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The photolytic or oxidative liberation of a cyclic (amino)(alkyl)carbene (CAAC)-stabilized arylborylene in the presence of organoazides yielded borylene-organoazide complexes (4a,b) has been achieved in a manner akin to the first step of the Staudinger reaction. Similarly, a CAAC-stabilized aminoborylene also afforded borylene-organoazide complexes (6a-c), which further undergo rearrangement to produce aminoborane triazene species (7a,b).

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Expression of exon-specific isoforms from alternatively spliced mRNA is a fundamental mechanism that substantially expands the proteome of a cell. However, conventional methods to assess alternative splicing are either consumptive and work-intensive or do not quantify isoform expression longitudinally at the protein level. Here, we therefore developed an exon-specific isoform expression reporter system (EXSISERS), which non-invasively reports the translation of exon-containing isoforms of endogenous genes by scarlessly excising reporter proteins from the nascent polypeptide chain through highly efficient, intein-mediated protein splicing. We applied EXSISERS to quantify the inclusion of the disease-associated exon 10 in microtubule-associated protein tau (MAPT) in patient-derived induced pluripotent stem cells and screened Cas13-based RNA-targeting effectors for isoform specificity. We also coupled cell survival to the inclusion of exon 18b of FOXP1, which is involved in maintaining pluripotency of embryonic stem cells, and confirmed that MBNL1 is a dominant factor for exon 18b exclusion. EXSISERS enables non-disruptive and multimodal monitoring of exon-specific isoform expression with high sensitivity and cellular resolution, and empowers high-throughput screening of exon-specific therapeutic interventions.

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The one-electron reduction of a cyclic (alkyl)(amino)carbene (CAAC)-stabilized arylborylene carbonyl complex yields a dimeric borylketyl radical anion, resulting from an intramolecular aryl migration to the CO carbon atom. Computational analyses support the existence of a [(CAAC)B(CO)Ar].- radical anion intermediate. Further reduction leads to a highly nucleophilic dianionic (boraneylidene)methanolate.

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The present study examined variables related to the quality of the therapeutic alliance in out-patients with schizophrenia. We expected recovery orientation and insight to be positively, and self-stigma to be negatively associated with a good therapeutic alliance. We expected these associations to be independent from age, clinical symptoms (i.e. positive and negative symptoms, depression), and more general aspects of relationship building like avoidant attachment style and the duration of treatment by the current therapist. The study included 156 participants with DSM-IV diagnoses of schizophrenia or schizoaffective disorder in the maintenance phase of treatment. Therapeutic alliance, recovery orientation, self-stigma, insight, adult attachment style, and depression were assessed by self-report. Symptoms were rated by interviewers. Hierarchical multiple regressions revealed that more recovery orientation, less self-stigma, and more insight independently were associated with a better quality of the therapeutic alliance. Clinical symptoms, adult attachment style, age, and the duration of treatment by current therapist were unrelated to the quality of the therapeutic alliance. Low recovery orientation and increased self-stigma might undermine the therapeutic alliance in schizophrenia beyond the detrimental effect of poor insight. Therefore in clinical settings, besides enhancing insight, recovery orientation, and self-stigma should be addressed.

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BACKGROUND: Because the mere definition of insight from the therapist's viewpoint may not be sufficient to identify treatment targets for adherence enhancement, we need assessment strategies which are more sensitive to the patient's perspective. Illness perception (IP), defined as the beliefs a patient holds about his/her health problems, has been shown to affect coping in the context of a physical or mental illness, e.g. compliance behaviour. To assess IP in people diagnosed with schizophrenia, the Illness Perception Questionnaire for Schizophrenia (IPQS) was developed. The aim of the present study was to analyse the psychometric properties of the German version of the IPQS. SAMPLING AND METHODS: The study sample consisted of 128 German-speaking outpatients suffering from chronic schizophrenia or schizoaffective disorder. To achieve comparability with the validation of the English scale version, the same constructs were assessed: psychopathology, depression, and beliefs about medication. Furthermore, insight into one's illness was assessed. Internal consistency, test-retest reliability and construct validity including convergent and discriminant validity were analysed. RESULTS: Five of eight IPQS subscales were found to be internally reliable and all subscales demonstrated high stability over time. Correlations with validity measures indicated that the subscales assess dimensions of a construct, which is distinct from psychopathology, depression, beliefs about medication and insight, except for the Identity subscale which substantially overlapped with measures of insight. CONCLUSIONS: The German version of the IPQS is an essentially reliable and valid measure of IP for German-speaking people with a schizophrenia spectrum disorder. This may encourage its usage in further studies investigating the impact of subjective beliefs about mental health problems on outcome and recovery in schizophrenia.

