regression were used to reveal the effect of LNR on overall survival (OS) and disease specific survival (DSS). The optimal cut-off value of LNR for predicting OS and DSS was determined by the time-dependent Receiver Operating Characteristic analysis. By the univariate Cox proportional hazard regression, LNR was significantly associated with OS and DSS in patients with medullary thyroid cancer (MTC), papillary thyroid cancer and anaplastic thyroid cancer (all  Thyroid cancer (TC) is the most common endocrine malignancy, and the incidence had been accelerating worldwide over the past few decades , 2. In tThe pathological types of TC, mainly containing papillary, medullary, follicular and undifferentiated, not only differs on pathogenesis, but also on the metastatic behavior and prognosis. For instance, nearly 30% to 80% patients of PTC have regional LN metastasis . But forPrevious studies have demonstrated the prognostic significance of lymph nodes (LNs) metastases , 9, whicFinally, a total of 4,940 eligible patients with Stage IV thyroid cancer were included in the present study Table , containP < 0.05) (Table P < 0.05). Extent of lymphadenectomy showed a significant association with OS , and with DSS . And the number of positive nodes examined had significant effect on OS , however, the effect was not found on DSS .By the univariate Cox regression analysis, we found that age (≥ 45 years), sex , grade, AJCC staging, histological types, radiation treatment, extent of lymphadenectomy and number of positive nodes were all significantly associated with OS  Table . And genP < 0.05) (Table P < 0.0001).Similarly, LNR was found to increase the risk of disease specific death in patients with PTC, MTC and ATC, even after adjustment for other variables .By the univariate Cox analysis, LNR was examined to be significantly associated with OS in patients with PTC, FTC, MTC and ATC  Table . After aP < 0.0001; DSS: AUC = 0.581, P < 0.0001). Then the MTC patients were divided into two groups by the cut-off values of LNR. The Kaplan-Meier analysis showed that a higher LNR was associated with poorer OS (P < 0.0001)   Figure  and DSS ) Figure .P < 0.0001), and could predict OS after adjusting for sex, age, race, grade, AJCC stage and radiation treatment . As we analyze the predictive value of LNR on DSS, LNR≥40.7% could significantly increase the risk of DSS than LNR<40.7% , and remains significant after adjustment for other variables .Univariate and multivariate Cox analysis were used to identify the significance of LNR on OS and DSS in MTC patients Table .ComparedTo the best of our knowledge, this is the first empirically based study on the risk of LNR in patients with advanced stage TC. Current guidelines from the National Comprehensive Cancer Network (NCCN) and American Thyroid Association (ATA)  recommenPrevious studies have identified that LNR was an important prognostic factor in several cancers –13. As fP < 0.05), illustrating the contribution of LNR to the risk of disease specific death. However, its association with OS could not be confirmed by multivariate Cox regression analysis after adjusting for other variables. Based on the present study, we could not conclude that LNR contributes to morality risk in patients with stage IV PTC. ATC, accounting for 1.3–9.8% of total TC, is the histological type that has the most aggressive progression [P < 0.05), and also by Cox multivariate regression analysis (P < 0.05) after adjusting for variables. Based on those findings, LNR was also associated with clinical outcomes in patients with advanced stage ATC. Due to the limited number of ATC patients, further analysis was censored.PTC is the most common histological type of thyroid cancer and elicits good therapeutic response to surgery and radioiodine treatment. For patients with advanced stage PTC, LNR has been suggested to be useful to predict prognosis by several studies , 22. We gression . Most ofgression , indicatP = 0.002) [P = 0.001). The difference of our study is the patients included that they were staged as advanced stage. And by the cutoff value of LNR for MTC patients, it was demonstrating that 76.5% LNR was a potential value to distinguish patients from higher risk of overall death, and 40.7% LNR could also predict the risk of disease specific death. Although the AUC=0.569 was not fully enough to explain the contribution of LNR on the mortality risk of disease specific death, LNR could still predict OS and provide more clinical significance for the postoperative treatment in advanced stage MTC patients.It is known to us that the rates of nodal metastases were relatively high in patients with MTC. The more LNs removal indicated the more complete excision of tumor during surgery in patients with MTC. According to the latest 2015 ATA guidelines, patients with MTC confined to the neck and cervical LNs should undergo dissection of the central (levels VI–VII) and the involved lateral neck compartment (level II–V). Due to the high rate of occult disease, prophylatic central neck dissection is advised in all cN0 patients . It was = 0.002) , which wAlthough the study reveals numerous important positive findings, it has several potential drawbacks. The main limitation of the study is the inherent bias, which exists in retrospective study. Patients included were from SEER database, thus some cases without complete information was deleted. Also, both the LNs dissected by surgeons and LNs examined by the pathologists could influence the outcome of the study. Second, the SEER database does not provide information on treatment, which could not be adjusted during the multivariate regression analysis. In addition, the study was based on the stage IV MTC patients with limited number of patients, further study with larger samples is needed to validate our results.In conclusion, we investigated the prognostic value of LNR in patients with stage IV TC based on SEER database. Our results indicated that a higher LNR was significantly associated with poorer OS and DSS in MTC patients with advanced stage who experience surgical treatment with node positive, and 76.5% LNR was the optimal cut-off point to predict OS in MTC patients. LNR, as a function of the nodes positive and the nodes examined, could provide evaluation of lymphadenectomy and give suggestions on the prognosis of postoperative MTC patients.https://seer.cancer.gov/registries/terms.html). The registries could broadly represent the Unite States population as a whole, accounting for 28% of population from academic and nonacademic hospitals. In view of the data from SEER were de-identified, written informed consent cannot be assessed. The present study was conducted in accordance with the Declaration of Helsinki and relevant guidelines, and was approved by the independent ethics committee/institutional review board at the Second Affiliated Hospital of Fujian Medical University.Data was obtained from the SEER program, which consists of 18 population-based cancer registries  with unknown age records, 2) with benign or borderline tumors, 3) without or with unknown positive nodes, 3) without or with unknown number of node examined. Pathologic diagnosis was based on the primary site by the International Classification of Disease for Oncology, Third Edition (ICD-O-3). Totally, patients’ information on age, sex, race, AJCC staging, grade, histological types, radiation treatment, total number of LNs examined, positive number of LNs examined (LNs containing metastases), overall survival (OS) and disease specific survival (DSS) were extracted into the analysis.P-value < 0.05 was considered as statistically significant. SAS  program was used for analysis.Cox proportional hazard regression analysis was used to identify risk factors of OS and DSS. In the subgroups of histological types, univariated and multivariated Cox regression analysis was used to identify the risk of LNR on OS and DSS. The optimal cut-off value for LNR in medullary TC (MTC) was determined by the time-dependent receiver operating characteristic (ROC) analysis. Then the comparisons between groups divided by the optimal cut-off point of LNR was determined by the Kaplan-Meier method. Finally, univariated and multivariated Cox regression analysis was used to reveal the effect of LNR on survival in MTC with adjusting for age, sex, race, AJCC staging, grade and radiation treatment. All


Cannabis sativa that has a broad spectrum of potential therapeutic effects in neuropsychiatric and other disorders. However, few studies have investigated the possible interference of CBD on the sleep-wake cycle. The aim of the present study was to evaluate the effect of a clinically anxiolytic dose of CBD on the sleep-wake cycle of healthy subjects in a crossover, double-blind design. Twenty-seven healthy volunteers that fulfilled the eligibility criteria were selected and allocated to receive either CBD (300 mg) or placebo in the first night in a double-blind randomized design (one volunteer withdrew from the study). In the second night, the same procedure was performed using the substance that had not been administered in the previous occasion. CBD or placebo were administered 30 min before the start of polysomnography recordings that lasted 8 h. Cognitive and subjective measures were performed immediately after polysomnography to assess possible residual effects of CBD. The drug did not induce any significant effect (p > 0.05). Different from anxiolytic and antidepressant drugs such as benzodiazepines and selective serotonin reuptake inhibitors, acute administration of an anxiolytic dose of CBD does not seem to interfere with the sleep cycle of healthy volunteers. The present findings support the proposal that CBD do not alter normal sleep architecture. Future studies should address the effects of CBD on the sleep-wake cycle of patient populations as well as in clinical trials with larger samples and chronic use of different doses of CBD. Such studies are desirable and opportune.Cannabidiol (CBD) is a component of  Cannabis sativa, has been shown to have