Life events, anxious depression and personality: a prospective and genetic study.

Background: The association between life events and anxious depression might be due to causality or to gene-environment correlation. We examined unidirectional and reciprocal causality and a gene-environment correlation model, in which genes that influence the vulnerability for anxious depression also increase the risk of exposure to life events. The effect of genes that influence environmental exposure might be mediated through personality and we therefore also examined the association between life events and personality (neuroticism and extraversion). Method: Information on life events, anxious depression, neuroticism and extraversion was collected in 5782 monozygotic (MZ) and dizygotic (DZ) twins who participated in a longitudinal survey study of the Netherlands Twin Register. To examine causality, data were analysed longitudinally. To examine gene-environment correlation, the co-twin control method was used. Results: Anxious depression and, to a lesser extent, neuroticism scores increased after exposure to life events. Anxious depression and neuroticism also predicted the experience of life events. Prospectively, extraversion was not associated with life events. Anxious depression, neuroticism and extraversion scores did not differ between the non-exposed subjects of MZ and DZ twin pairs and unrelated subjects discordant for life events. Conclusions: Our findings suggest that reciprocal causation explains the relationship between life events and anxious depression and between life events and neuroticism. Extraversion is not related to life events. No evidence was found for gene-environment correlation, i.e. the genes that influence anxious depression, neuroticism or extraversion do not overlap with the genes that increase the risk of exposure to life events

An Easy-to-Use Prognostic Model for Survival Estimation for Patients with Symptomatic Long Bone Metastases

BACKGROUND: A survival estimation for patients with symptomatic long bone metastases (LBM) is crucial to prevent overtreatment and undertreatment. This study analyzed prognostic factors for overall survival and developed a simple, easy-to-use prognostic model. METHODS: A multicenter retrospective study of 1,520 patients treated for symptomatic LBM between 2000 and 2013 at the radiation therapy and/or orthopaedic departments was performed. Primary tumors were categorized into 3 clinical profiles (favorable, moderate, or unfavorable) according to an existing classification system. Associations between prognostic variables and overall survival were investigated using the Kaplan-Meier method and multivariate Cox regression models. The discriminatory ability of the developed model was assessed with the Harrell C-statistic. The observed and expected survival for each survival category were compared on the basis of an external cohort. RESULTS: Median overall survival was 7.4 months (95% confidence interval [CI], 6.7 to 8.1 months). On the basis of the independent prognostic factors, namely the clinical profile, Karnofsky Performance Score, and presence of visceral and/or brain metastases, 12 prognostic categories were created. The Harrell C-statistic was 0.70. A flowchart was developed to easily stratify patients. Using cutoff points for clinical decision-making, the 12 categories were narrowed down to 4 categories with clinical consequences. Median survival was 21.9 months (95% CI, 18.7 to 25.1 months), 10.5 months (95% CI, 7.9 to 13.1 months), 4.6 months (95% CI, 3.9 to 5.3 months), and 2.2 months (95% CI, 1.8 to 2.6 months) for the 4 categories. CONCLUSIONS: This study presents a model to easily stratify patients with symptomatic LBM according to their expected survival. The simplicity and clarity of the model facilitate and encourage its use in the routine care of patients with LBM, to provide the most appropriate treatment for each individual patient. LEVEL OF EVIDENCE: Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence

Cardiac myosin-binding protein C mutations and hypertrophic cardiomyopathy haploinsufficiency, deranged phosphorylation, and cardiomyocyte dysfunction