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OBJECTIVE: Low levels of insight are a risk factor for treatment nonadherence in schizophrenia, which can contribute to poor clinical outcome. On the other hand, high levels of insight have been associated with negative outcome, such as depression, hopelessness, and lowered quality of life. The present study investigates mechanisms underlying the association of insight and depressive symptoms and protective factors as potential therapeutic targets. METHODS: One hundred and forty-two outpatients with schizophrenia or schizoaffective disorder (35.2% women, mean age of 44.83 years) were studied using questionnaires and interviews to assess insight, depressive symptoms, recovery attitude, and illness appraisals with regard to course, functional impairments, and controllability. Psychotic and negative symptoms were assessed as control variables. The cross-sectional data were analyzed using structural equation models and multiple linear regression analyses with latent variables. RESULTS: Higher levels of insight and psychotic symptoms were associated with more depressive symptoms. The association of negative symptoms with depressive symptoms was not significant. The relationship between insight and depressive symptoms was mediated by the participants' perception of their illness as being chronic and disabling, as well as suppressed by their expectation of symptom control due to treatment. Finally, the association of insight and depressive symptoms was less pronounced in the patients with a positive recovery attitude than in those without this protective factor. CONCLUSIONS: To achieve recovery, which includes symptom reduction, functional improvement, and subjective well-being, it is necessary to prevent depressive symptoms as indicators of a demoralization process, which may arise as a consequence of growing insight. Possible treatment strategies focusing on changes of dysfunctional beliefs about the illness and the self and inducing a positive recovery attitude are discussed.

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Attitudes toward medication are important predictors of medication adherence in schizophrenia. However, monitoring their strength and influence in clinical settings is challenged by the absence of assessments separating them from adherence and subjective response and distinguishing between attitudes toward pharmacotherapy in general and antipsychotic medications. This study examined the applicability of the Beliefs about Medication Questionnaire (BMQ) in outpatients with schizophrenia (N = 131). Confirmatory factor analysis (CFA) could not support the original four-factor structure. A subsequent exploratory factor analysis revealed the factors Antipsychotics Necessity, Antipsychotics Concern, and Pharmacotherapy Distrust were supported by an acceptable fit of a completing CFA. These subscales have satisfactory internal reliability, test-retest reliability, and local fit indices. Modest correlations with insight and illness perception indicate construct validity. Criterion validity was supported by a significantly higher medication adherence of accepting patients compared with skeptical patients. The BMQ is a psychometrically sound and valid measure of attitudes toward medication in outpatients with schizophrenia.

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BACKGROUND: Assessing attachment style in people with schizophrenia may be important to identify a risk factor in building a strong therapeutic relationship and so indirectly to understand the development of mal-compliance as one of the major obstacles in the treatment of schizophrenia. AIMS: The present study analysed the psychometric properties of the German version of the Psychosis Attachment Measure (PAM), which assesses avoidant and anxious attachment style. METHODS: A sample of 127 patients suffering from chronic schizophrenia or schizoaffective disorder participated in this study. In testing discriminant validity, we assessed psychopathology, depression, therapeutic relationship and service engagement. Internal consistency, test-retest reliability and factor structure were analysed. RESULTS: The German version of PAM exhibited acceptable to good internal and test-retest reliabilities and the two-factor structure of the English version could be replicated. Avoidant attachment style was related to higher levels of positive symptoms and to a poorer therapeutic relationship. In the context of external validation, a regression analysis revealed that a poor therapeutic relationship correlated with avoidant attachment style, independent of anxious attachment style and depressive symptoms. Anxious attachment was associated with higher treatment adherence. Both insecure attachment styles (avoidant and anxious) were found to be correlated with higher levels of depression, but only attachment anxiety had an independent predictive value for self-reported depression in regression analysis. CONCLUSIONS: The German version of PAM displayed satisfactory psychometric properties and seems to be a reliable measure for assessing attachment style in individuals with schizophrenia. Validation of PAM led to the finding that only the avoidant attachment style might be a risk factor when building a strong therapeutic relationship in schizophrenia. In future studies, other factors influencing therapeutic relationship should be taken into account. Anxious attachment style may be a risk factor for depression, but it also has an enhancing effect on treatment adherence.