several therapeutic effects including antipsychotic (Cannabidiol (CBD), one of the major compounds of sychotic , antidepsychotic , anti-epsychotic  anti-infsychotic , and anasychotic , besidessychotic .Cannabidiol may play a therapeutic role in sleep regulation . In healAt lower doses, CDB (15 mg/day) co-administered with tetrahydrocannabinol  increased wakefulness . More reAlthough some studies have demonstrated the potential effect of CBD on sleep behavior, research about the effects of CBD on the slow wave sleep (SWS) of humans with regular sleep is still lacking. The impact of CBD on sleep, possible side-effects or the advantages of lack of them, including objective measures through polysomnography, has not yet been investigated. Thus, the objective of the present study was to assess the effect of the acute administration of an anxiolytic dose 300 mg, , 2017 of; PSQI, Pittsburgh Sleep Quality Index). After these procedures, 27 participants were considered eligible for the study  and were randomized into two groups  matched in terms of sex, age, and years of education. To ensure the adequacy of the matching procedure, one participant of each pair had his treatment blindly chosen between the two treatment options available and the other participant (matched to the first one) was assigned to the remaining option.Participants were recruited through advertisements in the local media of the city of Ribeirão Preto, São Paulo, Brazil. Initially, 335 individuals who were interested in participating were evaluated, 265 of whom were excluded in the recruitment interview . The remaining 70 participants were asked to keep a sleep log and completed the rating scales on sleep patterns  presence of organic brain syndromes; (ii) use of psychoactive drugs, including nicotine; (iii) presence of general medical conditions, assessed by the patient’s report during the interview and/or through physical examination; (iv) presence of psychiatric disorders (assessed with the SCID-IV); (v) pregnancy; (vi) previous history of any sleep disorder ; and (vii) recent changes in sleep time . Thus, the volunteers were all non-smokers and had not taken any medications for at least 3 months before the study. Moreover, none of them had used marijuana more than five times in their lives (no use in the last year) and none had ever used any other illegal drug. All subjects gave their written consent to participate after being fully informed about the research procedures, which were approved by the Hospital das Clínicas de Ribeirão Preto of University of São Paulo ethics committee (HCRP No. 17912/2013).The following instruments were used: (a) Visual Analog Mood Scale – VAMS ; (b) StaThe apparatus used for the polysomnography exams consisted of different devices including electroencephalogram with the international 10–20 system (to rule out the occurrence of epileptic seizures), electrooculogram, electromyogram of chin muscles and upper and lower limbs, nasal pressure cannula, oral thermistor, thoracic and abdominal respiratory inductive plethysmography straps, pulse oximetry, electrocardiogram, and snoring and body position sensors. Video and sound were also recorded during the exam.LYNX Tecnologia Eletrônica, Rio de Janeiro, Brazil). Sleep stages were recorded in periods of 30 s, according to the criteria established by Polysomnography recordings were obtained through a computerized system , 99.9% purity without THC  was dissolved in corn oil . The samSubjects were instructed to abstain from alcohol for 24 h and caffeine for at least 24 h before each visit to the laboratory. Subjects who reported having less than 6 h of sleep the previous night were excluded from the trial. After at least 8 h of fasting, subjects were instructed to have a light, standardized meal 2 h before the experiment. For the present study, a randomized, double blind, and crossover model was used. Once one volunteer gave up participating the study, the 26 participants were assessed on two different occasions, in a 2-week interval, with identical procedures except for the substance that was administered. In each visit, participants were first submitted to a cognitive and subjective evaluation, then an oral dose of CBD (300 mg) or placebo was administered 30 min before the polysomnographic recordings began.Figure 1.After arrival at the Clinical Research Unit of the Ribeirão Preto Medical School University Hospital  written informed consent was signed, the subjective measures  of the participants were collected and the electrodes used for the polysomnography exam were placed. Next, the subjective measures were completed once again  and, 30 min before the beginning of the polysomnographic examination, the single dose of CBD (300 mg) or placebo was administered. Polysomnography recordings were performed over 8 h. On the morning after the examination, the electrodes were removed from the subject and the VAMS, STAI, WAIS, and PVT were completed. The steps of the experimental protocol are shown in t-tests were performed at each phase and/or order to compare the differences between groups. In case of significant time effect, the Bonferroni’s post hoc test was used for multiple comparisons. In cases where sphericity conditions were not reached, the degrees of freedom of the repeated factor were corrected with the Huynh-Feldt epsilon. All the analyses were performed with the Statistical Package for the Social Sciences (SPSS) v.20.0.Clinical and demographic data were analyzed with descriptive statistics and expressed in terms of mean ± standard error of the mean. The Kolmogorov-Smirnov test was used to check for normality. Non-parametric Wilcoxon or Friedman tests analyzed results that failed this test. The remained data was analyzed by two-way repeated-measures ANOVA. A preliminary analysis indicated no gender effect; thus, the factors analyzed were drug, order of drug administration (placebo-CBD versus CBD-placebo), and the interaction between drug and phase. A three-way repeated-measures ANOVA was employed to analyze data throughout the three phases of each exam. In case of significant interactions, paired Student’s Table 1.The demographic characteristics of the subjects as well as measures from the scales assessing sleep and body mass index are described in Table 2. The results are presented according to the seven components assessed in the PSQI.The data of the PSQI, used in the selection of volunteers, are reported in The data obtained in the seven components and the total PSQI score are indicative of good sleep quality. Total PSQI scores greater than five suggest difficulties in at least two components or moderate difficulties in more than three components .Table 3. The comparative analyses between CBD and placebo indicate that none of the parameters evaluated presented statistically significant changes.The main polysomnographic results of the administration of CBD and placebo are described in F1,24 = 2.46; p > 0.05) or order of administration , but the interaction between drug and order was significant . To check if this interaction could have potentially interfered with the results, we split the subjects, comparing the placebo and CBD groups separately in the two orders (first placebo or CBD). Again, there was no difference between groups in the two situations.No statistically significant differences were found between groups in the VAMS, STAI, Digit Symbol Substitution and Symbol Copying Tests, and PVT. In the analysis of the WAIS, the results in the Symbol Copying Tests showed no effects of drug  and selective serotonin and norepinephrine reuptake inhibitors (SNRIs) may interfere with sleep architecture and decrease restorative sleep, leading to increased awakenings, reduced REM sleep, increased REM latency, as well as increased periodic limb movement during sleep . In addiCannabidiol’s anti-anxiety  and antiThe relative representativeness of the small sample size and the use of a single dose of CBD can perhaps be regarded as a limitation of our study, as it does not allow the assessment of the effects of chronic treatment with CBD on sleep. In the study by Despite these limitations, this is the first controlled study to evaluate the effects of CBD on sleep architecture using polysomnography. Although the absence of interference with the sleep cycle is not sufficient for concluding that sleep is not affected, the results obtained contribute for the understanding of the effects of CBD in the modulation of sleep in humans.We found no differences between CBD and placebo in respect to polysomnographic findings or cognitive and subjective measures in a sample of healthy subjects. Unlike widely used anxiolytic and antidepressant drugs such as benzodiazepines and SSRIs, the acute administration of an anxiolytic dose of CBD does not appear to interfere with the sleep cycle of healthy volunteers. Future studies should address the effects of CBD on the sleep-wake cycle of patient populations as well as evaluate the chronic effects of CBD in larger samples of patients with sleep and neuropsychiatric disorders.JC, JH, FG, AZ, and AE: conception or design of the work. IL, JS, and AE: data collection. AE, FG, IL, AZ, and AC: data analysis and interpretation. JC, IL, AZ, JH, and FG: drafting the article. JC, JH, FG, AZ, AE, AC, JS, and IL: critical revision of the article. JC, JH, FG, AZ, AE, AC, JS, and IL: final approval of the version to be published.Phytecs Pharm (USP Resolution No. 15.1.130002.1.1). The University of São Paulo has an agreement with Prati-Donaduzzi  to “develop a pharmaceutical product containing synthetic cannabidiol and prove its safety and therapeutic efficacy in the treatment of epilepsy, schizophrenia, Parkinson’s disease, and anxiety disorders.” JH and JC have received travel support from and are medical advisors of BSPG-Pharm. AZ is medical advisor of BSPG-Pharm. The other 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.AZ, JH, FG, and JC are co-inventors  of the patent “Fluorinated CBD compounds, compositions and uses thereof. Pub. No.: WO/2014/108899. International Application No.: PCT/IL2014/050023” Def. US no. Reg. 62193296; 29/07/2015; INPI on 19/08/2015 (BR1120150164927). The University of São Paulo has licensed the patent to