Background-Mutations in the MYBPC3 gene, encoding cardiac myosin-binding protein C (cMyBP-C), are a frequent cause of familial hypertrophic cardiomyopathy. In the present study, we investigated whether protein composition and function of the sarcomere are altered in a homogeneous familial hypertrophic cardiomyopathy patient group with frameshift mutations in MYBPC3 (MYBPC3(mut)). Methods and Results-Comparisons were made between cardiac samples from MYBPC3 mutant carriers (c. 2373dupG, n=7; c. 2864_2865delCT, n=4) and nonfailing donors (n=13). Western blots with the use of antibodies directed against cMyBP-C did not reveal truncated cMyBP-C in MYBPC3(mut). Protein expression of cMyBP-C was significantly reduced in MYBPC3(mut) by 33 +/- 5%. Cardiac MyBP-C phosphorylation in MYBPC3(mut) samples was similar to the values in donor samples, whereas the phosphorylation status of cardiac troponin I was reduced by 84 +/- 5%, indicating divergent phosphorylation of the 2 main contractile target proteins of the beta-adrenergic pathway. Force measurements in mechanically isolated Triton-permeabilized cardiomyocytes demonstrated a decrease in maximal force per cross-sectional area of the myocytes in MYBPC3(mut) (20.2 +/- 2.7 kN/m(2)) compared with donor (34.5 +/- 1.1 kN/m(2)). Moreover, Ca2+ sensitivity was higher in MYBPC3(mut) (pCa(50)=5.62 +/- 0.04) than in donor (pCa(50)=5.54 +/- 0.02), consistent with reduced cardiac troponin I phosphorylation. Treatment with exogenous protein kinase A, to mimic beta-adrenergic stimulation, did not correct reduced maximal force but abolished the initial difference in Ca2+ sensitivity between MYBPC3(mut) (pCa(50)=5.46 +/- 0.03) and donor (pCa(50)=5.48 +/- 0.02). Conclusions-Frameshift MYBPC3 mutations cause haploinsufficiency, deranged phosphorylation of contractile proteins, and reduced maximal force-generating capacity of cardiomyocytes. The enhanced Ca2+ sensitivity in MYBPC3(mut) is due to hypophosphorylation of troponin I secondary to mutation-induced dysfunction. (Circulation. 2009; 119: 1473-1483.

Gender shift in realisation of preferred type of gp practice: longitudinal survey over the last 25 years

<p>Abstract</p> <p>Background</p> <p>An increasing number of newly trained Dutch GPs prefer to work in a group practice and as a non-principal rather than in a single-handed practice. In view of the greater number of female doctors, changing practice preferences, and discussions on future workforce problems, the question is whether male and female GPs were able to realise their initial preferences in the past and will be able to do so in the future.</p> <p>Methods</p> <p>We have conducted longitudinal cohort study of all GPs in the Netherlands seeking a practice between 1980 and 2004. The Netherlands Institute of Health Services Research (NIVEL) in Utrecht collected the data used in this study by means of a postal questionnaire. The overall mean response rate was 94%.</p> <p>Results</p> <p>Over the past 20 years, an increasing proportion of GPs, both male and female, were able to achieve their preference for working in a group practice and/or in a non-principal position. Relatively more women than men have settled in group practices, and more men than women in single-handed practices; however, the practice preference of men and women is beginning to converge. Dropout was highest among the GPs without any specific practice preference.</p> <p>Conclusion</p> <p>The overwhelming preference of male and female GPs for working in group practices is apparently being met by the number of positions (principal or non-principal) available in group practices. The preference of male and female GPs regarding the type of practice and job conditions is expected to converge further in the near future.</p

Selective attrition and bias in a longitudinal health survey among survivors of a disaster