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BACKGROUND: Paradoxically, insight is associated with positive outcomes, such as better treatment adherence and recovery, and negative outcomes, such as depression, hopelessness, low self-esteem, and quality of life. Self-stigma as a moderating variable can be decisive whether more insight leads to better or worse outcome. On the other hand, self-stigma can act as a mediator between insight and outcomes. We therefore examined self-stigma both as a moderator and a mediator. METHODS: Insight, self-stigma, demoralization, symptoms, and functioning were assessed among 145 outpatients with schizophrenia spectrum disorders using questionnaires and structured interviews. Structural equation modeling was used to analyze the cross-sectional data. RESULTS: Results confirmed self-stigma as a moderator: The association of insight and demoralization was stronger as self-stigma increased. Self-stigma also partially mediated the positive relationship between insight and demoralization. Moreover, demoralization fully mediated the adverse associations of self-stigma with psychotic symptoms and global functioning. DISCUSSION: Given the decisive role of self-stigma regarding the detrimental consequences of insight, interventions should address self-stigma, particularly if psychoeducational or other interventions have increased insight. Therapeutic implications for changes of dysfunctional beliefs related to illness and self and change of self-concept in the context of recovery at the level of narrative identity are discussed.

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BACKGROUND: Despite the fact that medication adherence is among the most important health related behaviors in relapse prevention and recovery in schizophrenia, it is often not sufficiently endorsed by patients. Poor insight and negative attitudes towards medication are risk factors for non-adherence. Their relationship and the influence of more general attitudes towards pharmacotherapy besides attitudes towards antipsychotics have not been fully understood. The present study investigated whether these factors independently influence adherence or whether they mediate one another. METHODS: A cross-sectional sample of 150 outpatients completed the Beliefs about Medication Questionnaire. It assesses patients' beliefs about antipsychotic medication in terms of necessity and concerns and more general beliefs about pharmacotherapy in terms of distrust. Additionally, the patients' global awareness of illness (Scale to assess Unawareness of Mental Disorder), and medication adherence (Brief Adherence Rating Scale, Service Engagement Scale) were assessed. RESULTS: Using structural equation modeling, the study found evidence for a mediational model. Awareness of illness contributed to medication adherence via patients' perceived necessity of antipsychotics. The model further revealed a direct negative relationship between concerns regarding antipsychotics and adherence and an indirect negative effect of a general distrust regarding pharmacotherapy and adherence via antipsychotic specific attitudes. CONCLUSION: Interventions to enhance medication adherence may be more effective if they focus on treatment related attitudes rather than on global insight into illness. Clinicians may not only enhance the patients' perceived necessity of antipsychotic treatment but also explore and address concerns and the patients' distrust in pharmacotherapy in a more personalized way.

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Knowledge regarding socio-demographic and clinical risk factors of medication nonadherence does not always help in addressing adherence in individual patients. Classifying patients according to subjective adherence influencing factors may aid practitioners in choosing adequate strategies for improving medication adherence. A total of 171 outpatients with schizophrenia and schizoaffective disorder were classified according to factors influencing their medication adherence assessed using the Rating of Medication Influences Scale. Additionally, psychotic symptoms, depression, and insight, also known to influence pharmacological treatment motivation, were assessed. A cluster analysis yielded 3 groups that were distinguished both by the relative ranking of adherence influences and by specific associations with risk factors of nonadherence. For the "Interpersonal, Future-oriented Group" (n=59, 35% of the sample), interpersonal factors (positive therapeutic relationship, positive attitudes of significant others towards medication), immediate positive consequences of the medication intake (daily benefits, no perceived pressure to take medication), and avoiding future negative consequences of non-compliance, such as relapse and re-hospitalization, were essential for adherence. The "Autonomous, Future-oriented Group" (n=69, 40% of the sample) appraised interpersonal factors as being less important as compared to the other groups. This group exhibited significantly fewer depressive symptoms than the first group and had significantly more stable partnerships as compared to the other groups. The "Autonomous, Present-oriented Group" (n=43, 25% of the sample) was mainly motivated by immediate positive consequences and displayed higher levels of cognitive disorganization and negative symptoms than the second group, as well as the lowest level of insight of all groups. Treatment strategies addressing adherence enhancement in schizophrenia may profit by considering both the patient's subjective adherence attitude profile as well as the specific pattern of risk factors for nonadherence including depression, lack of insight, negative syndrome, cognitive disorganization and socio-demographic factors, which are differentially associated with each adherence attitude profile.