Allergic rhinitis (AR) is associated with various developmental issues that affecting dentition. We aimed to determine whether AR is associated with an increased risk of traumatic dental injuries (TDIs) in Taiwanese individuals. We used the Taiwan National Health Insurance Research Database (NHIRD) to conduct a nested case-control study. We compared an AR cohort with a matched cohort of patients without AR. New TDI cases were determined during our study period. To compare TDI risk between our study cohorts, we used Cox proportional regression analysis, and hazard ratios (HR) with 95% confidence intervals (CI) were calculated to quantify the association between AR exposure and TDI risk. In total, 76749 patients with AR  were identified. In the AR and the non-AR cohorts, 312 patients in total had TDI. Patients with AR had a significantly higher risk of TDI than those without AR . The risk of TDI was markedly higher in the AR cohort, except in the 3–12-year-old group, and with a CCI ≥ 1. AR patients had a future risk of TDI, indicating a potentially linked disease pathophysiology. The association between AR and TDI is greater among general patients. Clinicians and caregivers should be aware of potential TDI co-morbidity in patients with AR. Allergic rhinitis (AR) is the most common airway-obstructing disease, affecting 17.9%–26.3% of adolescents . AdditioThis raises the question of whether AR may lead to traumatic dental injury (TDI). TDI is a serious dental public health problem that results in fractured, displaced, or lost teeth and can have significant negative functional, esthetic, and psychological effects. In addition to pain and increased infection risk, the consequences of TDI include changes in physical appearance and speech defects, and can thus affect the patient’s quality of life. TDI is more time-consuming and costly to treat than many other outpatient accidental injuries .TDI occurs frequently in children and young adults, comprising 5% of all injuries. Boys are generally injured more frequently than girls . GeneralOur study aimed to determine the risk of TDI in patients with AR in Taiwan. We conducted a retrospective cohort study to estimate the relative risk of the incidence of TDI in a nationwide AR cohort, as compared with a non-AR cohort selected from a 1 million representative population. We hypothesized that we would be able to predict the tendency for TDI in AR patients. In the high-risk group, more attention was given to prevention of TDI by preventative and interceptive orthodontic treatment and by providing a safe environment. Furthermore, these findings may be used to influence public policies in long-term care and childcare.This study employed a retrospective cohort study design.The Taiwan National Health Insurance Program was established in 1995. This system provides universal health coverage and equal medical access to all Taiwanese individuals. In 2011, the coverage rate of the National Health Insurance was 99.6%; almost the entire population of Taiwan (23 million) was enrolled in this program. A computerized database  was set up, derived from the Taiwan National Health Insurance Program and managed by the Taiwan National Health Research Institute (NHRI), which is a nonprofit foundation established by the government. The NHIRD includes patients’ demographic information, encrypted identification numbers, sex, birth dates, admission dates, diagnostic data and procedures, dates of diagnosis, dates of medical treatment, International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnostic codes, and drug codes.We conducted a nested case-control study using the NHIRD. From 2000 to 2008, nationwide cohorts were identified on the basis of diagnostic codes: AR and non-AR codes. The cohorts included in our study included individuals aged > 3 years.The NHIRD encrypts patients’ personal information to protect privacy, and provided researchers with anonymous identification numbers associated with relevant claims information, including the patient’s sex, date of birth, medical services received, and prescriptions. Therefore, patient consent was not required to access the NHIRD .http://nhird.nhri.org.tw/).All data and related metadata were deposited in an appropriate public repository. The data on the study population obtained from the NHIRD are maintained in the NHIRD  in 2000, whereas those diagnosed with AR before that year were excluded. In addition, we excluded patients with any acute conditions, such as those with ICD-9 codes for physician-diagnosed cerebrovascular disease and epilepsy, to reduce possible confounding effects.For comparison, the non-AR cohort was identified from among individuals aged > 3 years and who had no AR diagnostic codes. Each patient with AR was matched to a non-AR patient on the basis of age, sex, duration of enrollment, and cohort entry date. All patient in our cohorts were followed up until dental trauma occurred or until 2010.As outcomes, we focused on the risk of dental trauma with AR. During our study period, we determined all physician-diagnosed dental trauma cases. Diagnostic codes for dental trauma included ICD-9:873.63—open wound of tooth (broken) (fractured) (owing to trauma), without mention of complications—and 873.73—open wound of tooth , complicated.Chi-square tests were used to compare the baseline characteristics between our two cohorts. We used Cox proportional regression models to compare the risk of dental trauma and to determine adjusted hazard ratios (aHR), which were adjusted for patients’ age, sex, and their Charlson comorbidity index (CCI) score. The non-AR data were used as a reference. A P-value of < 0.05 was considered statistically significant. The cumulative incidence curves of dental trauma in the study cohort were estimated using Kaplan-Meier analyses and the differences between the two cohorts were compared using the log-rank test. All analyses were performed using SAS software, version 9.2 .In total, 76749 patients with AR  were identified during the period of 2000–2008, as shown in There were no significant differences between the AR and non-AR cohorts in terms of age, sex, and duration of follow-up, as shown in During our study period, 312 dental trauma cases were identified in the cohorts, involving 218 patients with AR and 94 without AR, as shown in TDI is a condition with a poor prognosis that influences appearance and function. Our aim was to estimate the risk of TDI in patients with AR, to determine the need for further preventive treatment and for measures to make the environment safe. The database used in this study was released for research purposes by the National Health Research Institutes in 2008. As of 2007, 98.4% of Taiwan’s population (approximately 22.96 million) was enrolled in the NHIRD. The data of the present study were retrieved from 1 million randomly sampled enrollees from the total NHIRD. In this nationwide, population-based, randomized, and longitudinal study, we demonstrated an increased risk of TDI in AR patients, which was 1.92-fold higher than that in the non-AR cohort, after adjustment for sex, age, and medical comorbidities. In each group, the risk of TDI was markedly higher in the AR cohort, except in the 3–12-year-old group, and with a CCI ≥ 1. In the CCI (0) group in particular, excluding most systemic diseases would be more near really risk of TDI with AR. These results support our hypothesis that patients with AR have a higher prevalence of TDI,Airway obstruction is the main syndrome of AR, even if it is not a continuous phenomenon. AR is considered to be one of the major causes of airway obstruction in children , which cIn our study, we excluded patients with cerebrovascular disease and epilepsy to avoid the factors of iatrogenic injury and illness. However, the risk of TDI may be affected by the presence of other systemic diseases that cause oral complications, such as periodontitis or trismus. Deyo’s CCI score differed significantly between the AR and non-AR cohorts, with the AR cohort having more systemic diseases. This tendency may elevate the risk of TDI. To identify the health levels in patients with AR, we used the CCI to discriminate between patients with AR and those without AR, in 3 groups: low (CCI = 0), moderate (CCI = 1) and high (CCI ≥ 2). We found statistically significant differences between cohorts in the low CCI group , but not in the moderate and high CCI groups. The results expressed the risk of TDI between AR and non-AR patients affected by systemic diseases; the CCI = 0 group approximated the risk of TDI between AR and non-AR patients without systemic diseases.In the various age groups, the primary and mixed dentition group did not attain statistically significant differences between the groups . In the AR also affects human behavioral disorders, such as ADHD and oppositional defiant disorder, particularly among children . NeverthThe study had the following limitations. First, the NHIRD did not include orthodontic and cosmetic patients; such corrections may reduce the developmental disorder caused by AR. Second, the maximal follow-up time of our study was 8 years; however, developmental disorders caused by AR persist life-long. Although there were clear differences in the follow-up time between patients with AR and those without AR , furtherIn conclusion, this large-scale, nationwide, population-based, longitudinal study demonstrated an association between AR and the risk of TDI. Although the exact mechanism is presently unclear, these findings may provide further insights into the association and possible shared pathophysiology between AR and TDI. The importance of prevention measures for TDI in patients with AR should be emphasized by ensuring a safer environment. Furthermore, these findings may be used to influence public policies in long-term care and childcare.S1 File(PDF)Click here for additional data file.