BACKGROUND: Little is known about the response mechanisms among survivors of disasters. We studied the selective attrition and possible bias in a longitudinal study among survivors of a fireworks disaster. METHODS: Survivors completed a questionnaire three weeks (wave 1), 18 months (wave 2) and four years post-disaster (wave 3). Demographic characteristics, disaster-related factors and health problems at wave 1 were compared between respondents and non-respondents at the follow-up surveys. Possible bias as a result of selective response was examined by comparing prevalence estimates resulting from multiple imputation and from complete case analysis. Analysis were stratified according to ethnic background (native Dutch and immigrant survivors). RESULTS: Among both native Dutch and immigrant survivors, female survivors and survivors in the age categories 25–44 and 45–64 years old were more likely to respond to the follow-up surveys. In general, disasters exposure did not differ between respondents and non-respondents at follow-up. Response at follow-up differed between native Dutch and non-western immigrant survivors. For example, native Dutch who responded only to wave 1 reported more depressive feelings at wave 1 (59.7%; 95% CI 51.2–68.2) than Dutch survivors who responded to all three waves (45.4%; 95% CI 41.6–49.2, p < 0.05). Immigrants who responded only to wave 1 had fewer health problems three weeks post-disaster such as depressive feelings (M = 69.3%; 95% CI 60.9–77.6) and intrusions and avoidance reactions (82.7%; 95% CI 75.8–89.5) than immigrants who responded to all three waves (respectively 89.9%; 95% CI 83.4–96.9 and 96.3%; 95% CI 92.3–100, p < .01). Among Dutch survivors, the imputed prevalence estimates of wave 3 health problems tended to be higher than the complete case estimates. The imputed prevalence estimates of wave 3 health problems among immigrants were either unaffected or somewhat lower than the complete case estimates. CONCLUSION: Our results indicate that despite selective response, the complete case prevalence estimates were only somewhat biased. Future studies, both among survivors of disasters and among the general population, should not only examine selective response, but should also investigate whether selective response has biased the complete case prevalence estimates of health problems by using statistical techniques such as multiple imputation

Effectiveness of life skills training on increasing self-esteem of high school students

AbstractObjective This study designed to investigate effectiveness of training life skills on adolescents’ students. Method This study is a pseudo-experimental study which accomplished on 160 students in Karaj city. Subjects of the study selected randomly from list of students in all of the schools of Karaj; then they divided randomly in two groups. Trained counsellors taught the life skills to students of the study group, and 80 reminder subjects assigned as control group. After educating the training program, subjects administered Cooper Smith self-esteem questionnaire (58-items version). Results Findings of the study indicated that life skills training lead to significant increase of self-esteem in study group in contrast to control group subjects. Conclusion Psycho education and mental health programs such as life skills training could cause to increase the necessary skills in students and decline school and educational problems

Patients with Rare Cancers in the Drug Rediscovery Protocol (DRUP) Benefit from Genomics-Guided Treatment

Purpose: Patients with rare cancers (incidence less than 6 cases per 100,000 persons per year) commonly have less treatment opportunities and are understudied at the level of genomic targets. We hypothesized that patients with rare cancer benefit from approved anticancer drugs outside their label similar to common cancers. Experimental Design: In the Drug Rediscovery Protocol (DRUP), patients with therapy-refractory metastatic cancers harboring an actionable molecular profile are matched to FDA/European Medicines Agency–approved targeted therapy or immunotherapy. Patients are enrolled in parallel cohorts based on the histologic tumor type, molecular profile and study drug. Primary endpoint is clinical benefit (complete response, partial response, stable disease ≥ 16 weeks). Results: Of 1,145 submitted cases, 500 patients, including 164 patients with rare cancers, started one of the 25 available drugs and were evaluable for treatment outcome. The overall clinical benefit rate was 33% in both the rare cancer and nonrare cancer subgroup. Inactivating alterations of CDKN2A and activating BRAF aberrations were overrepresented in patients with rare cancer compared with nonrare cancers, resulting in more matches to CDK4/6 inhibitors (14% vs. 4%; P ≤ 0.001) or BRAF inhibitors (9% vs. 1%; P ≤ 0.001). Patients with rare cancer treated with small-molecule inhibitors targeting BRAF experienced higher rates of clinical benefit (75%) than the nonrare cancer subgroup. Conclusions: Comprehensive molecular testing in patients with rare cancers may identify treatment opportunities and clinical benefit similar to patients with common cancers. Our findings highlight the importance of access to broad molecular diagnostics to ensure equal treatment opportunities for all patients with cancer