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OBJECTIVE: Poor social relations are supposed to contribute to adverse health behaviour. We examined this association and the role of low socio-economic position. METHODS: We regressed health behaviour on composite variables of the two exposures of social relations and socio-economic position (SEP). Social relations included networks and support; health behaviour was analysed in terms of smoking, poor nutrition and physical inactivity; socio-economic position comprised of income and education. Cross sectional data from a population based epidemiological study in German (4,814 men and women aged 45-75) was analysed. RESULTS: Among the indicators for social relations, social isolation was consistently associated with adverse health behaviour; social support showed modest effect. A combination of poor social relations and low SEP displayed stronger (additive) associations with adverse health behaviour than each factor alone. However, superadditivity was excluded. CONCLUSION: Given the important role of health adverse behaviour in chronic disease development, results underline the relevance of social environment and socio-economic structure in Public Health interventions.

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BACKGROUND: Social networks and social support are supposed to contribute to the development of unequal health within populations. However, little is known about their socio-economic distribution. In this study, we explore this distribution. METHODS: This study analyses the association of two indicators of socio-economic position, education and income, with different measures of social networks and support. Cross-sectional data have been derived from the baseline examination of an epidemiological cohort study of 4.814 middle aged urban inhabitants in Germany (Heinz Nixdorf Recall Study). Bivariate and multivariate logistic regression analysis were carried out to estimate the risk of having poor social networks and support across socio-economic groups. RESULTS: Socially disadvantaged persons more often report poor social networks and social support. In multivariate analyses, based on education, odds ratios range from 1.0 (highest education) to 4.9 (lowest education) in a graded way. Findings based on income show similar effects, ranging from 1.0 to 2.5. There is one exception: no association of SEP with close ties living nearby and regularly seen was observed. CONCLUSION: Poor social networks and low social support are more frequent among socio-economically disadvantaged people. To some extent, this finding varies according to the indicator chosen to measure these social constructs.

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OBJECTIVES: Exposure to cardiovascular (CV) risk factors may result in coronary atherosclerosis and myocardial disease, which is reflected in the extent of coronary artery calcification (CAC) and resting ECG abnormalities, respectively. We studied the association of CAC with ECG abnormalities in a general population without myocardial infarction or revascularization. METHODS: The total cohort of 4814 subjects (45-75 years) were randomly selected from the general population for the Heinz Nixdorf Recall Study, an ongoing study designed to assess the prognostic value of modern risk stratification methods. In addition to measuring standard risk factors, digitized resting ECGs and the EBT-based Agatston score were obtained. Subjects were separated into those without (n=1929) and with CV disease (CVD) or treated risk factors (tRF) (n=2558). RESULTS: In both groups, a positive CAC-score was more frequent and CAC-scores were higher in men and women with ECG abnormalities as compared to those with normal ECGs (p<0.05 each). In persons without CVD/tRF, a CAC > or =75th percentile was more frequent in those with LVH (42.4%) and QTc >440 ms (34.2%) as compared to normal ECGs (23.0%, p<0.01 for both). In persons with CVD/tRF, a CAC-score > or =75th percentile was found in subjects with A-Fib (46.3%), borderline-LVH (39.1%), ECG signs of MI (40.5%) and major ECG abnormalities (40.3%) versus 31.2% in those with normal ECGs (p<0.03 for all). In multivariate analysis, LVH (p=0.025) and major ECG abnormalities (p=0.04) remained independently associated with CAC in subjects without and with CVD/tRF, respectively. CONCLUSIONS: ECG-based evidence of myocardial disease is often associated with an elevated CAC burden, suggesting a link between epicardial and myocardial manifestations of risk factor exposure. The association of CAC burden with different ECG abnormalities in different clinical groups may have implications for the interpretation of the resting ECG and CAC burden in risk stratification.

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The Heinz Nixdorf Recall Study, which was inaugurated in 2000, is an ongoing population-based study to evaluate the prediction of cardiovascular events by integrating new imaging and nonimaging modalities in risk assessment. A focus is the additional prognostic value of coronary artery calcification (CAC). Currently used risk stratification algorithms often describe the individuals' risk based on few established risk factors only inaccurately. Using noninvasive quantification of CAC progression, the natural history of atherosclerosis with its repetitive, frequently subclinical plaque ruptures, may detect an unstable course of the disease long before the disease irreversibly manifests in sudden death or myocardial infarction. While the independent additional prognostic value of CAC quantification has been shown in asymptomatic patients at intermediate risk, only few studies provided evidence for an independent prognostic value of serial CAC measurements. In the Heinz Nixdorf Recall Study, the impact of established and new risk factors, e.g., the metabolic syndrome, psychosocial and environmental risk factors, or genetic variables, can be assessed. Further, the association of CAC progression with the incidence of other cardiovascular diseases such as heart failure or aortic or aortic valve calcification can be described. Since April 2006, the participants of the study return to the study center 5 years after baseline recruitment to assess health status and to determine the risk factor profile. Based on recently published data, serial CAC measurements have been granted allowing for (1) characterization of the natural history of CAC progression, and (2) identification of its determinants. The rationale of serial CAC quantification is discussed in this article.The Heinz Nixdorf Recall Study will contribute to the appraisal of new imaging modalities in risk stratification.