Chronic diseases, like diabetes mellitus, heart disease and cancer are leading causes of death and disability. These conditions are at least partially preventable or modifiable, e.g. by enhancing patients’ self-management. We aimed to examine the effectiveness of telephone-based health coaching (TBHC) in chronically ill patients.This prospective, pragmatic randomized controlled trial compares an intervention group (IG) of participants in TBHC to a control group (CG) without TBHC. Endpoints were assessed two years after enrolment. Three different groups of insurees with 1) multiple conditions (chronic campaign), 2) heart failure (heart failure campaign), or 3) chronic mental illness conditions  were targeted. The telephone coaching included evidence-based information and was based on the concepts of motivational interviewing, shared decision-making, and collaborative goal setting. Patients received an average of 12.9 calls. Primary outcome was time from enrolment until hospital readmission within a two-year follow-up period. Secondary outcomes comprised the probability of hospital readmission, number of daily defined medication doses (DDD), frequency and duration of inability to work, and mortality within two years. All outcomes were collected from routine data provided by the statutory health insurance. As informed consent was obtained after randomization, propensity score matching (PSM) was used to minimize selection bias introduced by decliners. For the analysis of hospital readmission and mortality, we calculated Kaplan-Meier curves and estimated hazard ratios (HR). Probability of hospital readmission and probability of death were analysed by calculating odds ratios (OR). Quantity of health service use and inability to work were analysed by linear random effects regression models. PSM resulted in patient samples of 5,309  in the chronic campaign, of 660  in the heart failure campaign, and of 239  in the mental health campaign. In none of the three campaigns, there were significant differences between IG and CG in time until hospital readmission. In the chronic campaign, the probability of hospital readmission was higher in the IG than in the CG ; no significant differences could be found for the other two campaigns. In the heart failure campaign, the IG showed a significantly reduced number of hospital admissions , although the corresponding reduction in the number of hospital days was not significant. In the chronic campaign, the IG showed significantly increased number of DDDs. Most striking, there were significant differences in mortality between IG and CG in the chronic campaign  as well as in the heart failure campaign .While TBHC seems to reduce hospitalization only in specific patient groups, it may reduce mortality in patients with chronic somatic conditions. Further research should examine intervention effects in various subgroups of patients, for example for different diagnostic groups within the chronic campaign, or duration of coaching.DRKS00000584German Clinical Trials Register  Health care systems are faced with an increasing number of patients with chronic conditions such as cardiovascular, respiratory, or metabolic diseases due to the increasing prevalence of individual  and environmental risk factors (e.g. air pollution), demographic changes (e.g. longer life expectancy), and medical progress. If not treated or managed adequately, chronic conditions result in a reduction of patients’ life quality , 2, and Telephone support for self-management or disease management is a promising approach to improve care for patients with chronic conditions –9. TelepMeanwhile, several additional studies have investigated the effects of generic telephone health coaching for patients with chronic conditions. The largest RCT in the US with 174,120 participants with various chronic conditions showed that generic telephone health coaching with elements of shared decision-making, patient information, self-management, and communication skills reduced hospitalization rates, surgical procedures, and health care costs . HoweverIn summary, the most coherent effects were found for telephone health coaching on psychosocial and self-reported outcomes like perceived health and self-efficacy. Study results in a real world setting are still ambiguous for economic effects. More research is needed to determine the cost-effectiveness of generic telephone health coaching services for patients with various chronic conditions . FinallyThe aim of this study was to evaluate the effectiveness of a telephone-based health coaching intervention (TBHC) for patients with chronic conditions in Germany. The primary hypothesis was that TBHC will extend the time period until the patient’s hospital readmission compared to usual care without TBHC.This prospective, pragmatic randomised controlled trial compared participants of TBHC to usual care. The rationale, study design and statistical analysis procedures have been published . The HamStudy participants were recruited between June 2010 and October 2011, had to be at least 18 years old, insured with the “Kaufmännische Krankenkasse (KKH)” , and diagnosed with one or more of the following chronic conditions : diabetes type 2, coronary artery disease, hypertension, heart failure, asthma, chronic obstructive pulmonary disease (COPD), chronic depression or schizophrenia. The allocation of patients to one of the campaigns was based on the principal diagnosis within the routine data set. For patients with type 2 diabetes, hypertension or coronary artery diseases a risk score for hospital readmission was calculated based on a logistic regression model. The model was developed using stepwise logistic regression. The final regression model included following variables: 43 ICD-10 codes, sex, age, annual income, living area , hospital stays, hospital days and hospital costs within the last 12 months, and 13 ATC codes . This model has been validated by analyzing the receiver operating characteristic curve (ROC)  and the Based on various variables from routine data a logistic regression model was designed to predict hospital readmission using SPSS 19. These variables comprise e.g. health care costs, ICD-diagnoses, age and gender. This model has been validated by analyzing the receiver operating characteristic curve (ROC)  and the Patients were excluded if they had insufficient German language skills or were not able to read or use a phone.The TBHC was developed originally by Health Dialog Inc. for chronically ill patients to enhance health behaviour change , 19. Com“chronic campaign” for patients with type 2 diabetes, hypertension, asthma, COPD, and/or coronary artery disease;“heart failure campaign” for patients with heart failure;“mental health campaign” for patients with depression or schizophrenia.More detailed information on the topics addressed by the intervention can be found as supporting information: see Coaching was conducted by 20 experienced nurses in two call centres located in Munich and Halle/Saale. They were supervised 2–4 times per year by two experienced supervisors from the project group .The coaching approach was divided in 3 phases:Phase 1 : The first call was for getting to know each other and for gathering information about the chronic condition, its severity, clinical parameters, health behaviour, and medication. The most important health issues and the motivation for change were assessed.Phase 2 (“orientation phase”): First goals were agreed upon, and the coach increased the insuree’s motivation for change. More information about the patient’s knowledge about his condition and coping with it was gathered.Phase 3 (“maintenance phase”): The coach recalled the agreements made in the last call, fostered the motivation for change, acknowledged success and set new goals together with the insurant. Symptoms and adherence to medication were continuously monitored, information material was sent out. Topics were necessary and useful medical check-ups, information on prevention, nutrition and diet, exercise, and stress management (see appendix 2).www.hon.ch) and related to specific criteria (www.afgis.de), two quality certifications for reliable online health information. Today, NetDoktor is one of the most visited health platforms in the German speaking world. Data on the coaching process, individual goal setting, medication, and clinical parameters (e.g. HbA1c and blood pressure) was recorded by an electronic documentation system. Written patient information for specific conditions, medication plans and weight-control tables could be sent to the participants. Additionally, patients in the heart failure campaign got a booster call. This call was only used to get data on the maintenance of actions (e.g. weighing and medication adherence), without any coaching intervention.The minimum frequency was defined as one telephone contact every six weeks with a maximum intervention duration of one year, which was extended to a maximum of two years in specific patients who needed further support. Specific intervention manuals for the coaches regarding different situations (e.g. for vaccination programs), available topics and accessible information materials provided support for the coaches. The coaches were further assisted by a health platform (netdoktor.de) providing evidence-based and up-to-date health information. NetDoktor is a health portal written and edited by health professionals, certified by HONcode  of medication, frequency and duration of inability to work, as well as mortality. Calculation of duration of inability to work is based on the individual summarized duration of inability to work per study period (two years). Information on the frequency of inability to work is calculated from summing up the number of single episodes of inability to work per participant in the study period (two years).All outcomes were analysed based on pseudonymised routine (claims) data collected and provided by the KKH, which were available for the complete randomized sample. The data contained information on all contacts with the health care system , medication, and inability to work. The KKH assembled and pseudonymized the routine data. Disease-specific outcomes like disease-related hospital admission were disregarded due to comparability between the campaigns and due to the high trial complexity. Patient-reported outcomes like quality of life, depression and anxiety will be published separately as the sample differs due to different response rates.To provide the necessary comparability between intervention and control group we used a stratified random allocation design that was based on sociodemographic values with a 4:1 allocation ratio. The stratification variables differed in the campaigns: For the “heart failure campaign” the allocation parameters were amount of hospital days  and sex, for the “chronic campaign” allocation parameters were “hospital cases”  and age  as previous data analyses showed that those were the most influential parameters on hospital costs.Yet, due to ethical reasons, randomization had to be conducted before obtaining informed consent; thus the randomised intervention group consisted of coaching participants and decliners. The health insurance had to avoid the fact that they would not have been able to offer health coaching to all informed insures if informed consent would have been asked before. Subsequent to randomisation, members of the intervention group received a postal invitation to participate in the TBHC and an additional acquisition call. Insurees were included as participants, when they had sent back the informed consent and the confirmation of participation. If they did not send back the required confirmation, they were grouped as decliners. Members of the control group did not receive an invitation, but only the informed consent form for participating in the study.For each of the three campaigns participants were compared to insurees in the control group (CG). Potential selection bias was minimized by propensity score matching (PSM), which balanced baseline characteristics of patients in the IG and CG. Based on routine data from a 12-month pre-period, a linear propensity score was calculated using the following matching variables: age, participation in disease management program, employment status, marital status, federal state, early retirement, eligibility for statutory sick pay, costs of rehabilitation, hospital costs, outpatient physician and non-physician costs, medication costs, defined daily dose (DDD), costs of non-physician outpatient services and medical supplies, as well as the Elixhauser Index based on ICD codes  for daysThe sample was analysed using three approaches. Intention-to-Treat-I (ITT-I) followed the initial randomisation and resulted in coaching participants and decliners in the intervention group. In Intention to-treat-II analysis (ITT-II) the decliners were dropped from the intervention group. Finally, a per-protocol approach was conducted. Because of likely biased results in ITT-I due to included IG-decliners and in the per-protocol analysis because of including only those patients who completed the treatment, we focus on the presentation of results from the ITT-II approach. This approach can be regarded as most “realistic”. The other approaches served as sensitivity analysis and are not presented in detail.For the analysis of the primary outcome  as well as mortality (time to death), we calculated Kaplan-Meier curves and estimated hazard ratios from proportional hazard models. Probability of hospital readmission and probability of death were analysed by calculating odds ratio (OR). Quantity of health service use and inability to work was analysed by linear fixed effects regression models. As opposed to conventional PSM, the existence of a pre-period and a follow-up allowed us to control for latent heterogeneity in covariates by differencing out time-invariant additive selection bias through the application of the difference-in-difference method. The difference-in-difference (DD) is defined as follows:t = 0) and a follow-up (t = 1) the respective outcomes for the treatment group and the controls in time t hereby are denoted by Given two-time-points with a pre-period , 364 (47.2%) and 135 (35.9%), respectively, consented to participate in the intervention. PSM resulted in patient samples of 5,309  in the chronic campaign, 660  in the heart failure campaign, and 239  in the mental health campaign to be used for the primary analysis .Within the three campaigns, participants (IG) and controls (CG) were very similar with respect to age, sex, and comorbidity measured by the Elixhauser Index at baseline . HoweverThe intervention was carried out as planned. The mean amount of calls was 12.9 (SD = 7.3) for all participants, with the lowest quartile (Q1) receiving up to 7 calls, a median of 13 calls and an upper quartile receiving up to 18 calls. This implies an interquartile range of 11. Participants in the chronic campaign received an average of 12.8 calls (SD = 6.5), in the heart failure campaign 14.0 calls (SD = 8.4) and in the mental health campaign 13.7 calls (SD = 14.4). The calls lasted for an average of 20.6 minutes (SD = 8.4) for all participants, 21.2 minutes (SD = 8.4) for the chronic campaign, 17.5 minutes (SD = 7.3) for the heart failure campaign and 17.5 minutes (SD = 7.1) for the mental health campaign. About 7% of the participants received nutrition counselling, .The main goals the coaches aimed at were the understanding of illness (in 58.7% of the participants), colon cancer screening (46.8%), vaccination against pneumococcae (44.7%), self-monitoring of blood pressure (32.6%), preparation and discussion of physician visit (21.2%), and weight reduction (17.6%). All goal categories are available as supporting information: see In none of the campaigns, IG and CG differed significantly regarding the time to readmission to hospital during the two-year follow-up period . The hazIn all groups, more than 50% of the patients were readmitted to hospital during follow-up. In the chronic campaign, the odds of hospital readmission during follow-up was higher in the IG (1.65) than in the CG (1.46), resulting in an odds ratio of 1.13 (p = 0.045). No significant differences were found for the other two campaigns. Linear random effects difference-in-difference regression analysis of hospital use, medication and inability to work showed a significantly reduced number of hospital admission in the IG of the heart failure campaign ; yet, the corresponding reduction in the number of hospital days  did not reach the level of significance .Furthermore, the number of DDDs increased significantly by 155.03 (p = 0.001) in the IG of the chronic campaign. All other regression results were not statistically significant which implies that there were no differences with respect to the frequency and duration of inability to work. The descriptives of health care utilization can be found in In the chronic campaign, 75 (2.8%) patients of the IG died during follow-up compared to 109 (4.2%) patients of the CG, resulting in an OR = 0.64 (p = 0.005) and a hazard ratio of HR = 0.64 (p = 0.005). In the heart failure campaign, 34 (10.1%) patients of the IG died compared to 62 (19.3%) patients of the CG, resulting in an OR = 0.44 (p = 0.001) and a hazard ratio HR = 0.47 (p = 0.001). In the mental health campaign only 1 patient of the CG died . Thus, tResults of the ITT-I-approach differ considerably from the ITT-II-analysis . This caIn contrast, the per-protocol analysis differed only slightly .However, due to the small sample size, even very small changes in effects can result in changed significances. For instance, within the heart failure campaign, hospital admissions are significant in ITT-II, but not in the per-protocol analysis (vice versa in the chronic campaign).Telephone health coaching is expected to improve chronic disease management, which in turn is expected to avoid corresponding hospital admission. We compared insurees of a German statutory health insurance selected by predictive risk modelling with various chronic conditions who obtained one year of TBHC within three different campaigns  to a randomized and matched control group using routine data. The coaching did not result in extending the time period until the patient`s next hospital readmission compared with usual care during 24 months of follow-up in general as expected in our primary study hypothesis. Probability of hospital readmission was instead found to be significantly higher for participants in chronic campaign. However, for participants in the heart failure campaign, but not for participants of the chronic or mental health campaign, the number of hospital admissions was significantly reduced at 24 months follow-up, but no differences could be observed with regard to number of hospital days. We could not confirm the hypothesis that telephone health coaching reduces hospital admissions. However, participants of the TBHC intervention were significantly less likely to die within the 2-year follow-up period than participants of the CG, both in the chronic and particularly the heart failure campaign, which can be regarded as a very important patient-relevant effect of the TBHC.A strength of the study is its large sample size, as we were able to include over 2,700 insured patients in the IG. This trial is surely one of the largest randomized controlled trials of TBHC to date. Furthermore, we could use routine data from the statutory health insurance company for all study participants, thus avoiding problems of non-response and potential sample or systematic biases . The datThere are some limitations to the work presented: diagnoses for chronic conditions like depression, as data are documented primarily for accounting purposes, could be biased by financial incentives. Additionally, general practitioners are not well trained in making psychiatric diagnoses. Consequently, there might be a bias concerning the validity of these diagnoses. Another limitation is the lack of insurees’ clinical data, which makes it difficult to assess disease severity and other characteristics and risk factors that might have influenced the disease course, thus potentially influencing results and interpretations.A major cause for potential bias lies in the fact, that we could enrol patients only after randomisation due to ethical reasons of the health insurance. A selection bias could have resulted due to the high percentage of 57% of decliners to participation. The participants of the TBHC group could have been less impaired or may have a higher health consciousness than the control group , which in turn could have resulted in lower mortality rates. We tried to reduce this risk of bias by establishing a control group via propensity score matching, balancing baseline characteristics of patients in the IG and CG, and by differencing out time-invariant additive selection bias through the application of the difference-in-difference method. As a result of the matching process, observable differences between intervention and control group were eliminated. However, not all potentially relevant variables were available within our routine data set, so the matching procedure may have missed out other relevant variables. For example, information on socioeconomic status was not available from routine data, but has a potential influence on health status and service use. Therefore, we cannot completely exclude a healthy user bias, but we are confident that we ruled out the most significant impact. Moreover, the chronic campaign was composed of a very heterogeneous group of patients with different diagnoses with various health-related problems. Therefore, the coaching intervention might have different effects for different subgroups of patients within this campaign, which should be a focus of subsequent analysis. Another possible source of bias could result from the fact that the population consists of insured individuals with a higher socioeconomic status than the general population. However, for all citizens, the health care benefits of the compulsory insurance are fundamentally equal and defined by law, and almost every citizen in Germany is insured for health care. The German health care system is based on self-government and solidarity and is contribution-financed. The majority of the population (approx. 89%) are mandatory members of the public health insurance system. The remaining 11% have private health insurance .With the exception to the number of hospital admission in the heart failure campaign, our results did not confirm the hypothesis of TBHC reducing hospital use. This result is consistent with two systematic reviews. In the review by Hutchinson and colleagues , the autTo our knowledge, up to date only two studies came to different conclusions. A large randomized controlled trial showed decreases in hospital admissions , and a cFocusing only on patients with chronic heart failure, Inglis and colleagues provided a systematic review and meta-analysis including 41 studies on structured telephone support or non-invasive home tele-monitoring . Their rThe observed reduction of mortality in the chronic campaign was similar to that achieved in one previous trial , but conAlthough we tried to avoid the possible bias due to enrolment after randomization by propensity score matching, differences between intervention and control group are still possible. Therefore, future trials should incorporate a randomization strategy after obtaining informed consent—thereby minimizing potential sources of bias—with subsequent intention-to-treat analysis. If such a design should be difficult to realizes, a further possibility might be to use an appropriate modification of a post-randomized consent (Zelen´s) design . FurtherBased on the results of our study and previous research, it seems that TBHC has only limited effects on hospital use, medication, and ability to work. Most important however, our results show that TBHC may reduce mortality as a strong patient-relevant outcome. Possible explanations include a better disease management and a higher awareness when to seek additional medical support by the participants, thus avoiding acute exacerbations of chronic conditions. The significant and patient-relevant reduction in mortality may be a strong argument to further invest in the development, implementation, and evaluation of promising TBHC interventions.S1 FileTelephone-based health coaching for chronically ill patients: study protocol for a randomized controlled trial.(PDF)Click here for additional data file.S2 FileCONSORT 2010 checklist of information to include when reporting a randomised trial.(DOC)Click here for additional data file.S3 FileTemplate forIntervention Description and Replication checklist.(DOCX)Click here for additional data file.S1 TableRegression model to identify patients with a risk of rehospitalisation higher than 50%.(DOCX)Click here for additional data file.S2 TableDescriptives of coaching goals.(DOCX)Click here for additional data file.S3 TableFrequencies of diseases* as defined by the Elixhauser Index, at Baseline (Post-PSM), by campaign.(DOCX)Click here for additional data file.