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AIMS: Long-term exposure to urban air pollution may accelerate atherogenesis and increase cardiopulmonary mortality. We aim to examine the relationship between the long-term residential exposure to traffic and prevalence of coronary heart disease (CHD). METHODS AND RESULTS: We used baseline data from the German Heinz Nixdorf RECALL study, a population-based, prospective cohort study. For 3399 participants from two cities, we assessed the long-term personal traffic exposure and background air pollution, comparing residents living within 150 m of major roads with those living further away. The principal outcome variable was clinically manifest CHD. We evaluated the association with multivariable logistic regression, controlling for background air pollution and individual level risk factors. Of 3399 participants, 242 (7.1%) had CHD. The crude odds ratio (OR) for prevalence of CHD at high traffic exposure was significantly elevated (1.62, 95%CI 1.12-2.34) and rose to 1.85 (95%CI 1.21-2.84) after adjusting for cardiovascular risk factors and background air pollution. Subgroup analysis showed stronger effects for men (OR 2.33, 95%CI 1.44-3.78), participants younger than 60 years (OR 2.67, 95%CI 1.24-5.74) and never-smokers (OR 2.72, 95%CI 1.40-5.29). CONCLUSION: This study provides epidemiological evidence that the long-term exposure to traffic-related emissions may be an important risk factor for CHD.

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Many surveys and cohort studies have used a random-zero sphygmomanometer blood pressure device (RZS) to measure subjects' blood pressure and to assess the value of blood pressure in predicting cardiovascular events. Recent studies used automated oscillometric blood pressure devices (AODs) that systematically measure higher blood pressure values than RZSs do, hampering comparability of values between these studies. In 2000-2003, the authors randomly used both an RZS and an AOD in an ongoing cohort study in Germany. This analysis aimed to compare blood pressure values by device and to develop an algorithm to convert estimates of blood pressure values from one device to the other. In a randomized subset of 2,365 subjects aged 45-75 years, each subject was measured three times with each device in a randomized order. The mean difference (AOD-RZS) between the devices was 3.9 mmHg for systolic blood pressure and 2.6 mmHg for diastolic blood pressure. The authors found that linear regression models including age, sex, and blood pressure level can be used to convert RZS blood pressure values to AOD blood pressure values, and vice versa. Results may help to better compare blood pressure values in epidemiologic studies that used different blood pressure devices.

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BACKGROUND: This report presents population-based estimates of the prevalence of peripheral arterial disease (PAD), chronic critical limb ischemia (CLI), and Moenckeberg's medial calcinosis (MC) in Germany. PATIENTS AND METHODS: From the year 2000 to 2003, a total of 4,814 subjects aged 45-75 years were included in the study. In 30 of the subjects (0.6%), determination of the ankle brachial index (ABI) was not possible, leaving 4,735 subjects (99.4%) in the data set. PAD was considered present in all subjects with an ABI < 0.9 in one leg, and/or a history of prior treatment for PAD. CLI was considered present if the highest ankle artery pressure measured < 70 mmHg. Prevalence of MC was calculated for ABI cut-off values of 1.3 and 1.5. FINDINGS: The overall prevalence of PAD according to the ABI criteria was 6.4% among men and 5.1% among women. After accounting for history of PAD, the prevalence increased to 8.2% among men and 5.5% among women. Taking the ABI criteria and medical history into account, males had a higher prevalence of PAD, with large increases in males aged 65-69 and 70-75 years. Chronic CLI was rare in the investigated population, and was found in only five older subjects (0.1%). With the criterion of ABI > 1.3, about 13.3% of males and 6.9% of females had MC. In contrast to PAD, the prevalence of MC did not increase with age. With the criterion of ABI > 1.5, MC was present in only 1.1% and 0.5% of men and women, respectively, but only 30 (0.6%) subjects had incompressible ankle arteries with a cuff pressure > 260 mmHg. CONCLUSION: Prevalences of PAD based only on ABI generally underestimate the true prevalence of PAD in population-based studies. CLI predominantly affects older subjects. In addition, cut-off values for MC must be newly determined.

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