Two mechanisms of the model, rumination and executive control, were examined in isolation and in interaction in order to investigate OGM over time. Across two time points, six months apart, a total of 149 adolescents (13–16 years) completed the minimal-instruction autobiographical memory test, a measure of executive control with both emotional and nonemotional stimuli, and measures of brooding rumination and reflective pondering. The results showed that executive control for emotional information was negatively associated with OGM, but only when reflective pondering levels were high. Therefore, in the context of higher levels of reflective pondering, greater switch costs  when processing emotional information predicted a decrease in OGM over time.The CaR-FA-X model (Williams et al.,  There are two forms of OGM: categorical memories, defined as memories for categories of events , and extended memories, defined as general events that last over an extended time frame .Autobiographical memory (AM) is a type of episodic memory storage system for past personal experiences and semantic information about the self , the generative search is disrupted early and thus truncated, leading in turn to OGM. The different mechanisms can work in isolation or in interaction . Executive control refers to a collection of cognitive processes responsible for the control, coordination, and flexibility of cognitive processes toward goal-directed behavior  does predict OGM at a one-year follow-up , whereas Hitchcock et al.’s (M = 11.90 years). Rumination is relatively unstable in childhood , recruited from four schools in Scotland, U.K. At the first data collection point, the pupils were in Secondary Year 2 (S2), Secondary Year 3 (S3), Secondary Year 4 (S4), or Secondary Year 5 (S5). At the second data collection point, all pupils had moved up a year . Ethical approval was obtained for the study, and each parent or guardian provided written consent. Written assent was provided by each adolescent for both waves (W1 and W2) of the study. All adolescents with appropriate parental consent and written assent participated. No exclusion criterion was applied at recruitment, which was similar to other studies  = – 1.58, p = .12. Participants were assessed at two time points, 6 months apart. Thirteen participants (8.8% attrition) from W1 did not complete the second testing session. Scheduling difficulties, early graduation, and personal family issues were the main causes of attrition.The sample consisted of 149 secondary school adolescents  between 13 and 16 years old , an emotional and nonemotional computerized executive control task, a measure of reflective pondering and brooding rumination, and self-report questionnaires of depressive and anxiety symptoms. At both time points, the executive control task and the AMT were counterbalanced to control for order effects and fatigue. To reduce mood-priming effects, the rumination, anxiety, and depression measures were administered last and were also counterbalanced using a random number generator.loyal, joy, smile, achieve, loved, ambitious; W1 negative word set: mistake, rejected, weakness, needy, angry, tired; W2 positive word set: friendly, happy, respect, caring, sunny, perfect; W2 negative word set: failure, disliked, ugly, useless, worse, lonely). OGM was measured as a single, unidimensional trait for positive and negative words combined  and 90.2% of the responses at the second time point (κW2 = .86). The MI-AMT has shown good interrater reliability in previous studies with adolescent populations: κ = .87 in Heron et al.  and second (αW2 = .76) time points, as well as modest test–retest reliability .Responses were coded by the first author (25% were double-coded by a trained independent researcher) as specific , categoric , extended , a semantic associate , an omission (no memory provided), or part of a rest category  as per a narrative analysis of each memory.n et al. , κ = .78h et al. , and κ =and Raes . The AMTExternal processing refers to processing information from the external world, whereas internal processing refers to the processing of information held in working memory. Previous research has suggested that measuring executive control for externally represented information may not be the most beneficial way to either measure executive control or uncover any relationship between executive control and rumination  faces taken from the Karolinska Directed Emotional Faces  and the nonemotion condition . The task displayed modest test–retest reliability in both the emotion condition  and the nonemotion condition .Switch costs were calculated as the reaction time difference between switch and no-switch trials and were used as the main unit of analysis . Executive control was operationalized as the range of reaction time scores on the IST. Higher reaction times  reflected lower levels of executive control, and lower reaction times  reflected greater levels of executive control. There were no cutoff scores to define the high- and low-impairment groups; instead, the range of scores across the task was used , the RRS is a 21-item self-report questionnaire that measures ruminative responses. Higher scores are indicative of a greater ruminative tendency. The brooding rumination and reflective pondering subscales were extracted from the RRS, following the work of Treynor et al.  and reflective pondering . The task also displayed good test–retest reliability for both the brooding scale  and the reflective pondering scale . Similar psychometric properties have been reported with adolescent populations. Cox, Funasaki, Smith, and Mezulis . The internal consistency in the present study was excellent , as was test–retest reliability .The BDI-II is a 21-item self-report measure of depressive symptom severity (each item ranging from 0 to 3), developed to measure symptoms of depression in adolescent (13 years of age and over) and adult samples. Scores are summed to calculate a total BDI-II score, which can range from 0 to 63. As per previous research  self-report measure of anxiety. Rated on a 4-point Likert-type scale, higher scores are indicative of greater anxiety. Scores are summed from specific subscales and items to calculate a total MASC-II score, which can range from 0 to 150. Excellent Cronbach’s alpha values were found for the MASC-II scores (αW1 = .94 and αW2 = .94), as well as good test–retest reliability . The MASC-II has demonstrated good internal consistency  with other anxiety measures but nonsignificantly (r = .19) with measures of depression, and it has been shown to discriminate anxious children and adolescents from the general population as well as from other clinically diagnosed populations . Data were missing completely at random . Missing data were imputed using multiple imputation (MI) with SPSS 22. MI is effective for up to 80% missing data and provides unbiased estimates when the data are missing completely at random, as in the present data set. Imputed values matched the original values , and five data sets were imputed. MI allowed for analysis on 100% of the participant data. Pooled estimates were created through SPSS version 22. The estimates were averaged across all five imputed data sets when pooled estimates were not available in SPSS  = 4.16, p < .001, and explained 29% of the variance. Model 1 was significant at p < .001, Model 2 was significant at p < .001, and Model 3 was significant at p < .001. All variance inflation factors were <3, indicating no problems with multicollinearity.A hierarchical multiple regression analysis was conducted to assess whether brooding rumination, reflective pondering, or executive control for emotional or nonemotional information (measured by larger switch costs) would prospectively predict overgeneral memory. Average standardized betas (computed by summing the standardized coefficient estimates across results from the five imputed data sets and dividing by five) are reported in Table F = 8.82, p < .001. Baseline OGM was the only significant predictor of OGM at W2. Brooding rumination, reflective pondering, and switch costs for emotion and nonemotional information were added at Step 2. This step was nonsignificant, so once again only baseline OGM was a significant predictor, Fchange = 0.45, p = .775. Thus, we found no evidence that brooding rumination, reflective pondering, or switch costs for the emotion and nonemotion conditions individually predicted OGM. At Step 3, the interaction variables were added. The interaction terms explained an additional 4% of the variance in OGM at W2. Although the R2change at this step for the collective variance of these coefficients was not statistically significant, Fchange = 1.92, p = .111, ∆R2 = .04, reflective pondering did significantly interact with switch costs in the emotion condition to predict OGM at W2 .The first step of the regression accounted for a significant proportion of the variance in OGM. Almost one quarter 24%) of the variation in OGM could be accounted for by the variables entered at the first step in the regression, 4% of theβ = – .28, p = .01) or the proportion of overgeneral memories minus omissions . Similarly, in the opposite direction, beta values were similar for the number of specific memories , the proportion of specific memories , and the proportion of specific memories minus omissions .To check that these results did not differ as a function of the scoring algorithm used for OGM, the analyses were rerun using the proportion of OGM as the outcome variable, with and without the inclusion of omissions, and using the number and proportion of specific memories, with and without omissions. The beta values were similar when the unit of analysis was either the proportion of overgeneral memories , p = .04. At the mean value of reflective pondering, there was a nonsignificant negative relation between executive control and OGM, β = .06 , p = .44. When reflective pondering was low, we found a nonsignificant positive relation between executive control and OGM, β = .09 , p = .38.Follow-up simple slope analyses were conducted to test whether the relation between executive control for emotional information and OGM differed at low, mean, and high levels of reflective pondering. The simple slope analyses decomposing the baseline executive control for the Emotional Information × Baseline Reflective Pondering interaction showed that when reflective pondering is high, there is a significant negative relation between executive control and OGM, The primary aims of this study were to prospectively examine the capture and rumination and executive control mechanisms of the CaR-FA-X model and to investigate whether they independently and in interaction predicted OGM in adolescence. We found that executive control for emotional information was negatively associated with OGM, but only when reflective pondering levels were high. Thus, in the context of higher levels of reflective pondering, as switch costs increased  when processing emotional information, there was a decrease in OGM . Moreover, this relation held after controlling for baseline OGM scores and symptoms of depression and anxiety. This suggests that reflective pondering is a moderator in the executive control and OGM relationship, particularly when processing emotional material. Interestingly, brooding rumination, reflective pondering, and executive control for emotional or nonemotional information did not independently predict OGM.Although executive control and rumination did not independently predict OGM in the present study with adolescents, rumination interacted with executive control to predict OGM over time, but not in the way that the model suggests. We did not find rumination and executive control to interact to predict greater OGM, as is proposed in the CaR-FA-X model. However, we did find that greater switch costs when processing emotional information can lead to improved specificity over time, but only in the context of high levels of reflective pondering. These results build upon the CaR-FA-X model to show that nonclinical adolescents who have difficulty in processing emotional information have greater memory specificity over time, but only when those adolescents are also high reflective ruminators.Although a link between rumination and executive control has been highlighted in the adult (De Lissnyder, Koster, Derakshan, & De Raedt, Contrary to previous research in adult samples (De Lissnyder, Koster, Goubert, et al., Employing a sample of community adolescents, our findings build on previous work with “at risk” adolescent populations. Rawal and Rice  reportedInterestingly, the present findings and those of Rawal and Rice  and HitcThere has been considerable heterogeneity between studies with regard to the aspects of executive control measured, and future research will be needed, given the limited (and conflicting; Hitchcock et al., Our findings show that the relationship between reflective pondering and executive control in reducing OGM in adolescence was specific to processing emotional stimuli. The literature does tend to support the notion that rumination is closely associated with the processing of emotional information (De Lissnyder, Koster, Goubert, et al., Our study has a number of strengths. First, it used a prospective longitudinal design with participants who were at an important period of adolescence. We were able to investigate changes over a six-month period at a time at which executive processes and the prefrontal cortex are still developing. Second, our assessment of rumination allowed us to investigate the different effects of brooding rumination and reflective pondering on executive control and AM scores. Third, the objective measure of executive control provided the opportunity to measure executive control when processing emotional and nonemotional information. Finally, we controlled for symptoms of anxiety and depression as research has suggested even subclinical levels can impact task performance on executive tasks (Ansari, Derakshan, & Richards, In addition to the strengths of the present study, several observations and future recommendations must be noted. The novel characteristics of this study, although advantageous, require validation. Accordingly, replication of these findings and expanding on the complex relationship between the mechanisms of the CaR-FA-X model in adolescence would enhance our theoretical understanding of OGM. For this study, we employed the IST. We considered this task valuable for the present research questions, however we are aware that that this task does not allow for examination of control processes within specific aspects of executive functions (i.e., inhibition, switching and updating; Miyake et al., Previous research has noted that memory for autobiographical events includes both episodic and sematic details (Brown et al., Despite the noted considerations, our findings have several important theoretical and clinical implications. We add to the CaR-FA-X model by demonstrating the adaptive nature of reflective pondering on OGM, when executive control is low. We also show that this relation is specific to processing emotional information. Given that the main finding emerging from the present study was the adaptive nature of reflective pondering, particularly in the context of low executive control when processing emotional information, interventions aimed at increasing reflective pondering may serve to reduce OGM. This study provides a novel contribution to the field and future research is warranted to confirm the adaptive nature of reflective pondering on the executive control and OGM relationship, and subsequently symptoms of depression.


Empathy is an important concept in psychology and cognitive neuroscience. Despite the controversy around its definition, most researchers would agree that empathy is a multidimensional phenomenon which involves a vicarious experience of another person’s affective state and an understanding of another person’s affective experience. Self-report measures of empathy constitute an important tool for both research and clinical practice. The main goal of this study was to adapt and study the psychometric properties of the Questionnaire of Cognitive and Affective Empathy (QCAE), a worldwide used measure of empathy, in a Portuguese community sample (N = 562). Confirmatory factor analyses supported the factor structure of the original QCAE. Results show that the Portuguese version of the QCAE has sound psychometric properties, with good structural validity and internal consistency for both scales  and respective subscales of the instrument . We tested both a five correlated factor structure (Model 1) and a second-order model that postulates the affective and cognitive dimensions (Model 2). Our results show that while both models present acceptable goodness of fit indices, Model 1 performs slightly better. In conclusion, the Portuguese version of the QCAE may prove a useful tool for future cross-cultural assessments of empathy in both research and clinical practice. Empathy is an ubiquitous concept that has met with increasing interest from several basic and applied fields. It has steadily permeated the speeches of politicians , business leaders and other public figures . It is a term now firmly embedded in the lexicon of business, finance and marketing fields. Its positive social impact is heralded in books targeting the general public, and thousands of training programs have been outlined in order to instill empathic behavior in health practitioners and other social service professionals [Unsurprisingly, the concept of empathy also draws immense research interest. Research has shown that empathy is strongly associated with general wellbeing and social functioning , 3 and iJust as other social science constructs, the conceptualization of empathy has evolved alongside the historically predominant perspectives in psychology and social sciences . Even nThe emergence and advances of cognitive neuroscience have helped to shed light on the neurophysiological underpinnings of empathy in humans , pinpoinIn the study of empathy, reliable self-report instruments are essential due to their relative good cost-effectiveness. By resorting to a questionnaire, a single researcher may be able to assess larger samples in a fast and collective manner. Furthermore, with this method, repeated measurements  are more easily implemented. The four most frequently used questionnaires of empathy in research are Hogan’s Empathy Scale , MehrabRecently, in an attempt to overcome some of these shortcomings, Reniers and colleagues  created With the present study we aimed to analyze the psychometric properties of the QCAE in a large Portuguese community sample. This is important for a number of reasons: 1) to further probe the factor structure and reliability of the QCAE; 2) to further probe its validity in non-English-speaking cultures; and 3) to make a sound self-report instrument of empathy available for research with Portuguese samples, allowing for future cross-cultural assessments.M = 27.5, SD = 10.32); females had a mean age of 26.28 (SD = 9.67) whereas males had a mean age of 31.74 (SD = 12.02). Males were significantly older than females, as confirmed with a Welch’s t-test, t(216) = 4.11, p<0.001.Participants were invited to take part in this study via email through the Communication and Image departments of Portuguese universities across the country and through social media platforms such as Facebook and LinkedIn. After providing informed consent to participate, a total of 562 Portuguese adults  filled in a standard demographics’ questionnaire and an online version of the QCAE. Age varied between 18 and 60 years old  and about the research team, participants who agreed with these terms proceeded with the present study. First, they provided information about demographic variables, including sex, age, country of origin, and highest level of education achieved. Next, they were presented with the online version of the QCAE., comprised of 31 items answered on a 4-point Likert scale ranging from strongly disagree (1) to strongly agree (4). All of the QCAE’s items were originally drawn from a variety of well-known measurements, namely the Hogan Empathy Scale , Proximal Responsivity (4 items), and Peripheral Responsivity (4 items). Emotion contagion is characterized by the ability to automatically mirror other’s emotional states ; while proximal responsivity is defined as the emotional state that is elicited through the perception of a close one’s feelings and moods ; and lastly, peripheral responsivity is defined by the emotional response that emerges in response to social contexts that are more socially detached to the subject .The affective empathy dimension assesses the ability to be sensitive to and to vicariously experience another’s emotional state, whereas the cognitive empathy dimension assesses the ability to form an understanding of another’s internal emotional state. The affective empathy dimension is subdivided into Perspective Taking (10 items), and Online Simulation (9 items). Perspective Taking consists in the ability to infer things from other’s perspective , whilst the latter is the attempt to imagine oneself in another’s situation and infer their emotional state .The cognitive empathy dimension is subdivided into Scores of each subscale are obtained by summing up the corresponding individual item scores. Summing up the scores of emotion contagion, proximal responsivity, and peripheral responsivity provides a score for the affective empathy dimension; summing up the scores of perspective taking and online simulation subscales provides a score for the cognitive empathy dimension. Lastly, summing up the scores of cognitive empathy and affective empathy provides a total score for Empathy. Scores for the five subscales of the QCAE achieved acceptable to very good internal consistency indicators in the original version .For the current study, a Portuguese version of the QCAE was created. A translation and back-translation approach was followed . Two EngThe present study was intended as a psychometric analysis based on the internal structure and measurement invariance of the five-factor model of the instrument for both the first- and second-order structure originally proposed by Reniers and colleagues  Fig 2)..Fig 2). For completeness, and to obtain item loadings, we first conducted an item-level CFA analysis. Next, and similarly to the original version of the QCAE, we implemented a parceling approach to reduce the likelihood of bias in structural parameters , 47. WhiWe have, however, changed the parceling strategy used in order to reduce the likelihood of bias in structural parameters , 47. Ins2) goodness of fit test, Root Mean Squared Error of Approximation (RMSEA) and the Comparative Fit Index (CFI). Although the Chi-square test is usually reported in CFA, its use has been criticized due to its sensitivity to sample size effects, which may lead to too many type I errors when variables have non-normal distributions, with a high degree of kurtosis [Model fit was assessed by chi-square  was conducted to ascertain whether the instrument validly assesses the same constructs in both genders. Lastly, sex differences in empathy scores were inspected with Welch  t-tests , especiap < .001; [diagonally weighted least squares estimation method with robust standard errors  was selected in the CFA. Item-level CFA were performed on the five-factor structure models originally proposed by Reniers and colleagues [2(424) = 3466.083 p < .001, CFI = .910, TLI = .901, SRMR = .091 and RMSEA = .096; for Model 2, χ2(428) = 3413.284 p < .001, CFI = .908, TLI = .900, SRMR = .094 and RMSEA = .096). All item loading values were significant, with the exception of item 17, which revealed a value lower than 0.50, namely 0.023 (p = 0.419). A careful examination of item 17 highlighted its statistical and theoretical failure (cf. Discussion), and the item was therefore excluded from the Portuguese version of the QCAE. Following its removal, all 30 factor loadings were above .5 with p-values < .001  and between .608 and .926 (Model 2). In the male subsample, parcel loadings ranged between .528 and 1.054 (Model 1) and between .518 and 1.074 (Model 2). In the female subsample, parcel loadings ranged between .638 and .936 (Model 1) and between .633 and .937 (Model 2). As presented in Next, we followed a parceling approach to reduce the likelihood of bias in structural parameters . Items were parceled and the structure of the two models was assessed with a further set of five-factor CFA . Of notiRegarding internal consistency, Cronbach’s alphas at the subscale and total scale levels ranged from .62 to .87, while the cognitive and affective dimensions presented alphas of .87 and .80, respectively (Table E in 2 differences) and partial scalar invariance  was found after relaxing the intercept of parcels P41, P11, P52, and P51. Model 2 presented full metric  and partial scalar invariance  after relaxing the intercept of parcels P41, P51, P52, P31 and P11. These results suggest that both models were reliable across genders.The two models were well fit both for male and female samples , indicatt-test confirmed these differences: on the affective empathy scale, females had a mean of 33.46 (SE = 0.24) and males had a mean of 29.30 (SE = 0.40), t(560) = 8.83, p<0.001; on the cognitive empathy scale, females had a mean score of 59.11 (SE = 0.36) whereas males had a mean of 56.68 (SE = 0.67), t(560) = 3.38, p<0.05. These differences were observed across all subscales  = 2.49, p = .115) and its perspective taking subscale  = .334, p = .563).Similar to the original study, females scored significantly higher than males on all empathy measures. Independent-samples Welch’s ubscales . GLM uniubscales  confirmeIn the current study, the psychometric properties and validity of a Portuguese version of the QCAE, a recently developed self-report measure of empathy, were tested in a large community sample. Our goals were two-fold. We wanted to further probe the factor structure and reliability of the QCAE and probe its validity in non-English-speaking cultures. Most importantly, we wanted to make a sound self-report instrument of empathy available for research with Portuguese samples, allowing for future cross-cultural assessments. Here, we evaluated the internal structure of the five-factor models (a first-order structure and second-order structure) originally proposed by Reniers and colleagues  with a cCurrently most researchers would agree that empathy is a multidimensional phenomenon, which involves a vicarious experience of another person’s affective state (i.e. affective empathy) and an understanding of another person’s experience (i.e. cognitive empathy) e.g. –22. Yet,. Yet,22.All the items of the Portuguese QCAE presented good factor loadings, except for item 17 from the peripheral responsivity subscale (“It is hard for me to see why some things upset people so much”). This item revealed an extremely low loading value and had to be excluded from the Portuguese version. The three remaining items that compose this subscale  address emotional responses to social contexts that are detached to the subject, such as narrative works of art . Item 17, on the other hand, pertains to an even more detached and non-specific social context. Taken together, this evidence suggests a theoretical failure of item 17 in the Portuguese QCAE and this item was thus removed from the final version of the instrument. In fact, the peripheral responsivity subscale has been pointed out as one of the fragilities of the QCAE by authors who recently applied the measure to clinical samples , 41 and Another criticism that has been pointed out to the QCAE has to do with the label attributed to one of its cognitive empathy subscales called “online simulation”. This label may be misleading as an index of cognitive empathy because in social neuroscience simulation is traditionally used to refer to the automatic mirroring processes associated with affective empathy [e.g..The present study is not without its limitations. One of them is the unequal distribution of male and female participants, which could have biased our results. Our finding of measurement invariance across genders suggests that the same constructs are being measured across the two groups and, because partial scalar invariance was achieved, comparisons of the latent means across groups can be conducted . HoweverEmpathy for emotional facial expressions task [Another limitation is the absence of convergent validity tests of the QCAE with other measures of empathy. This was due to a lack of a validated Portuguese instrument assessing the same multidimensional conceptualization of empathy. A further concern, which is transversal to all self-report studies on empathy, is that self-report scores might not reflect actual abilities nor predict actual empathic responses in everyday situations. Future studies could include behavioral tasks of affective empathy, such as the ons task , 42, 60.ons task , 60. Impons task . Similarons task . This isons task .Finally, although the structure of two correlated higher order factors of cognitive and affective empathy (Model 2) was still considered acceptable, the five correlated factor structure (Model 1) presented a slight advantage based on the examination of the goodness of fit indices. These results, which provide a stronger support for the five correlated factor model, are in line with recent data from Myszkowski and colleagues . AdditioNevertheless, the goals of this study were fulfilled. The analyses of the psychometric properties of the Portuguese version of the QCAE provide further support of the original QCAE factor structure and reliability. Our results also indicate that this is a reliable, valid, and structurally sound measure of empathy which can be used in Portuguese samples. Self-report instruments measuring empathy in the general Portuguese population are scarce and a necessity given the increasing research and clinical practice interest in this construct. Plus, they are essential for efficient research. They are inexpensive, easy to assess and easy to use. Self-report instruments allow a single researcher to assess larger samples in a fast and collective manner. Hopefully, the availability of a sound self-report instrument will enrich research on empathy in Portugal, providing an important tool for the assessment of empathy as a multidimensional construct and allowing the possibility of future multicultural assessments. A sound measure of empathy is important not only for the study of individual differences and for the disambiguation of impairments in empathy in distinct psychopathologies , but also for the screening of general social cognition abilities or for gathering evidence-based information on the change of empathic abilities of subjects undergoing therapeutic interventions.S1 FileItems of the Portuguese QCAE; Table A (Parcels composition for Models 1 and 2); Table A (Parcels composition according to Reniers and colleagues  and Mysz(DOCX)Click here for additional data file.S1 Dataset(XLS)Click here for additional data file.


Mycobacterium tuberculosis, the bacillus that causes tuberculosis (TB). World TB Day is an opportunity to raise awareness about TB and the measures needed to tackle this devastating disease. The U.S. theme for World TB Day 2018, “Wanted: leaders for a TB-free United States. We can make history. End TB” highlights the importance of engaging and empowering public health partners, clinicians, and communities in efforts to eliminate TB.World TB Day is recognized each year on March 24, commemorating the date in 1882 when Dr. Robert Koch announced his discovery of MMWR found that in 2017, a provisional total of 9,093 TB cases were reported in the United States  (A study reported in this issue of https://www.cdc.gov/tb/worldtbday).CDC is working to eliminate TB in the United States by engaging new domestic and global partners, strengthening control of TB disease, and expanding testing and treatment of latent TB infection. Additional information about World TB Day and CDC’s TB elimination activities is available online (